Celastrol reduces lung inflammation induced by multiwalled carbon nanotubes in mice via NF-κb-signaling pathway.

Multiwalled carbon nanotubes (MWCNTs) have numerous applications in the field of carbon nanomaterials. However, the associated toxicity concerns have increased significantly because of their widespread use. The inhalation of MWCNTs can lead to nanoparticle deposition in the lung tissue, causing inflammation and health risks. In this study, celastrol, a natural plant medicine with potent anti-inflammatory properties, effectively reduced the number of inflammatory cells, including white blood cells, neutrophils, and lymphocytes, and levels of inflammatory cytokines, such as IL-1ß, IL-6, and TNF-α, in mice lungs exposed to MWCNTs. Moreover, celastrol inhibited the activation of the NF-κB-signaling pathway. This study confirmed these findings by demonstrating comparable reductions in inflammation upon exposure to MWCNTs in mice with the deletion of NF-κB (P50-/-). These results indicate the utility of celastrol as a promising pharmacological agent for preventing MWCNT-induced lung tissue inflammation.

ZL006 mitigates anxiety-like behaviors induced by closed head injury through modulation of the neural circuit from the medial prefrontal cortex to amygdala.

Closed head injury is a prevalent form of traumatic brain injury with poorly understood effects on cortical neural circuits. Given the emotional and behavioral impairments linked to closed head injury, it is vital to uncover brain functional deficits and their driving mechanisms. In this study, we employed a robust viral tracing technique to identify the alteration of the neural pathway connecting the medial prefrontal cortex to the basolateral amygdala, and we observed the disruptions in neuronal projections between the medial prefrontal cortex and the basolateral amygdala following closed head injury. Remarkably, our results highlight that ZL006, an inhibitor targeting PSD-95/nNOS interaction, stands out for its ability to selectively reverse these aberrations. Specifically, ZL006 effectively mitigates the disruptions in neuronal projections from the medial prefrontal cortex to basolateral amygdala induced by closed head injury. Furthermore, using chemogenetic approaches, we elucidate that activating the medial prefrontal cortex projections to the basolateral amygdala circuit produces anxiolytic effects, aligning with the therapeutic potential of ZL006. Additionally, ZL006 administration effectively mitigates astrocyte activation, leading to the restoration of medial prefrontal cortex glutamatergic neuron activity. Moreover, in the context of attenuating anxiety-like behaviors through ZL006 treatment, we observe a reduction in closed head injury-induced astrocyte engulfment, which may correlate with the observed decrease in dendritic spine density of medial prefrontal cortex glutamatergic neurons.

In vivo imaging reveals a synchronized correlation among neurotransmitter dynamics during propofol and sevoflurane anesthesia.

General anesthesia is widely applied in clinical practice. However, the precise mechanism of loss of consciousness induced by general anesthetics remains unknown. Here, we measured the dynamics of five neurotransmitters, including γ-aminobutyric acid, glutamate, norepinephrine, acetylcholine, and dopamine, in the medial prefrontal cortex and primary visual cortex of C57BL/6 mice through in vivo fiber photometry and genetically encoded neurotransmitter sensors under anesthesia to reveal the mechanism of general anesthesia from a neurotransmitter perspective. Results revealed that the concentrations of γ-aminobutyric acid, glutamate, norepinephrine, and acetylcholine increased in the cortex during propofol-induced loss of consciousness. Dopamine levels did not change following the hypnotic dose of propofol but increased significantly following surgical doses of propofol anesthesia. Notably, the concentrations of the five neurotransmitters generally decreased during sevoflurane-induced loss of consciousness. Furthermore, the neurotransmitter dynamic networks were not synchronized in the non-anesthesia groups but were highly synchronized in the anesthetic groups. These findings suggest that neurotransmitter dynamic network synchronization may cause anesthetic-induced loss of consciousness.

Molecular classification reveals the sensitivity of lung adenocarcinoma to radiotherapy and immunotherapy: multi-omics clustering based on similarity network fusion.

BACKGROUND: Due to individual differences in tumors and immune systems, the response rate to immunotherapy is low in lung adenocarcinoma (LUAD) patients. Combinations with other therapeutic strategies improve the efficacy of immunotherapy in LUAD patients. Although radioimmunotherapy has been demonstrated to effectively suppress tumors, the underlying mechanisms still need to be investigated. METHODS: Total RNA from LUAD cells was sequenced before and after radiotherapy to identify differentially expressed radiation-associated genes. The similarity network fusion (SNF) algorithm was applied for molecular classification based on radiation-related genes, immune-related genes, methylation data, and somatic mutation data. The changes in gene expression, prognosis, immune cell infiltration, radiosensitivity, chemosensitivity, and sensitivity to immunotherapy were assessed for each subtype. RESULTS: We used the SNF algorithm and multi-omics data to divide TCGA-LUAD patients into three subtypes. Patients with the CS3 subtype had the best prognosis, while those with the CS1 and CS2 subtypes had poorer prognoses. Among the strains tested, CS2 exhibited the most elevated immune cell infiltration and expression of immune checkpoint genes, while CS1 exhibited the least. Patients in the CS2 subgroup were more likely to respond to PD-1 immunotherapy. The CS2 patients were most sensitive to docetaxel and cisplatin, while the CS1 patients were most sensitive to paclitaxel. Experimental validation of signature genes in the CS2 subtype showed that inhibiting the expression of RHCG and TRPA1 could enhance the sensitivity of lung cancer cells to radiation. CONCLUSIONS: In summary, this study identified a risk classifier based on multi-omics data that can guide treatment selection for LUAD patients.

Associations between multiple metal exposure and fertility in women: A nested case-control study.

Metal pollution can cause a decline in female fertility, however, previous studies have focused more on the effect of a single metal on fertility. In this study, we evaluated the effect of metal mixtures on female fertility based on nested case-control samples. The plasma levels of 22 metal elements from 180 women were determined by an inductively coupled plasma mass spectrometer (ICP-MS). Minimum absolute contraction and selection operator (LASSO) penalty regression selected metals with the greatest influence on clinical outcome. Logistic regression was used to analyze the correlation between single metals and fertility while a Bayesian kernel function regression (BKMR) model was used to analyze the effect of mixed metals. Eight metals (Calcium (Ca), Chromium (Cr), Cobalt (Co), Copper (Cu), Zinc (Zn), Rubidium (Rb), Strontium (Sr) and Zirconium (Zr)) were selected by LASSO regression for subsequent analysis. After adjusting for covariates, the logistic model showed that Cu (Odds Ratio(OR):0.33, 95% CI: 0.13 - 0.84) and Co (OR:0.38, 95% CI: 0.15 -0.94) caused a significant reduction in fertility, and identified the protective effect of Zn (OR: 2.96, 95% CI:1.21 -7.50) on fertility. Trend tests showed that increased Cr, Cu, and Rb levels were associated with reduced fertility. The BKMR model showed that Cr, Co, Cu, and Rb had a nonlinear relationship with fertility decline when controlling for the concentrations of other metals and suggested that Cu and Cr might exert an influence on fertility. Analysis showed a negative correlation between Cu, Cr, Co, Rb, and fertility, and a positive correlation between Zn and fertility. Furthermore, we found evidence for the interaction between Cu and Cr. Our findings require further validation and may identify new mechanisms in the future.

Wearable and interactive multicolored photochromic fiber display.

Endowing flexible and adaptable fiber devices with light-emitting capabilities has the potential to revolutionize the current design philosophy of intelligent, wearable interactive devices. However, significant challenges remain in developing fiber devices when it comes to achieving uniform and customizable light effects while utilizing lightweight hardware. Here, we introduce a mass-produced, wearable, and interactive photochromic fiber that provides uniform multicolored light control. We designed independent waveguides inside the fiber to maintain total internal reflection of light as it traverses the fiber. The impact of excessive light leakage on the overall illuminance can be reduced by utilizing the saturable absorption effect of fluorescent materials to ensure light emission uniformity along the transmission direction. In addition, we coupled various fluorescent composite materials inside the fiber to achieve artificially controllable spectral radiation of multiple color systems in a single fiber. We prepared fibers on mass-produced kilometer-long using the thermal drawing method. The fibers can be directly integrated into daily wearable devices or clothing in various patterns and combined with other signal input components to control and display patterns as needed. This work provides a new perspective and inspiration to the existing field of fiber display interaction, paving the way for future human-machine integration.

A GAPDH serotonylation system couples CD8+ T cell glycolytic metabolism to antitumor immunity.

Apart from the canonical serotonin (5-hydroxytryptamine [5-HT])-receptor signaling transduction pattern, 5-HT-involved post-translational serotonylation has recently been noted. Here, we report a glyceraldehyde-3-phosphate dehydrogenase (GAPDH) serotonylation system that promotes the glycolytic metabolism and antitumor immune activity of CD8+ T cells. Tissue transglutaminase 2 (TGM2) transfers 5-HT to GAPDH glutamine 262 and catalyzes the serotonylation reaction. Serotonylation supports the cytoplasmic localization of GAPDH, which induces a glycolytic metabolic shift in CD8+ T cells and contributes to antitumor immunity. CD8+ T cells accumulate intracellular 5-HT for serotonylation through both synthesis by tryptophan hydroxylase 1 (TPH1) and uptake from the extracellular compartment via serotonin transporter (SERT). Monoamine oxidase A (MAOA) degrades 5-HT and acts as an intrinsic negative regulator of CD8+ T cells. The adoptive transfer of 5-HT-producing TPH1-overexpressing chimeric antigen receptor T (CAR-T) cells induced a robust antitumor response. Our findings expand the known range of neuroimmune interaction patterns by providing evidence of receptor-independent serotonylation post-translational modification.

Investigation on formaldehyde generation characteristics and influencing factors of PODE/methanol dual-fuel combustion mode.

Polyoxymethylene dimethyl ether (PODE) and methanol are important low-carbon substitutable fuels for reducing carbon emissions in internal combustion engines. In the research, the impacts of methanol ratio, injection timing, and intake temperature on HCHO generation and emission were investigated using both engine tests and numerical simulations. Results suggest that an increase in methanol ratio suppresses auto-ignition tendency of PODE, leading to the increase of ignition delay period, pressure peak, and heat release rate peak inside the cylinder. The decrease in in-cylinder combustion temperature contributes to an increase in HCHO emission due to partial oxidation of methanol in the cylinder and exhaust pipe. While the injection timing is gradually postponed from -10 °CA ATDC to 2 °CA ATDC, in-cylinder high-temperature area decreases, the quantity of unburned methanol increases, but part of HCHO is converted to HCO due to H radical influence, resulting in 72% increased HCHO emission. With the increment of intake temperature, the oxidation and decomposition of in-cylinder methanol accelerate, leading to an improvement in combustion stability, more uniform temperature distribution, and a decrease in unburned methanol, which results in lower HCHO emission. When the intake temperature is rose from 30 to 60 °C, HCHO emission decreases by 11.2%.

Targeting Neutrophil Extracellular Traps: A Novel Antitumor Strategy.

The clinical efficacy of surgery, radiotherapy, and chemotherapy for cancer is usually limited by the deterioration of tumor microenvironment (TME). Neutrophil extracellular traps (NETs) are decondensed chromatin extruded by neutrophils and are widely distributed among various cancers, such as pancreatic cancer, breast cancer, and hepatocellular carcinoma. In the TME, NETs interact with stromal components, immune cells and cancer cells, which allows for the reshaping of the matrix and the extracellular environment that favors the initiation, progression, and metastasis of cancer. In addition, NETs impair the proliferation and activation of T cells and NK cells, thus producing a suppressive TME that restricts the effect of immunotherapy. A better understanding of the function of NETs in the TME will provide new opportunities for the prevention of cancer metastasis and the discovery of novel therapy strategies.

DNA-Compatible Cyanomethylation of (Hetero)aryl Halides or Triflates under a Tandem Reaction for DNA-Encoded Library Synthesis.

A DNA-compatible reaction has been developed for the cyanomethylation of (hetero)aryl halides or triflates via a tandem process involving palladium-mediated Suzuki-Miyaura coupling and base-promoted isoxazole fragmentation. This one-pot protocol employs easily accessible starting materials, exhibits a wide substrate scope, and results in no significant DNA damage. Additionally, the resulting (hetero)arylacetonitriles can be converted into the corresponding carboxylic acids, which may be utilized for the synthesis of DNA-encoded chemical libraries.

U-Shaped Association of Standardized Serum 25-Hydroxyvitamin D with Risk of Low Muscle Mass: A Population-Based Cross-Sectional Study.

Background: In the United States (U.S.) general population, the association between standardized serum 25-hydroxyvitamin D (25(OH)D) concentration and risk of low muscle mass (LMM) remains unclear. Our research aimed to determine whether or not there was a relationship between serum 25(OH)D concentration and risk of LMM. Methods: We analyzed the cross-sectional data of the US population that participated in the National Health and Nutrition Examination Survey between 2011 and 2014. The relationship between serum 25(OH)D concentration and LMM risk was evaluated using restricted cubic spline (RCS) with multivariate logistic regression model and subgroup analysis. Results: In all, we included 10,256 people in our analysis. The RCS plot demonstrated a U-shaped relationship between serum 25(OH)D concentration and risk of LMM (P for nonlinearity <0.05). At a Vitamin D concentration of 38.5 nmol/L, LMM risk was at its lowest. Based on analyses stratified by age, sex, hypertension, and diabetes mellitus (DM), serum 25(OH)D concentration and risk of LMM were U-curve correlated for those age 40 or older, male, with hypertension, or without DM. However, LMM risk was positively related to serum 25(OH)D concentration in those younger than age 40 or in women. Conclusion: There is a U-shaped relationship between serum 25(OH)D concentration and the risk of LMM in the general U.S. population. Careful monitoring and appropriate Vitamin D supplementation might lessen the risk of LMM.

Mechanisms of N6­methyladenosine modification in tumor development and potential therapeutic strategies (Review).

N6­methyladenosine (m6A) modification, as the most common and abundant type of RNA modification in mammalian cells, participates in the processes of mRNA transcription, translation, splicing and degradation, serving to regulate RNA stability. In recent years, a large number of studies have indicated that m6A modification is able to affect tumor progression, participate in tumor metabolism, regulate tumor cell ferroptosis and change the tumor immune microenvironment, thereby affecting tumor immunotherapy. In the current review, the main features of m6A­associated proteins are presented with a focus on the mechanisms underpinning their roles in tumor progression, metabolism, ferroptosis and immunotherapy, also emphasizing the potential of targeting m6A­associated proteins as a promising strategy for the treatment of cancer.

Neutrophils extracellular traps and ferroptosis in diabetic wounds.

Wound healing is an extremely complex process involving multiple levels of cells and tissues. It is mainly completed through four stages: haemostasis, inflammation, proliferation, and remodelling. When any one of these stages is impaired, it may lead to delayed healing or even transformation into chronic refractory wounds. Diabetes is a kind of common metabolic disease that affects approximately 500 million people worldwide, 25% of whom develop skin ulcers that break down repeatedly and are difficult to heal, making it a growing public health problem. Neutrophils extracellular traps and ferroptosis are new types of programmed cell death identified in recent years and have been found to interact with diabetic wounds. In this paper, the normal wound healing and interfering factors of the diabetic refractory wound were outlined. The mechanism of two kinds of programmed cell death was also described, and the interaction mechanism between different types of programmed cell death and diabetic refractory wounds was discussed.

Deep learning for predicting the human epidermal growth factor receptor 2 status of breast cancer liver metastases based on contrast-enhanced computed tomography: a development and validation study.

Background: This study investigated the value of a deep learning (DL) model based on computed tomography (CT) enhancement for predicting human epidermal growth factor receptor 2 (HER2) expression in patients with liver metastasis from breast cancer. Methods: Data were collected for 151 female patients with liver metastasis from breast cancer who underwent abdominal enhanced CT examination in the Department of Radiology at the Affiliated Hospital of Hebei University between January 2017 and March 2022. Liver metastases were confirmed in all patients by pathology. The HER2 status of the liver metastases was assessed and enhanced CT examinations were performed before treatment. Of the 151 patients, 93 were HER2 negative and 58 were HER2 positive. Liver metastases were manually labeled with rectangular frames, layer by layer, and the labeled data were processed. Five basic networks (ResNet34, ResNet50, ResNet101, ResNeXt50, and Swim Transformer) were used for training and optimization, and the model's performance was tested. Receiver operating characteristic (ROC) curves were used to analyze the area under the curve (AUC), as well as the accuracy, sensitivity, and specificity of the networks in predicting HER2 expression in breast cancer liver metastases. Results: Overall, ResNet34 demonstrated the best prediction efficiency. The accuracy of the validation and test set models in predicting HER2 expression in liver metastases was 87.4% and 80.5%, respectively. The AUC, sensitivity, and specificity of the test set model in predicting HER2 expression in liver metastases were 0.778, 77.0%, and 84.0%, respectively. Conclusions: Our DL model based on CT enhancement has good stability and diagnostic efficacy, and is a potential non-invasive method for identifying HER2 expression in liver metastases from breast cancer.

PYGL-mediated glucose metabolism reprogramming promotes EMT phenotype and metastasis of pancreatic cancer.

Epithelial-mesenchymal transition (EMT) is closely associated with tumor invasion and metastasis. However, key regulators of EMT in pancreatic ductal adenocarcinoma (PDAC) need to be further studied. Bioinformatics analyses of pancreatic cancer public datasets showed that glycogen phosphorylase L (PYGL) expression is elevated in quasimesenchymal PDAC (QM-PDAC) and positively associated with EMT. In vitro cellular experiments further confirm PYGL as a crucial EMT regulator in PDAC cells. Functionally, PYGL overexpression promotes cell migration and invasion in vitro and facilitates liver metastasis in vivo, while PYGL knockdown has opposite effects. Mechanically, hypoxia induces PYGL expression in a hypoxia inducible factor 1α (HIF1α)-dependent manner and promotes glycogen accumulation. Elevated PYGL mobilizes accumulated glycogen to fuel glycolysis via its activity as a glycogen phosphorylase, thus inducing the EMT process, which could be suppressed by the glycolysis inhibitor 2-deoxy-D-glucose (2-DG). Clinically, PYGL expression is upregulated in PDAC and correlates with its malignant features and poor prognosis. Collectively, the data from our study reveal that the hypoxia/PYGL/glycolysis-induced EMT promotes PDAC metastasis, which establishes the rational for targeting hypoxia/PYGL/glycolysis/EMT signaling pathway against PDAC.

Association of Systemic Immune Inflammation Index with Estimated Pulse Wave Velocity, Atherogenic Index of Plasma, Triglyceride-Glucose Index, and Cardiovascular Disease: A Large Cross-Sectional Study.

In the U.S. general population, there is a lack of understanding regarding the association between the systemic immune inflammation (SII) index and estimated pulse wave velocity (ePWV), atherogenic index of plasma (AIP), and triglyceride-glucose (TyG) index and cardiovascular disease (CVD). As a result, the objective of our research was to investigate the association between the SII index and ePWV, AIP, and TyG index and incident CVD. We used the National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2018 to conduct this study. The correlation between the SII index and ePWV, AIP, and TyG index was examined using generalized additive models with smooth functions. In addition, the association between SII index and triglyceride (TC), high-density lipoprotein cholesterol (HDL-C), and fast glucose (FBG) also were explored. Finally, we further performed multivariable logistic regression analysis, restricted cubic spline (RCS) plots, and subgroup analysis to study the connection between the SII index and CVD. Our analysis included 17389 subjects from the NHANES database. A substantial positive association existed between SII, WV, and the TyG index. In addition, with the increase of the SII index, AIP showed a trend of decreasing first, then rising, and then decreasing. The SII index was inversely and linearly associated with triglyceride (TG), while positively and linearly associated with fast glucose (FBG). However, high-density lipoprotein cholesterol (HDL-C) had a tendency of first declining, then climbing, and finally falling with the rise in the SII index. After adjusting for potential confounders, compared with the lowest quartiles, the odds ratios with 95% confidence intervals for CVD across the quartiles were 0.914 (0.777, 1.074), 0.935 (0.779, 1.096), and 1.112 (0.956, 1.293) for SII index. The RCS plot showed an inverse U-shaped curve relationship between the SII index and CVD. Overall, this study found a strong correlation between a higher SII index and ePWV and the TyG index. Additionally, these cross-sectional data also revealed a U-shaped connection between the SII index and CVD.

Celastrol alleviates oxidative stress induced by multi-walled carbon nanotubes through the Keap1/Nrf2/HO-1 signaling pathway.

Multi-walled carbon nanotubes (MWCNTs) mainly induce oxidative stress through the overproduction of reactive oxygen species (ROS), which can lead to cytotoxicity. Celastrol, a plant-derived compound, can exert antioxidant effects by reducing ROS production. Our results indicated that exposure to MWCNTs decreased cell viability and increased ROS production. Nrf2 knockdown (kd) led to increased ROS production and enhanced MWCNT-induced cytotoxicity. Keap1-kd led to decreased ROS production and attenuated cytotoxicity. Treatment with celastrol significantly decreased ROS production and promoted Keap1 protein degradation through the lysosomal pathway, thereby enhancing the translocation of Nrf2 from the cytoplasm to the nucleus and increasing HO-1 expression. The in vivo results showed that celastrol could alleviate the inflammatory damage of lung tissues, increase the levels of the antioxidants, GSH and SOD, as well as promote the expression of the antioxidant protein, HO-1 in MWCNT-treated mice. Celastrol can alleviate MWCNT-induced oxidative stress through the Keap1/Nrf2/HO-1 signaling pathway.

Autophagy impairment is involved in midazolam-induced lipid droplet accumulation and consequent phagocytosis decrease in BV2 cells.

An increasing number of experimental and clinical observation suggest that the use of anaesthetics is closely associated with postoperative central nervous system (CNS) complications, such as delirium and cognitive dysfunction. Brain energy rescue is an emerging therapeutic strategy for central nervous system disease (CNSDs). However, the effect of anaesthetics on nerve cell energy utilisation, especially microglia, and its potential effects on cell function still unclear. Elucidating the effects of anaesthetics on lipid droplets, which are specific lipid storage organs, and phagocytosis of microglia is crucial to discover a new therapeutic concept for postoperative CNS complications. Here, we studied the effects of the commonly used anaesthetic midazolam on lipid droplets and phagocytosis in immortalised microglial BV2 cells. Lipid droplets were assessed by flow cytometry and triglyceride quantification. The phagocytosis of BV2 cells was evaluated by detecting their phagocytosis by latex beads. Additionally, the autophagy of BV2 cells was evaluated by western blot and observation under microscopy. Our results showed that midazolam caused lipid droplet accumulation and reduced phagocytosis in BV2 cells, and inhibition of lipid droplet accumulation partially restored phagocytosis. Furthermore, midazolam blocks autophagic degradation by increasing phosphorylated TFEB in BV2 cells, inhibition of midazolam-increased phosphorylated TFEB might contribute to the improvement of autophagic flux by rapamycin. Moreover, promoting autophagy reverse the lipid droplet accumulation and phagocytosis decrease. This study suggests autophagy is a target for attenuating lipid droplet accumulation, normal degradation of lipid droplets is important for maintaining microglia phagocytosis and attenuating the side effects of midazolam on the CNS.

A multi-scale, multi-region and attention mechanism-based deep learning framework for prediction of grading in hepatocellular carcinoma.

BACKGROUND: Histopathological grading is a significant risk factor for postsurgical recurrence in hepatocellular carcinoma (HCC). Preoperative knowledge of histopathological grading could provide instructive guidance for individualized treatment decision-making in HCC management. PURPOSE: This study aims to develop and validate a newly proposed deep learning model to predict histopathological grading in HCC with improved accuracy. METHODS: In this dual-centre study, we retrospectively enrolled 384 HCC patients with complete clinical, pathological and radiological data. Aiming to synthesize radiological information derived from both tumour parenchyma and peritumoral microenvironment regions, a modelling strategy based on a multi-scale and multi-region dense connected convolutional neural network (MSMR-DenseCNNs) was proposed to predict histopathological grading using preoperative contrast enhanced computed tomography (CT) images. Multi-scale inputs were defined as three-scale enlargement of an original minimum bounding box in width and height by given pixels, which correspondingly contained more peritumoral analysis areas with the enlargement. Multi-region inputs were defined as three regions of interest (ROIs) including a squared ROI, a precisely delineated tumour ROI, and a peritumoral tissue ROI. The DenseCNN structure was designed to consist of a shallow feature extraction layer, dense block module, and transition and attention module. The proposed MSMR-DenseCNN was pretrained by the ImageNet dataset to capture basic graphic characteristics from the images and was retrained by the collected retrospective CT images. The predictive ability of the MSMR-DenseCNN models on triphasic images was compared with a conventional radiomics model, radiological model and clinical model. RESULTS: MSMR-DenseCNN applied to the delayed phase (DP) achieved the highest area under the curve (AUC) of 0.867 in the validation cohort for grading prediction, outperforming those on the arterial phase (AP) and portal venous phase (PVP). Fusion of the results on triphasic images did not increase the predictive ability, which underscored the role of DP for grading prediction. Compared with a single-scale and single-region network, the DP-phase based MSMR-DenseCNN model remarkably raised sensitivity from 67.4% to 75.5% with comparable specificity of 78.6%. MSMR-DenseCNN on DP defeated conventional radiomics, radiological and clinical models, where the AUCs were correspondingly 0.765, 0.695 and 0.612 in the validation cohort. CONCLUSIONS: The MSMR-DenseCNN modelling strategy increased the accuracy for preoperative prediction of grading in HCC, and enlightens similar radiological analysis pipelines in a variety of clinical scenarios in HCC management.

Mechanosensitive ion channel Piezo1 mediates mechanical ventilation-exacerbated ARDS-associated pulmonary fibrosis.

INTRODUCTION: Pulmonary fibrosis is a major cause of the poor prognosis of acute respiratory distress syndrome (ARDS). While mechanical ventilation (MV) is an indispensable life-saving intervention for ARDS, it may cause the remodeling process in lung epithelial cells to become disorganized and exacerbate ARDS-associated pulmonary fibrosis. Piezo1 is a mechanosensitive ion channel that is known to play a role in regulating diverse physiological processes, but whether Piezo1 is necessary for MV-exacerbated ARDS-associated pulmonary fibrosis remains unknown. OBJECTIVES: This study aimed to explore the role of Piezo1 in MV-exacerbated ARDS-associated pulmonary fibrosis. METHODS: Human lung epithelial cells were stimulated with hydrochloric acid (HCl) followed by mechanical stretch for 48 h. A two-hitmodel of MV afteracidaspiration-inducedlunginjuryin mice was used. Mice were sacrificed after 14 days of MV. Pharmacological inhibition and knockout of Piezo1 were used to delineate the role of Piezo1 in MV-exacerbated ARDS-associated pulmonary fibrosis. In some experiments, ATP or the ATP-hydrolyzing enzyme apyrase was administered. RESULTS: The stimulation of human lung epithelial cells to HCl resulted in phenotypes of epithelial-mesenchymal transition (EMT), which were enhanced by mechanical stretching. MV exacerbated pulmonary fibrosis in mice exposed to HCl. Pharmacologicalinhibitionorknockout of Piezo1 attenuated the MV-exacerbated EMT process and lung fibrosis in vivo and in vitro. Mechanistically, the observed effects were mediated by Piezo1-dependent Ca2+ influx and ATP release in lung epithelial cells. CONCLUSIONS: Our findings identify a key role for Piezo1 in MV-exacerbated ARDS-associated pulmonary fibrosis that is mediated by increased ATP release in lung epithelial cells. Inhibiting Piezo1 may constitute a novelstrategyfor the treatment of MV-exacerbated ARDS-associated pulmonary fibrosis.