Lipopolysaccharide (LPS)-induced liver injury is the main factor in acute liver failure. The current study aims to investigate the protection of limonin, an antioxidant compound from citrus fruit, ...against LPS-induced liver toxicity and elucidate the potential mechanisms. We found that limonin elevated cell viability and reduced LDH release in LPS-treated HepG2 cells. Limonin also inhibited LPS-induced pyroptosis by inhibiting membrane rupture, reducing ROS generation, and decreasing gasdermin D activation. Moreover, limonin inhibited the formation of a NOD-like receptor protein 3 (NLRP3)/Apoptosis-associated speck-like protein containing a CARD (ASC) complex by reducing the related protein expression and the colocalization cytosolic of NLRP3 and caspase-1 and then suppressed IL-1β maturation. Ultimately, we established LPS-induced hepatotoxicity in vivo by using C57BL/6 mice administrated LPS (10 mg/kg) intraperitoneally and limonin (50 and 100 mg/kg) orally. We found that limonin dereased the serum ALT and AST activity and LDH release and increased the hepatic GSH amount in LPS-treated mice. Additionally, the liver histological evaluation revealed that limonin protects against LPS-induced liver damage. We further demonstrated that limonin ameliorated LPS-induced hepatotoxicity by inhibiting pyroptosis via the NLRP3/gasdermin D signaling pathway. In summary, this study uncovered the mechanism whereby limonin mitigated LPS-induced hepatotoxicity and documented that limonin might be a promising candidate drug for LPS-induced hepatotoxicity.
A segmentation map, either static or dynamic, refers to a two-dimensional picture that may vary with time and indicates the segmentation label per pixel. Both the semantic map and the occupancy map ...in video-based point cloud compression (V-PCC) belong to the segmentation map we referred to. The semantic map can work for many machine vision tasks like tracking and has been used as a layer of image representation in some image compression methods. The occupancy map constitutes a part of the point cloud coding bitstream. Since segmentation maps are widely used, how to efficiently compress them is of interest. We propose a segmentation map lossless compression scheme namely CC-SMC, exploiting the nature of segmentation maps that usually contain limited colors and sharp edges. Specifically, we design a chain coding-based scheme combined with quadtree-based block partitioning. For intraframe coding, one block is partitioned recursively with a quadtree structure, until the block contains only one color, is smaller than a threshold, or satisfies the defined chain coding condition. We revise the three-orthogonal chain coding method to incorporate contextual information and design effective intraframe prediction methods. For interframe coding, one block may find a reference block; the chain difference between the current and the reference blocks is coded. We implement the proposed scheme and test it on several different kinds of segmentation maps. Compared with advanced lossless image compression techniques, our proposed scheme obtains more than 10% bits reduction as well as more than 20% decoding time-saving. The code is available at https://github.com/Yang-Runyu/CC-SMC.
•A chain coding-based scheme for segmentation map compression, named CC-SMC.•Interframe chain coding to exploit the correlation of chain codes between blocks.•CC-SMC saves >10% bitrate and >20% decoding time compared to previous methods.
This work proposed a three-phase modelling framework using the convolutional neural network (CNN) method to predict the performance a ball mill based on the externally measurable variables in the ...milling process. The data of the model were generated from the discrete element method under different conditions, including acoustic emission (AE) signals, power draw and grinding rate. In the pre-training and training phases, the CNN model was able to predict particle size distributions and grinding rates with R2 higher than 0.92. The model was then applied to the large mill system and the results showed that the model maintained its performance in the new system with limited training datasets. The transfer learning of the model was tested by comparing the model with an untrained model and the results showed the loss error (MSE) of transfer model converged to a lower level within 20 epochs while the untrained model could only converge to a larger error after 400 epochs, indicating with the pre-trained model required far less training time and data for better prediction. The potentials and limitations of the model were also discussed.
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•A CNN model was developed to predict the ball mill process.•Training and testing datasets were generated from DEM simulations.•A three-phase modelling framework was proposed to train and test the CNN model.•Particle size and grinding rate were predicted reasonably well by the model.•The transfer learning of the model was demonstrated by comparing with an untrained model.
We conducted a numerical study of the mixed charging process and gas-solid flow in the COREX melter gasifier by combining discrete element method (DEM) with computational fluid dynamics (CFD). A ...full-scale COREX melter gasifier model was established to investigate the charging and blasting processes. The model was validated by comparing with the experimental results under similar conditions. The particles above the raceway region descended faster than those near the centre and the wall. With increasing gas velocity, a larger high-velocity airflow region was formed at the tuyere inlet with increased raceway area. In addition, mixed charging pattern had a significant effect on radial ore-to-coal ratio. The ratio was larger in areas where the relative thickness of DRI was significantly larger than that of coal, and was large above the raceway. The upper packed bed structure had a negligible effect on raceway shape and size. Nevertheless, the gas velocity distribution in the packed bed was affected by the burden distribution, which had less fluctuation in the region where the burden was evenly distributed. The findings facilitate a better understanding of burden distribution and gas-solid flow in the COREX melter gasifier.
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•CFD-DEM simulations were conducted to study the combined charging and gas-solid flow processes in a COREX melter gasifier.•The effect of mixed charging pattern on burden distribution and gas flow was analysed.•The formation, shape and size of raceway with different gas velocities were discussed.
PurposeThe objective of this paper is to quantitatively assess shear band evolution by using two-dimensional discrete element method (DEM).Design/methodology/approachThe DEM model was first ...calibrated by retrospectively modelling existing triaxial tests. A series of DEM analyses was then conducted with the focus on the particle rotation during loading. An approach based on particle rotation was developed to precisely identify the shear band region from the surrounding. In this approach, a threshold rotation angle ω0 was defined to distinguish the potential particles inside and outside the shear band and an index g(ω0) was introduced to assess the discrepancy between the rotation response inside and outside shear band. The most distinct shear band region can be determined by the ω0 corresponding to the peak g(ω0). By using the proposed approach, the shear band development of two computational cases with different typical localised failure patterns were successfully examined by quantitatively measuring the inclination angle and thickness of shear band, as well as the microscopic quantities.FindingsThe results show that the shear band formation is stress-dependent, transiting from conjugated double shear bands to single shear band with confining stress increasing. The shear band evolution of two typical localised failure modes exhibits opposite trends with increasing strain level, both in inclination angle and thickness. Shear band featured a larger volumetric dilatancy and a lower coordination number than the surrounding. The shear band also significantly disturbs the induced anisotropy of soil.Originality/valueThis paper proposed an approach to quantitatively assess shear band evolution based on the result of two-dimensional DEM modelling.
A novel approach of measuring the surface roughness of spherical and flat micron-sized drug particles using scanning white-light interferometry was applied to investigate the surface morphology of ...micron-sized active pharmaceutical ingredients (APIs) and excipient particles used for inhalation aerosols. Bovine serum albumin (BSA) and α-lactose monohydrate particles were chosen as model API and excipient particles, respectively. Both BSA and lactose particles were prepared with different degrees of surface corrugation using either controlled spray drying (four samples of BSA) or decantation (two samples of lactose). Particle size distributions were characterized by laser diffraction, and particles were imaged by scanning electron microscopy (SEM). Surface roughness of the BSA and lactose particles was quantified by white-light optical profilometry using vertical scanning interferometry (VSI) at full resolution using a 50× objective lens with 2.0× and 0.5× fields of view for BSA and lactose, respectively. Data were analyzed using Vision software (version 32, WYKO), and surface roughness values are expressed as root-mean-square roughness (R rms). Furthermore, data were compared to topographical measurements made using conventional atomic force microscopy. Analysis of the optical profilometry data showed significant variation in BSA roughness ranging from 18.58 ± 3.80 nm to 110.90 ± 13.16 nm for the smoothest and roughest BSA particles, respectively, and from 81.20 ± 15.90 nm to 229.20 ± 68.20 nm for decanted and normal lactose, respectively. The R rms values were in good agreement with the AFM-derived values. The particle morphology was similar to SEM and AFM images. In conclusion, scanning white-light interferometry provides a useful complementary tool for rapid evaluation of surface morphology and roughness in particles used for dry powder inhalation formulation.
Ferroptosis, an emerging form of programmed cell death, has garnered substantial attention as a potential target for cancer therapy. However, despite the potential promise, no ferroptosis-related ...therapies have progressed to clinical trials. Identifying disease types sensitive to ferroptosis and developing specific ferroptosis-targeting drugs are critical focal points in the field of ferroptosis-based treatment.
In this study, we conducted a comprehensive database analysis and presented compelling evidence indicating a high expression of GPX4 in patients with acute lymphoblastic leukemia (ALL), significantly correlating with poor prognosis. Notably, elevated GPX4 expression is closely associated with ALL relapse, a major challenge in the treatment of this disease. Building upon these findings, we devised a novel peptide-based Proteolysis Targeting Chimeras (PROTAC) drug targeting GPX4 through computer-aided design. In contrast to existing drugs that target the conjugative enzyme active site, our design focused on a peptide drug targeting the non-active site of GPX4. Furthermore, we strategically selected MDM2, an E3 ligase highly expressed in ALL, for the PROTAC drug design. This deliberate choice amplifies the drug's effect on cancer cells while minimizing its impact on normal cells, achieving desirable selectivity for cancer cells. Leveraging nanogold delivery, we successfully facilitated intracellular action of the GPX4-targeting peptide PROTAC drug, denoted as Au-PGPD (peptide GPX4 PROTAC drug). Au-PGPD effectively induced GPX4 degradation and inhibited ALL cell proliferation. Remarkably, Au-PGPD exhibited significantly less efficacy on normal cells, underscoring the selectivity and safety of our design.
•The high expression of GPX4 in ALL was associated with poor prognosis and recurrence indicating GPX4 is a promising target for ALL therapy.•We provide a PROTAC drug targeting the non-enzymatic domain of GPX4.•For the GPX4 PROTAC drug design, an oncogene E3 ligase MDM2, which is highly expressed in ALL, is selected to achieve the selectivity of drug effect in cancer cells and reduce toxicity in normal cells.•This study serve as a proof of concept that the E3 ligases highly expressed in cancer cells should be selected for PROTAC drug design to enhance the drug selectivity for cancer cells, rather than the basal E3 ligases.
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•The air flow and powder dynamics in the inhaler-airway systems were simulated using CFD-DEM.•Effects of the airway deformation on air flow and powder dispersion were ...analysed.•Effects of the airway sizes on air flow and powder dispersion were analysed.•Airway deformation caused more particle deposition in the deformed region.•Deposition efficiency in the airway increases with decreasing airway size.
Aerosol drug delivery in the human airway is significantly affected by the morphology and size of the airway. This work developed a CFD-DEM model to simulate and analyze air flow and powder dynamics in combined inhaler-airway systems with different degrees of airway deformation (non-deformed, 50%, and 75% deformed) and sizes (adult, 0.80, and 0.62 scaled). The airways were generated based on a regular airway constructed from the MRI images through finite element method (for deformed airways) or scaling-down (for smaller airways). The airways were connected to Turbuhaler® through a connector. The results showed that under the same flow rate, the variation in the airway geometry and size had a minimum impact on the flow field and powder deposition in the device and the connector. However, deformation caused more particle deposition in the deformed region. Notably, the airway with 50% deformation had the most particles passing through the airway with the largest particle sizes due to its lower air velocity in the deformed area. Reducing airway size resulted in more powder deposition on the airway, particularly at the pharynx and mouth regions. This was because, with the same flow rate, the flow velocity in the smaller airway was higher, causing more particle–wall collisions in the mouth and pharynx regions. More importantly, the deposition efficiency in the 0.62-scaled airway was significantly higher than the other two airways, highlighting the importance of the different administration of aerosol drugs for young children.
This work presents a study of the granulation of iron fines in a horizontal high shear granulator. Both experiments and DEM simulations were conducted to investigate the effect of water content, ...impeller rotational speed and particle sizes on granulation performance. The experimental results showed that the granule size increased with increasing water content, but the granules had the most uniform size at 8% of water content. The DEM model was developed to understand the inter-particle force, particle motion and adhesion during granulating. The results show that the liquid bridge force and the amount of bonded small particles increased with increasing water content, resulting in larger granules with wider granule size distributions. Increasing impeller speed also increased granulation efficiency due to increased collisions between particles. The simulation of the granulation of particles with different size ratios showed that granulation efficiency increased with increasing size ratios of nucleating and adhesive particles.
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•A horizontal high-shear granulator was used in iron ore granulation process.•Experiments and DEM simulations were combined to study granulation process.•The particle force, adhesion and internal structure of granules were analysed.•High moisture and impeller rotational speed promote particle adhesion.
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•CFD-DEM simulations to investigate API-only powder dispersion in Turbuhaler®.•Effects of the mouthpiece and chamber design of powder dispersion were assessed.•The spiral structure of ...the mouthpiece plays an important role in powder dispersion.•The dome chamber design increased the FPF loaded due to increased powder dispersion time.•Powder dispersion was lined to the particle–wall collision energy.
Powder dispersion in dry powder inhalers (DPIs) is affected by powder formulations as well as the design of a device. This paper conducted a numerical investigation based on the coupled computational fluid dynamics (CFD) and discrete element method (DEM) to evaluate the changes of the design of a commercial DPI device Turbuhaler® on the aerosolization of an API-only formulation. Six different designs were proposed by modifying the mouthpiece and chamber of the original geometry which was reconstructed from a CT-scan of the Turbuhaler, and their performances in terms of powder deposition in the device and fine powder fraction (FPF) were evaluated. The resistance of the device was observed to vary with different designs. For the change of the mouthpiece, the device with a cylindrical mouthpiece had the least resistance and the lowest FPF emitted among all the devices, confirming the important role of the spiral mouthpiece on powder dispersion. Reducing the mouthpiece size caused more powder deposition in the inhaler due to higher airflow velocity, but FPF emitted increased compared to the original design as more powder dispersion occurred inside the mouthpiece. The half-length mouthpiece design reduced device resistance to increase airflow velocity and average collision energy, resulting in an increase in FPF loaded but a decrease in the number of collisions. For the change of the chamber, the domed chamber design increased the powder dispersion time and thus enhanced the frequency and energy of particle collisions, which eventually led to an increase in FPF loaded. At fixed flow rates, the powder dispersion efficiency was a function of the device resistance with higher device resistance causing an increase in the FPF loaded. However, it is important for the patient’s attainable pressure drop to be considered in this context. Correlations between the aerosolization efficiency and the ratio of the average collision energy and cohesion energy were established based on model-predicted quantities.
