Hepatocyte mitochondrial DNA mediates macrophage immune response in liver injury induced by trichloroethylene.

We have previously shown that excessive activation of macrophage proinflammatory activity plays a key role in TCE-induced immune liver injury, but the mechanism of polarization is unclear. Recent studies have shown that TLR9 activation plays an important regulatory role in macrophage polarization. In the present study, we demonstrated that elevated levels of oxidative stress in hepatocytes mediate the release of mtDNA into the bloodstream, leading to the activation of TLR9 in macrophages to regulate macrophage polarization. In vivo experiments revealed that pretreatment with SS-31, a mitochondria-targeting antioxidant peptide, reduced the level of oxidative stress in hepatocytes, leading to a decrease in mtDNA release. Importantly, SS-31 pretreatment inhibited TLR9 activation in macrophages, suggesting that hepatocyte mtDNA may activate TLR9 in macrophages. Further studies revealed that pharmacological inhibition of TLR9 by ODN2088 partially blocked macrophage activation, suggesting that the level of macrophage activation is dependent on TLR9 activation. In vitro experiments involving the extraction of mtDNA from TCE-sensitized mice treated with RAW264.7 cells further confirmed that hepatocyte mtDNA can activate TLR9 in mouse peritoneal macrophages, leading to macrophage polarization. In summary, our study comprehensively confirmed that TLR9 activation in macrophages is dependent on mtDNA released by elevated levels of oxidative stress in hepatocytes and that TLR9 activation in macrophages plays a key role in regulating macrophage polarization. These findings reveal the mechanism of macrophage activation in TCE-induced immune liver injury and provide new perspectives and therapeutic targets for the treatment of OMDT-induced immune liver injury.

Macrophage autophagy contributes to immune liver injury in trichloroethylene sensitized mice: Critical role of TNF-α mediating mTOR pathway.

Trichloroethylene (TCE) induces occupational medicamentosa-like dermatitis due to TCE (OMDT) with immune liver injury, and TNF-α plays an important role in macrophage polarization and liver injury. However, TNF-α regulating macrophage polarization in liver injury induced by TCE is still unknown. Thus, on the basis of our previous research, we established the TCE-sensitized BALB/c mouse model with R7050, a specific inhibitor of TNFR1. Then, we observed significant decreases in autophagy related protein and gene levels in M1 macrophage in TCE positive group, and R7050 can relieve M1 macrophage autophagy. We also found the phosphorylated form of mammalian target of Rapamycin (mTOR) was activated and the expression of p-mTOR protein increased induce by TCE. In vitro, we found TNFR1 and CD11c were increased in RAW264.7 cell line with TNF-α. And then we use Zafirlukast (Zaf), an TNFR1 antagonist, CD11c and TNFR1 reduced significantly, we also found p-mTOR expression increased after TNF-α treatment, but decreased in TNF-α + Zaf group. Further, we used Rapamycin (RAP), a mTOR-specific inhibitor, to establish a TCE-sensitized mice model and found the expression levels of p62 and p-mTOR proteins increased and LC3B decreased in the TCE positive group, while RAP treatment reversed the trends of all of these proteins. Rapamycin prevented the TNF-α-induced p-mTOR increase and dramatically downregulated IL-1ß expression in the RAW264.7 cell line with TNF-α treatment. The results uncover a novel role for TNF-α/TNFR1, which promotes M1 polarization of macrophage and suppresses macrophage autophagy via the mTOR pathway.

80 × 120 AI-enhanced LiDAR system based on a lightweight intensity-RGB-dToF sensor fusion neural network deployed on an edge device.

Collecting higher-quality three-dimensional points-cloud data in various scenarios practically and robustly has led to a strong demand for such dToF-based LiDAR systems with higher ambient noise rejection ability and limited optical power consumption, which is a sharp conflict. To alleviate such a clash, an idea of utilizing a strong ambient noise rejection ability of intensity and RGB images is proposed, based on which a lightweight CNN is newly, to the best of our knowledge, designed, achieving a state-of-the-art performance even with 90 × less inference time and 480 × fewer FLOPs. With such net deployed on edge devices, a complete AI-LiDAR system is presented, showing a 100 × fewer signal photon demand in simulation experiments when creating depth images of the same quality.

The role of Kupffer cell activation in immune liver damage induced by trichloroethylene associated with the IFN-γ/STAT1 signaling pathway.

Trichloroethylene (TCE) is a metal detergent commonly used in industry that can enter the human body through the respiratory tract and skin, causing occupational medicamentosa-like dermatitis due to TCE (OMDT) and multiple organ damage, including liver failure. However, the pathogenesis of liver injury remains unclear. Kupffer cells (KCs) are important tissue macrophages in the body because the polarization of KCs plays a crucial role in immune-mediated liver injury. However, the mechanism of KCs polarization in TCE-induced immune liver injury has not been thoroughly elucidated. In this study, we investigated the effect of TCE-induced KCs polarization on liver function and signal transduction pathways using the TCE sensitization model developed by our group. BALB/c mouse skin was exposed to TCE for sensitization, and an increase in the expression of M1 macrophage-specific markers (CD16/CD32, iNOS), M1 macrophage-specific cytokines IL-1ß, and IFN-γ, P-JAK-1 and P-STAT1 levels were also found to be dramatically increased. When using low doses of gadolinium trichloride (GdCl3), the expression of these proteins and mRNA was significantly reduced. This phenomenon indicates that GdCl3 blocks TCE-induced polarization of KCs and suggests that the IFN-γ/STAT1 signaling pathway may be involved in the polarization process of KCs. These findings clarify the relationship between the polarization of KCs and immune liver injury and highlight the importance of further study of immune-mediated liver injury in TCE-sensitized mice.

Point Siamese Network for Person Tracking Using 3D Point Clouds.

Person tracking is an important issue in both computer vision and robotics. However, most existing person tracking methods using 3D point cloud are based on the Bayesian Filtering framework which are not robust in challenging scenes. In contrast with the filtering methods, in this paper, we propose a neural network to cope with person tracking using only 3D point cloud, named Point Siamese Network (PSN). PSN consists of two input branches named template and search, respectively. After finding the target person (by reading the label or using a detector), we get the inputs of the two branches and create feature spaces for them using feature extraction network. Meanwhile, a similarity map based on the feature space is proposed between them. We can obtain the target person from the map. Furthermore, we add an attention module to the template branch to guide feature extraction. To evaluate the performance of the proposed method, we compare it with the Unscented Kalman Filter (UKF) on 3 custom labeled challenging scenes and the KITTI dataset. The experimental results show that the proposed method performs better than UKF in robustness and accuracy and has a real-time speed. In addition, we publicly release our collected dataset and the labeled sequences to the research community.

Combinations of Small RNA, RNA, and Degradome Sequencing Uncovers the Expression Pattern of microRNA⁻mRNA Pairs Adapting to Drought Stress in Leaf and Root of Dactylis glomerata L.

Drought stress is a global problem, and the lack of water is a key factor that leads to agricultural shortages. MicroRNAs play a crucial role in the plant drought stress response; however, the microRNAs and their targets involved in drought response have not been well elucidated. In the present study, we used Illumina platform (https://www.illumina.com/) and combined data from miRNA, RNA, and degradome sequencing to explore the drought- and organ-specific miRNAs in orchardgrass (Dactylis glomerata L.) leaf and root. We aimed to find potential miRNA⁻mRNA regulation patterns responding to drought conditions. In total, 519 (486 conserved and 33 novel) miRNAs were identified, of which, 41 miRNAs had significant differential expression among the comparisons (p < 0.05). We also identified 55,366 unigenes by RNA-Seq, where 12,535 unigenes were differently expressed. Finally, our degradome analysis revealed that 5950 transcripts were targeted by 487 miRNAs. A correlation analysis identified that miRNA ata-miR164c-3p and its target heat shock protein family A (HSP70) member 5 gene comp59407_c0 (BIPE3) may be essential in organ-specific plant drought stress response and/or adaptation in orchardgrass. Additionally, Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) analyses found that "antigen processing and presentation" was the most enriched downregulated pathway in adaptation to drought conditions. Taken together, we explored the genes and miRNAs that may be involved in drought adaptation of orchardgrass and identified how they may be regulated. These results serve as a valuable genetic resource for future studies focusing on how plants adapted to drought conditions.

Genome-wide association study of rust traits in orchardgrass using SLAF-seq technology.

BACKGROUND: While orchardgrass (Dactylis glomerata L.) is a well-known perennial forage species, rust diseases cause serious reductions in the yield and quality of orchardgrass; however, genetic mechanisms of rust resistance are not well understood in orchardgrass. RESULTS: In this study, a genome-wide association study (GWAS) was performed using specific-locus amplified fragment sequencing (SLAF-seq) technology in orchardgrass. A total of 2,334,889 SLAF tags were generated to produce 2,309,777 SNPs. ADMIXTURE analysis revealed unstructured subpopulations for 33 accessions, indicating that this orchardgrass population could be used for association analysis. Linkage disequilibrium (LD) analysis revealed an average r2 of 0.4 across all SNP pairs, indicating a high extent of LD in these samples. Through GWAS, a total of 4,604 SNPs were found to be significantly (P < 0.01) associated with the rust trait. The bulk analysis discovered a number of 5,211 SNPs related to rust trait. Two candidate genes, including cytochrome P450, and prolamin were implicated in disease resistance through prediction of functional genes surrounding each high-quality SNP (P < 0.01) associated with rust traits based on GWAS analysis and bulk analysis. CONCLUSIONS: The large number of SNPs associated with rust traits and these two candidate genes may provide the basis for further research on rust resistance mechanisms and marker-assisted selection (MAS) for rust-resistant lineages.

C5b-9 promotes ferritinophagy leading to ferroptosis in renal tubular epithelial cells of trichloroethylene-sensitized mice.

Trichloroethylene (TCE) is a common environmental contaminant that can cause a severe allergic reaction called TCE hypersensitivity syndrome, which often implicates the patient's kidneys. Our previous study revealed that C5b-9-induced tubular ferroptosis is involved in TCE-caused kidney damage. However, the study did not explain how tubule-specific C5b-9 causes free iron overload, a key event in ferroptosis. Here, we aimed to explore the role of NCOA4-mediated ferritinophagy in C5b-9-induced iron overload and ferroptosis in TCE-sensitized mice. Our results showed that TCE sensitization does not affect iron import or export, but does affect iron storage, causing ferritin degradation and free iron overload. In addition, mitochondrial ROS was upregulated, and these changes were blocked by C5b-9 inhibition. Interestingly, TCE-induced ferritin degradation and ferroptosis were significantly antagonized by the application of the mitochondrial ROS inhibitor, Mito-TEMPO. Moreover, all of these modes of action were further verified in C5b-9-attack signalling HK-2 cells. Further investigation demonstrated that C5b-9-upregulated mitochondrial ROS induced a marked increase in nuclear receptor coactivator 4 (NCOA4), a master regulator of ferritinophagy. In addition, the application of NCOA4 small interfering RNA not only significantly reversed ferritinophagy caused by C5b-9 but also reduced C5b-9-induced ferroptosis in HK-2 cells. Taken together, these results suggest that tubule-specific C5b-9 deposition activates NCOA4 through the upregulation of mitochondrial ROS, causing ferritin degradation and elevated free iron, which ultimately leads to tubular epithelial cell ferroptosis and kidney injury in TCE-sensitized mice.

C5a/C5aR1 axis as a key driver promotes epithelial-to-mesenchymal transition in airway epithelial cells in silica nanoparticles-induced pulmonary fibrosis.

Previous studies have shown that silica nanoparticles (SiNPs) exposure can affect the respiratory, cardiovascular, reproductive and other systems, with the lung being the primary target organ for the direct effect, causing damage with a central feature of pulmonary inflammation and fibrosis. However, the underlying mechanisms of pulmonary fibrosis due to SiNPs are not fully understood. The aim of the study was to investigate the role of complement anaphylatoxin C5a in SiNPs-induced pulmonary fibrosis. A mouse model of SiNPs-induced pulmonary fibrosis was established, and pulmonary fibrosis-related indicators, epithelial-to-mesenchymal transition (EMT), C5a/C5aR1 and high mobility group protein B1 (HMGB1) proteins were measured. An in vitro study using the human lung epithelial cell line BEAS-2B investigated whether C5a leads to epithelial-to-mesenchymal trans-differentiation. In vivo studies revealed that SiNPs-induced pulmonary fibrosis mainly manifested as EMT trans-differentiation in airway epithelial cells, which subsequently led to excessive deposition of extracellular matrix (ECM). Furthermore, we found that C5a and C5aR1 proteins were also increased in SiNPs-induced pulmonary fibrosis tissue. In vitro studies also showed that C5a directly activated HMGB1/RAGE signaling and induced EMT in BEAS-2B cells. Finally, treatment of SiNPs-exposed mice with the C5aR1 inhibitor PMX205 effectively reduced C5aR1 levels and inhibited the activation of HMGB1/RAGE signaling and the expression of EMT-related proteins, culminating in a significant alleviation of pulmonary fibrosis. Taken together, our results suggest that C5a/C5aR1 is the main signaling pathway for SiNPs-induced pulmonary fibrosis, which induces EMT in airway epithelial cells via the HMGB1/RAGE axis.

Rural Post-Earthquake Resettlement Mode Choices: Empirical Case Studies of Sichuan, China.

Earthquakes occur frequently in rural areas of Sichuan, China, causing huge damage and high mortality. The built environment plays a significant role in providing residents with safe and resilient settlements in such areas. There is yet little research on how rural families in developing countries cope with geological disasters like earthquakes, and how built environmental factors would influence their resettlement choices which would directly affect their quality of life afterward. Urban planning activities should be accompanied by these insights to design and create human-centric resettlements accordingly. In this study, the resettlement choices after three major earthquakes in Sichuan were studied for this reason. Random sampling and face-to-face questionnaire surveys were combined with factor analysis and binary logistic regression to understand the resettlement modes desired by the residents and the influencing factors. The results show that residents who have lived in their current places long and whose houses were not built recently are more likely to choose the in-situ resettlement. Accessibility to employment and public services has a significant impact on residents' choice of in-situ resettlement or reallocated resettlement, and so does the previous resettlement experience. The research results can provide useful suggestions for Chinese rural area post-earthquake resettlement planning following a human-centric approach with empirical data.

Renal tubular in TCE-sensitization-induced immune kidney injury: Role of mitochondrial DNA in activating the cGAS-STING signaling pathway.

Occupational medicamentose-like dermatitis due to trichloroethylene (OMDT) is a systemic allergic disease similar to drug eruption-like dermatitis that occurs in workers after exposure to trichloroethylene. In addition to skin and mucosa damage, OMDT patients often accompanied by severe multiorgan damage, including kidney injury. However, the mechanism remains unclear. The aim of our research was to explore the role of increased cytosolic mitochondrial DNA in the activation of cGAS-STING signaling and in the kidney injury of trichloroethylene sensitization mice using a mouse model and an in vitro model. By analyzing the kidneys of TCE-sensitized mice, we found obvious tubular mitochondrial damage, decreased expression of COX-IV and TFAM proteins and increased cytosolic mitochondrial DNA in TCE-sensitized-positive mice. Further study found that cytosolic mitochondrial DNA activated cGAS-STING signaling, resulting in the nuclear translocation of P-IRF3 and NF-κB P65 and the transcription and synthesis of type Ⅰ interferons and cytokines, which ultimately led to immune kidney injury in trichloroethylene-sensitized mice. Interestingly, pretreatment with C-176, a STING inhibitor, not only blocked the nuclear translocation of P-IRF3 and NF-κB P65, but also alleviated the kidney injury induced by TCE sensitization. Consistently, in vitro studies also found that mitochondrial DNA pretreatment can activate the cGAS-STING pathway, causing the nuclear translocation of P-IRF3 and NF-κB P65 and the transcription of type Ⅰ interferons and cytokines in HK-2 cells. Overall, our results suggested that cytosolic mitochondrial DNA plays an important role in the activation of the cGAS-STING pathway and TCE sensitization-induced immune kidney injury.

Altered Intra- and Inter-regional Functional Connectivity of the Anterior Cingulate Gyrus in Patients With Tremor-Dominant Parkinson's Disease Complicated With Sleep Disorder.

Objective: To investigate changes in brain function at the regional and whole-brain levels in patients with tremor-dominant Parkinson's disease (TDPD) complicated by sleep disorder (SD) by regional homogeneity (ReHo) and functional connectivity (FC) analysis of whole-brain resting-state functional magnetic resonance images. Materials and Methods: ReHo and seed-based FC analyses were conducted among 32 patients with TDPD and SD (TDPD-SD), 24 with TDPD and no SD (TDPD-NSD), and 23 healthy controls (HCs) to assess spontaneous brain activity and network-level brain function. Correlation analyses were used to examine the associations between brain activity and the clinical data. Results: Anterior cingulate gyrus (ACC) ReHo values differed significantly among the groups. ACC ReHo values were increased in TDPD-SD vs. HC and TDPD-SD vs. TDPD-NSD. ACC ReHo values were reduced in TDPD-NSD vs. HC. TDPD-SD ReHo values were positively correlated with Pittsburgh Sleep Quality Index (PSQI) scores (r = 0.41, p = 0.020) but negatively correlated with Parkinson's Disease Sleep Scale (PDSS) scores (r = -0.38, p = 0.030). FC analysis using ACC as a mask showed that FC of the left olfactory cortex (L-OC), right straight gyrus (R-SG), right superior parietal gyrus (R-SPG), and right precuneus differed significantly among the groups. FC values between R-SG and ACC were significantly lower in TDPD-SD than in TDPD-NSD, while the FC of L-OC and R-OC with ACC was significantly lower in TDPD-SD than in HC. FC between ACC and L-OC, R-SPG, and the right precuneus was lower in TDPD-NSD than in HC. There was no correlation between the FC values and other clinical data in any of the groups. Conclusion: Localized abnormal activity in TDPD-SD was chiefly triggered by ACC. The change in the ReHo of ACC is closely related to the severity of TDPD-associated SD, revealing the role of this region as a regulator of the sleep mechanism in TDPD. Significant abnormal FC was found between R-SG and ACC in TDPD-SD but was not shown to correlate with clinical data.

Outcome prediction for patients with anterior circulation acute ischemic stroke following endovascular treatment: A single-center study.

Previous studies have identified various factors associated with the outcomes of acute ischemic stroke (AIS) but considered only 1 or 2 predictive factors. The present study aimed to use outcome-related factors derived from biochemical, imaging and clinical data to establish a logistic regression model that can predict the outcome of patients with AIS following endovascular treatment (EVT). The data of 118 patients with anterior circulation AIS (ACAIS) who underwent EVT between October 2014 and August 2018 were retrospectively analyzed. The patients were divided into 2 groups based on the modified Rankin Scale score at three months after surgery, where 0-2 points were considered to indicate a favorable outcome and 3-6 points were considered a poor outcome. Non-conditional logistic stepwise regression was used to identify independent variables that were significantly associated with patient outcome, which were subsequently used to establish a predictive statistical model, receiver operating characteristic (ROC) curve was used to show the performance of statistical model and analyze the specific association between each factor and outcome. Among the 118 patients, 47 (39.83%) exhibited a good and 71 (60.17%) exhibited a poor outcome. Multivariate analysis revealed that the predictive model was statistically significant (χ2=78.92; P<0.001), and that the predictive accuracy of the model was 83.1%, which was higher compared with that obtained using only a single factor. ROC curve analysis shows the area under curve of the statistical model was 0.823, the analysis of diagnostic threshold for prognostic factors indicated that age, diffusion-weighted imaging lesion volume, glucose on admission, National Institutes of Health Stroke Scale score on admission and hypersensitive C-reactive protein were valuable predictive factors for the outcome of EVT (P<0.05). In conclusion, a predictive model based on non-conditional logistic stepwise regression analysis was able to predict the outcome of EVT for patients with ACAIS.

Genome-wide survey of switchgrass NACs family provides new insights into motif and structure arrangements and reveals stress-related and tissue-specific NACs.

NAC proteins comprise of a plant-specific transcription factor (TF) family and play important roles in plant development and stress responses. Switchgrass (Panicum virgatum) is the prime candidate and model bioenergy grass across the world. Excavating agronomically valuable genes is important for switchgrass molecular breeding. In this study, a total of 251 switchgrass NAC (PvNACs) family genes clustered into 19 subgroups were analyzed, and those potentially involved in stress response or tissue-specific expression patterns were pinpointed. Specifically, 27 PvNACs were considered as abiotic stress-related including four membrane-associated ones. Among 40 tissue-specific PvNACs expression patterns eight factors were identified that might be relevant for lignin biosynthesis and/or secondary cell wall formation. Conserved functional domains and motifs were also identified among the PvNACs and potential association between these motifs and their predicted functions were proposed, that might encourage experimental studies to use PvNACs as possible targets to improve biomass production and abiotic stress tolerance.

M2 tumour-associated macrophages contribute to tumour progression via legumain remodelling the extracellular matrix in diffuse large B cell lymphoma.

Effects of M2 tumour-associated macrophages on the pathogenesis of diffuse large B cell lymphoma (DLBCL) are still controversial. Our data showed that the number of CD163-positive M2 macrophages correlated negatively with DLBCL prognosis. Macrophage depletion by clodronate liposomes significantly suppressed tumour growth in a xenograft mouse model of DLBCL using OCI-Ly3 cells. Moreover, M2 polarization of macrophages induced legumain expression in U937 cells. Exogenous legumain promoted degradation of fibronectin and collagen I, which was abolished by administration of a legumain inhibitor RR-11a. Overexpression of legumain in Raw 264.7 cells also induced tube formation of endothelial cells in matrigel. In the xenograft mouse model of DLBCL, decreased fibronectin and collagen I, as well as increased legumain expression and angiogenesis were found at the late stage tumours compared with early stage tumours. Co-localization of legumain and fibronectin was observed in the extracellular matrix of tumour tissues. Administration of the legumain inhibitor to the xenograft DLBCL model suppressed tumour growth, angiogenesis and collagen deposition compared with the control. Taken together, our results suggest that M2 tumour-associated macrophages affect degradation of the extracellular matrix and angiogenesis via overexpression of legumain, and therefore play an active role in the progression of DLBCL.