Hepatic GDP-fucose transporter SLC35C1 attenuates cholestatic liver injury and inflammation by inducing CEACAM1 N153 fucosylation.

BACKGROUND AND AIMS: Inflammatory response is crucial for bile acid (BA)-induced cholestatic liver injury, but molecular mechanisms remain to be elucidated. Solute Carrier Family 35 Member C1 (SLC35C1) can transport GDP-fucose into the Golgi to facilitate protein glycosylation. Its mutation leads to the deficiency of leukocyte adhesion and enhances inflammation in humans. However, little is known about its role in liver diseases. APPROACH AND RESULTS: Hepatic SLC35C1 mRNA transcripts and protein expression were significantly increased in patients with obstructive cholestasis (OC) and mouse models of cholestasis. Immunofluorescence revealed that the upregulated SLC35C1 expression mainly occurred in hepatocytes. Liver-specific ablation of Slc35c1 (Slc35c1 cKO) significantly aggravated liver injury in mouse models of cholestasis induced by bile duct ligation and 1% cholic acid-feeding, evidenced by increased liver necrosis, inflammation, fibrosis, and bile ductular proliferation. The Slc35c1 cKO increased hepatic chemokine Ccl2 and Cxcl2 expression and T-cell, neutrophil and F4/80 macrophage infiltration, but did not affect the levels of serum and liver BA in mouse models of cholestasis. LC-MS/MS analysis revealed that hepatic Slc35c1 deficiency substantially reduced the fucosylation of cell-cell adhesion protein CEACAM1 at N153. Mechanistically, cholestatic levels of conjugated BAs stimulated SLC35C1 expression by activating the STAT3 signaling to facilitate CEACAM1 fucosylation at N153, and deficiency in the fucosylation of CEACAM1 at N135 enhanced the BA-stimulated CCL2 and CXCL2 mRNA expression in primary mouse hepatocytes and PLC/PRF/5-ASBT cells. CONCLUSIONS: Elevated hepatic SLC35C1 expression attenuates cholestatic liver injury by enhancing CEACAM1 fucosylation to suppress CCL2 and CXCL2 expression and liver inflammation.

Runt-related transcription factor-1 ameliorates bile acid-induced hepatic inflammation in cholestasis through JAK/STAT3 signaling.

BACKGROUND AND AIMS: Bile acids trigger a hepatic inflammatory response, causing cholestatic liver injury. Runt-related transcription factor-1 (RUNX1), primarily known as a master modulator in hematopoiesis, plays a pivotal role in mediating inflammatory responses. However, RUNX1 in hepatocytes is poorly characterized, and its role in cholestasis is unclear. Herein, we aimed to investigate the role of hepatic RUNX1 and its underlying mechanisms in cholestasis. APPROACH AND RESULTS: Hepatic expression of RUNX1 was examined in cholestatic patients and mouse models. Mice with liver-specific ablation of Runx1 were generated. Bile duct ligation and 1% cholic acid diet were used to induce cholestasis in mice. Primary mouse hepatocytes and the human hepatoma PLC/RPF/5- ASBT cell line were used for mechanistic studies. Hepatic RUNX1 mRNA and protein levels were markedly increased in cholestatic patients and mice. Liver-specific deletion of Runx1 aggravated inflammation and liver injury in cholestatic mice induced by bile duct ligation or 1% cholic acid feeding. Mechanistic studies indicated that elevated bile acids stimulated RUNX1 expression by activating the RUNX1 -P2 promoter through JAK/STAT3 signaling. Increased RUNX1 is directly bound to the promotor region of inflammatory chemokines, including CCL2 and CXCL2 , and transcriptionally repressed their expression in hepatocytes, leading to attenuation of liver inflammatory response. Blocking the JAK signaling or STAT3 phosphorylation completely abolished RUNX1 repression of bile acid-induced CCL2 and CXCL2 in hepatocytes. CONCLUSIONS: This study has gained initial evidence establishing the functional role of hepatocyte RUNX1 in alleviating liver inflammation during cholestasis through JAK/STAT3 signaling. Modulating hepatic RUNX1 activity could be a new therapeutic target for cholestasis.

Semaphorin 7A interacts with nuclear factor NF-kappa-B p105 via integrin ß1 and mediates inflammation.

Semaphorin7a (SEMA7A), a membrane-anchored member of the semaphorin protein family, could be involved in a diverse range of immune responses via its receptor integrin ß1. Recently, we reported that the SEMA7AR148W mutation (a gain-of-function mutation, Sema7aR145W in mice) is a risk factor for progressive familial intrahepatic cholestasis and nonalcoholic fatty liver disease via upregulated membrane localization. In this study, we demonstrated that integrin ß1 is a membrane receptor for nuclear factor NF-kappa-B p105 (NF-κB p105) and a critical mediator of inflammation. Integrin ß1 could interact with the C-terminal domain of NF-κB p105 to promote p50 generation and stimulate the NF-κB p50/p65 signalling pathway, upregulate TNF-α and IL-1ß levels, and subsequently render hepatocytes more susceptible to inflammation. The induction of integrin ß1 depends on elevated Sema7a membrane localization. Moreover, we revealed elevated levels of Sema7aWT (SEMA7AWT) in hepatocellular carcinoma (HCC) patients and an HCC mouse model. In line with our findings, the NF-κB p50/p65 pathway could also be activated by high Sema7a expression and repressed by integrin ß1 silencing. In conclusion, our findings suggest that the Sema7aR145W (SEMA7AR148W) mutation and high Sema7aWT (SEMA7AWT) expression both activate the NF-κB p50/p65 pathway via integrin ß1 and play a crucial role in inflammatory responses. Video Abstract.

Novel urinary protein panels for the non-invasive diagnosis of non-alcoholic fatty liver disease and fibrosis stages.

BACKGROUND & AIMS: There is an unmet clinical need for non-invasive tests to diagnose non-alcoholic fatty liver disease (NAFLD) and individual fibrosis stages. We aimed to test whether urine protein panels could be used to identify NAFLD, NAFLD with fibrosis (stage F ≥ 1) and NAFLD with significant fibrosis (stage F ≥ 2). METHODS: We collected urine samples from 100 patients with biopsy-confirmed NAFLD and 40 healthy volunteers, and proteomics and bioinformatics analyses were performed in this derivation cohort. Diagnostic models were developed for detecting NAFLD (UPNAFLD model), NAFLD with fibrosis (UPfibrosis model), or NAFLD with significant fibrosis (UPsignificant fibrosis model). Subsequently, the derivation cohort was divided into training and testing sets to evaluate the efficacy of these diagnostic models. Finally, in a separate independent validation cohort of 100 patients with biopsy-confirmed NAFLD and 45 healthy controls, urinary enzyme-linked immunosorbent assay analyses were undertaken to validate the accuracy of these new diagnostic models. RESULTS: The UPfibrosis model and the UPsignificant fibrosis model showed an AUROC of .863 (95% CI: .725-1.000) and 0.858 (95% CI: .712-1.000) in the training set; and .837 (95% CI: .711-.963) and .916 (95% CI: .825-1.000) in the testing set respectively. The UPNAFLD model showed an excellent diagnostic performance and the area under the receiver operator characteristic curve (AUROC) exceeded .90 in the derivation cohort. In the independent validation cohort, the AUROC for all three of the above diagnostic models exceeded .80. CONCLUSIONS: Our newly developed models constructed from urine protein biomarkers have good accuracy for non-invasively diagnosing liver fibrosis in NAFLD.

Gut Microbiota Deficiency Exacerbates Liver Injury in Bile Duct Ligated Mice via Inflammation and Lipid Metabolism.

Bile components play a critical role in maintaining gut microbiota homeostasis. In cholestasis, bile secretion is impaired, leading to liver injury. However, it remains to be elucidated whether gut microbiota plays a role in cholestatic liver injury. Here, we performed a sham operation and bile duct ligation (BDL) in antibiotic-induced microbiome depleted (AIMD) mice and assessed liver injury and fecal microbiota composition in these mice. Significant reductions in gut microbiota richness and diversity were found in AIMD-sham mice when compared to sham controls. Three-day BDL leads to great elevation of plasma ALT, ALP, total bile acids, and bilirubin where reduced diversity of the gut microbiota was also found. AIMD further aggravated cholestatic liver injury evidenced by significantly higher levels of plasma ALT and ALP, associated with further reduced diversity and increased Gram-negative bacteria in gut microbiota. Further analyses revealed increased levels of LPS in the plasma of AIMD-BDL mice where elevated expression of inflammatory genes and decreased expression of hepatic detoxification enzymes were also found in liver when compared to the BDL group. These findings indicate that gut microbiota plays a critical role in cholestatic liver injury. Maintaining its homeostasis may alleviate liver injury in patients with cholestasis.

DiT-SLAM: Real-Time Dense Visual-Inertial SLAM with Implicit Depth Representation and Tightly-Coupled Graph Optimization.

Recently, generating dense maps in real-time has become a hot research topic in the mobile robotics community, since dense maps can provide more informative and continuous features compared with sparse maps. Implicit depth representation (e.g., the depth code) derived from deep neural networks has been employed in the visual-only or visual-inertial simultaneous localization and mapping (SLAM) systems, which achieve promising performances on both camera motion and local dense geometry estimations from monocular images. However, the existing visual-inertial SLAM systems combined with depth codes are either built on a filter-based SLAM framework, which can only update poses and maps in a relatively small local time window, or based on a loosely-coupled framework, while the prior geometric constraints from the depth estimation network have not been employed for boosting the state estimation. To well address these drawbacks, we propose DiT-SLAM, a novel real-time Dense visual-inertial SLAM with implicit depth representation and Tightly-coupled graph optimization. Most importantly, the poses, sparse maps, and low-dimensional depth codes are optimized with the tightly-coupled graph by considering the visual, inertial, and depth residuals simultaneously. Meanwhile, we propose a light-weight monocular depth estimation and completion network, which is combined with attention mechanisms and the conditional variational auto-encoder (CVAE) to predict the uncertainty-aware dense depth maps from more low-dimensional codes. Furthermore, a robust point sampling strategy introducing the spatial distribution of 2D feature points is also proposed to provide geometric constraints in the tightly-coupled optimization, especially for textureless or featureless cases in indoor environments. We evaluate our system on open benchmarks. The proposed methods achieve better performances on both the dense depth estimation and the trajectory estimation compared to the baseline and other systems.

Reference ranges of T lymphocyte subsets by single-platform among healthy population in southwest China.

BACKGROUND: Appropriate reference ranges of T lymphocyte subsets are essential for immune status evaluation of patients with immunological diseases. We aim to establish the age- and sex-related reference intervals of T lymphocyte subsets by single-platform for the southwest China population using the indirect method with the data resulting from 53,822 cases of periodic health examination individuals in the Laboratory Information System (LIS) of West China Hospital from 2018 to 2020. METHODS: We used the Box-Cox conversion combined with the Tukey method to normalize the data and eliminate the outliers, and the nonparametric method to estimate the 95% distribution reference intervals. RESULTS: We initially established the reference ranges of T lymphocyte subsets by single-platform among healthy population in southwest China by indirect method (See text for details). Using the standard normal deviate test (z-test) suggested by Harris and Boyd according to CLSI EP28-A3C, which is more scientific, we found the reference ranges of T lymphocyte subsets should be differentiated by ages and genders since the reference ranges of T lymphocyte subsets by single-platform in different ages and genders are significantly different. CONCLUSIONS: We further demonstrated the absolute count of CD3 + T cell, CD3 + CD4 + T cell, CD3 + CD8 + T cell decreased with aging, which is more marked in men and CD3 + CD8 + T cell count, and the obtained reference intervals were superior to the reference intervals derived from the reagent specification currently in use.

Solute Carrier Organic Anion Transporter Family Member 3A1 Is a Bile Acid Efflux Transporter in Cholestasis.

BACKGROUND & AIMS: Bile acid transporters maintain bile acid homeostasis. Little is known about the functions of some transporters in cholestasis or their regulatory mechanism. We investigated the hepatic expression of solute carrier organic anion transporter family member 3A1 (SLCO3A1, also called OATP3A1) and assessed its functions during development of cholestasis. METHODS: We measured levels of OATP3A1 protein and messenger RNA and localized the protein in liver tissues from 22 patients with cholestasis and 21 patients without cholestasis, using real-time quantitative polymerase chain reaction, immunoblot, and immunofluorescence analyses. We performed experiments with Slco3a1-knockout and C57BL/6J (control) mice. Mice and Sprague-Dawley rats underwent bile duct ligation (BDL) or a sham operation. Some mice were placed on a 1% cholic acid (CA) diet to induce cholestasis or on a control diet. Serum and liver tissues were collected and analyzed; hepatic levels of bile acids and 7-α-C4 were measured using liquid chromatography/mass spectrometry. Human primary hepatocytes and hepatoma (PLC/PRF/5) cell lines were used to study mechanisms that regulate OATP3A1 expression and transport. RESULTS: Hepatic levels of OATP3A1 messenger RNA and protein were significantly increased in liver tissues from patients with cholestasis and from rodents with BDL or 1% CA diet-induced cholestasis. Levels of fibroblast growth factor 19 (FGF19, FGF15 in rodents) were also increased in liver tissues from patients and rodents with cholestasis. FGF19 signaling activated the Sp1 transcription factor and nuclear factor κB to increase expression of OATP3A1 in hepatocytes; we found binding sites for these factors in the SLCO3A1 promoter. Slco3a1-knockout mice had shorter survival times and increased hepatic levels of bile acid, and they developed more liver injury after the 1% CA diet or BDL than control mice. In hepatoma cell lines, we found OATP3A1 to take prostaglandin E2 and thyroxine into cells and efflux bile acids. CONCLUSIONS: We found levels of OATP3A1 to be increased in cholestatic liver tissues from patients and rodents compared with healthy liver tissues. We show that OATP3A1 functions as a bile acid efflux transporter that is up-regulated as an adaptive response to cholestasis.

Ablation of caspase-1 protects against TBI-induced pyroptosis in vitro and in vivo.

BACKGROUND: Traumatic brain injury (TBI) is a critical public health and socioeconomic problem throughout the world. Inflammation-induced secondary injury is one of the vital pathogenic parameters of TBI. Molecular signaling cascades of pyroptosis, a specific type of cellular necrosis, are key drivers of TBI-induced inflammation. METHODS: In this study, mice with genetically ablated caspase-1 (caspase-1-/-) were subjected to controlled cortical impact injury in vivo, and primary neuron deficient in caspase-1 through siRNA knockdown and pharmacologic inhibition was stimulated by mechanical scratch, equiaxial stretch, and LPS/ATP in vitro. We evaluated the effects of caspase-1 deficiency on neurological deficits, inflammatory factors, histopathology, cell apoptosis, and pyroptosis. RESULTS: During the acute post-injury period (0-48 h) in vivo, motor deficits, anti-inflammatory cytokines (TGF-ß and IL-10), pro-inflammatory cytokines (IFN-γ, IL-1ß, and IL-18), and blood lactate dehydrogenase (LDH), as well as pyroptosis-related proteins (caspase-1, caspase-1 fragments, caspase-11 and GSDMD), were increased. Caspase-1 was activated in the cortex of TBI mice. Inflammatory activation was more profound in injured wild-type mice than in caspase-1-/- mice. In vitro, mechanical scratch, equiaxial stretch, and LPS/ATP-induced neuron pyroptosis, apoptosis, LDH release, and increased expression of inflammatory factors. The effects of mechanical and inflammatory stress were reduced through inhibition of caspase-1 activity through siRNA knockdown and pharmacologic inhibition. CONCLUSION: Collectively, these data demonstrate that pyroptosis is involved in neuroinflammation and neuronal injury after TBI, and ablation of caspase-1 inhibits TBI-induced pyroptosis. Our findings suggest that caspase-1 may be a potential target for TBI therapy.

Automatic seizure detection using three-dimensional CNN based on multi-channel EEG.

BACKGROUND: Automated seizure detection from clinical EEG data can reduce the diagnosis time and facilitate targeting treatment for epileptic patients. However, current detection approaches mainly rely on limited features manually designed by domain experts, which are inflexible for the detection of a variety of patterns in a large amount of patients' EEG data. Moreover, conventional machine learning algorithms for seizure detection cannot accommodate multi-channel Electroencephalogram (EEG) data effectively, which contains both temporal and spatial information. Recently, deep learning technology has been widely applied to perform image processing tasks, which could learns useful features from data and process multi-channel data automatically. To provide an effective system for automatic seizure detection, we proposed a new three-dimensional (3D) convolutional neural network (CNN) structure, whose inputs are multi-channel EEG signals. METHODS: EEG data of 13 patients were collected from one center hospital, which has already been inspected by experts. To represent EEG data in CNN, firstly time series of each channel of EEG data was converted into the two-dimensional image. Then all channel images were combined into 3D images according to the mutual correlation intensity between different electrodes. Finally, a CNN was constructed using 3D kernels to predict different stages of EEG data, including inter-ictal, pre-ictal, and ictal stages. The system performance was evaluated and compared with the traditional feature-based classifier and the two-dimensional (2D) deep learning method. RESULTS: It demonstrated that multi-channel EEG data could provide more information for increasing the specificity and sensitivity in cpmparison result between the single and multi-channel. And the 3D CNN based on multi-channel outperformed the 2D CNN and traditional signal processing methods with an accuracy of more than 90%, an sensitivity of 88.90% and an specificity of 93.78%. CONCLUSIONS: This is the first effort to apply 3D CNN in detecting seizures from EEG. It provides a new way of learning patterns simultaneously from multi-channel EEG signals, and demonstrates that deep neural networks in combination with 3D kernels can establish an effective system for seizure detection.

WITHDRAWN: The role of TNFα in promoting hepatic MRP4 expression via the p38-Rb-E2F1 pathway in human obstructive cholestasis.

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Canalicular membrane MRP2/ABCC2 internalization is determined by Ezrin Thr567 phosphorylation in human obstructive cholestasis.

BACKGROUND & AIMS: Multidrug resistance-associated protein 2 (MRP2) excretes conjugated organic anions including bilirubin and bile acids. Malfunction of MRP2 leads to jaundice in patients. Studies in rodents indicate that Radixin plays a critical role in determining Mrp2 canalicular membrane expression. However, it is not known how human hepatic MRP2 expression is regulated in cholestasis. METHODS: We assessed liver MRP2 expression in patients with obstructive cholestasis caused by gallstone blockage of bile ducts, and investigated the regulatory mechanism in HepG2 cells. RESULTS: Western blot detected that liver MRP2 protein expression in obstructive cholestatic patients (n=30) was significantly reduced to 25% of the non-cholestatic controls (n=23). Immunoprecipitation identified Ezrin but not Radixin associating with MRP2 in human livers, and the increased amount of phospho-Ezrin Thr567 was positively correlated with the amount of co-precipitated MRP2 in cholestatic livers, whereas Ezrin and Radixin total protein levels were unchanged in cholestasis. Further detailed studies indicate that Ezrin Thr567 phosphorylation plays an important role in MRP2 internalization in HepG2 cells. Since increased expression of PKCα, δ and ε were detected in these cholestatic livers, we further confirmed that these PKCs stimulated Ezrin phosphorylation and reduced MRP2 membrane expression in HepG2 cells. Finally, we identified GP78 as the key ubiquitin ligase E3 involved in MRP2 proteasome degradation. CONCLUSIONS: Activation of liver PKCs during cholestasis leads to Ezrin Thr567 phosphorylation resulting in MRP2 internalization and degradation where ubiquitin ligase E3 GP78 is involved. This process provides a mechanistic explanation for jaundice seen in patients with obstructive cholestasis.

[Genetic Polymorphisms in Wnt Signaling Pathway and Acute Leukemia].

OBJECTIVE: To determine the impacts of Wnt signaling pathway products-polymorphisms of rs4135385, rs11079571 and rs7832767 located in ß-catenin gene (CTNNB1), Axin gene (AXIN2), and secreted frizzled-related protein gene (SFRP1) on the risk and treatment outcomes of acute leukemia. METHODS: Bone marrows (volume 1-1. 5 mL) were collected from 372 untreated patients with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), and peripheral blood samples (2. 0 mL) were obtained from 401 healthy controls for the purpose of total DNA extraction. Polymorphisms of rs4135385, rs11079571 and rs7832767 located in CTNNB1, AXIN2 and SFRP1 were genotyped with high-resolution melting method (HRM). Chi-square analyses were performed to compare the genotype and allele distributions of the three single nucleotides (SNPs) between the leukemia patients and healthy controls. Single factor variance tests were performed to compare the differences in clinical features among different genotype groups. Complete remission (CR) rates after induction chemotherapy were also compared between different genotype groups using Chi-square tests. RESULTS: No significant differences were found beiween the leukemia patients and healthy controls in the frequencies of alleles and genotypes of CTNNB1 rs4135385, SFRP1 rs7832767 polymorphisms. Those with A allele in AXIN2 rs11079571 polymorphism was less likely to have acute myelomonocytic/monocytic leukemia than those with G allele (P = 0. 016, OR=0. 677, 95%CI:0. 439-0. 930). Acute bead monocyte/mononuclear cell leukemia (AML-M4/5)patients with AA genotype presented higher platelet count (P = 0. 040), and higher complete remission rate after chemotherapy (P = 0. 040), compared with the patients with AG and GG genotypes. CONCLUSION: AML-M4/5 patients have less frequency of A allele in AXIN2 rs11079571 polymorphism than healthy controls. Patients carrying A allele have higher platelet counts and higher sensitivity to chemotherapy.

AGDF-Net: Learning Domain Generalizable Depth Features With Adaptive Guidance Fusion.

Cross-domain generalizable depth estimation aims to estimate the depth of target domains (i.e., real-world) using models trained on the source domains (i.e., synthetic). Previous methods mainly use additional real-world domain datasets to extract depth specific information for cross-domain generalizable depth estimation. Unfortunately, due to the large domain gap, adequate depth specific information is hard to obtain and interference is difficult to remove, which limits the performance. To relieve these problems, we propose a domain generalizable feature extraction network with adaptive guidance fusion (AGDF-Net) to fully acquire essential features for depth estimation at multi-scale feature levels. Specifically, our AGDF-Net first separates the image into initial depth and weak-related depth components with reconstruction and contrary losses. Subsequently, an adaptive guidance fusion module is designed to sufficiently intensify the initial depth features for domain generalizable intensified depth features acquisition. Finally, taking intensified depth features as input, an arbitrary depth estimation network can be used for real-world depth estimation. Using only synthetic datasets, our AGDF-Net can be applied to various real-world datasets (i.e., KITTI, NYUDv2, NuScenes, DrivingStereo and CityScapes) with state-of-the-art performances. Furthermore, experiments with a small amount of real-world data in a semi-supervised setting also demonstrate the superiority of AGDF-Net over state-of-the-art approaches.

Evaluation of Self-Degradation and Plugging Performance of Temperature-Controlled Degradable Polymer Temporary Plugging Agent.

Temporary plugging diversion fracturing (TPDF) technology has been widely used in various oil fields for repeated reconstruction of high-water-cut old oil wells and horizontal well reservoir reconstruction. Previous studies have carried out in-depth study on the pressure-bearing law and placement morphology of different types of temporary plugging agents (TPAs) in fractures, but there are relatively few studies on TPA accumulation body permeability. To solve this problem, an experimental device for evaluating the TPA performance with adjustable fracture pores is proposed in this paper. Based on the test of fracturing fluid breaking time and residue content, the low damage of fracturing fluid to the reservoir is determined. The TPA degradation performance test determines whether the TPA causes damage to the hydraulic fracture after the temporary plugging fracturing. Finally, by testing the TPA pressure-bearing capacity and the temporary plugging aggregation body permeability, the plugging performance and the aggregation body permeability are determined. The results show the following: (1) Guar gum fracturing fluid shows good gel-breaking performance under the action of breaking agent, and the recommended concentration of breaking agent is 300 ppm. At 90~120 °C, the degradation rate of the three types of TPAs can reach more than 65%, and it can be effectively carried into the wellbore during the fracturing fluid flowback stage to achieve the effect of removing the TPA in the fracture. (2) The results of the pressure-bearing performance of the TPA show that the two kinds of TPAs can quickly achieve the plugging effect after plugging start: the effect of ZD-2 (poly lactic-co-glycolic acid (PLGA)) particle-and-powder combined TPA on forming an effective temporary plugging accumulation body in fractures is better than that of ZD-1 (PLGA) pure powder. There are large pores between the particles, and the fracturing fluid can still flow through the pores, so the ZD-3 (a mixture of lactide and PLGA) granular temporary plugging agent cannot form an effective plugging. (3) The law of length of the temporary plugging accumulation body shows that the ZD-2 combined TPA has stronger plugging ability for medium-aperture simulated fracture pores, while the ZD-1 powder TPA has stronger plugging ability for small aperture simulated fracture pores, and the ZD-3 granular TPA should be avoided alone as far as possible. This study further enriches and improves the understanding of the mechanism of temporary plugging diverting fracturing fluid.

Digging Into Uncertainty-Based Pseudo-Label for Robust Stereo Matching.

Due to the domain differences and unbalanced disparity distribution across multiple datasets, current stereo matching approaches are commonly limited to a specific dataset and generalize poorly to others. Such domain shift issue is usually addressed by substantial adaptation on costly target-domain ground-truth data, which cannot be easily obtained in practical settings. In this paper, we propose to dig into uncertainty estimation for robust stereo matching. Specifically, to balance the disparity distribution, we employ a pixel-level uncertainty estimation to adaptively adjust the next stage disparity searching space, in this way driving the network progressively prune out the space of unlikely correspondences. Then, to solve the limited ground truth data, an uncertainty-based pseudo-label is proposed to adapt the pre-trained model to the new domain, where pixel-level and area-level uncertainty estimation are proposed to filter out the high-uncertainty pixels of predicted disparity maps and generate sparse while reliable pseudo-labels to align the domain gap. Experimentally, our method shows strong cross-domain, adapt, and joint generalization and obtains 1st place on the stereo task of Robust Vision Challenge 2020. Additionally, our uncertainty-based pseudo-labels can be extended to train monocular depth estimation networks in an unsupervised way and even achieves comparable performance with the supervised methods.

TUSR-Net: Triple Unfolding Single Image Dehazing with Self-Regularization and Dual Feature to Pixel Attention.

Single image dehazing is a challenging and illposed problem due to severe information degeneration of images captured in hazy conditions. Remarkable progresses have been achieved by deep-learning based image dehazing methods, where residual learning is commonly used to separate the hazy image into clear and haze components. However, the nature of low similarity between haze and clear components is commonly neglected, while the lack of constraint of contrastive peculiarity between the two components always restricts the performance of these approaches. To deal with these problems, we propose an end-to-end self-regularized network (TUSR-Net) which exploits the contrastive peculiarity of different components of the hazy image, i.e, self-regularization (SR). In specific, the hazy image is separated into clear and hazy components and constraint between different image components, i.e., self-regularization, is leveraged to pull the recovered clear image closer to groundtruth, which largely promotes the performance of image dehazing. Meanwhile, an effective triple unfolding framework combined with dual feature to pixel attention is proposed to intensify and fuse the intermediate information in feature, channel and pixel levels, respectively, thus features with better representational ability can be obtained. Our TUSR-Net achieves better trade-off between performance and parameter size with weight-sharing strategy and is much more flexible. Experiments on various benchmarking datasets demonstrate the superiority of our TUSR-Net over state-of-the-art single image dehazing methods.

Hepatic TNFRSF12A promotes bile acid-induced hepatocyte pyroptosis through NFκB/Caspase-1/GSDMD signaling in cholestasis.

Tumor necrosis factor receptor superfamily member-12A (TNFRSF12A) plays a critical role in inflammation and cell death. It is expressed in multiple tissues yet extremely low in normal liver. To date, little is known about its role in cholestasis. Therefore, we sought to delineate the role of TNFRSF12A in cholestasis and its underlying mechanisms. Human liver tissues were collected from patients with obstructive cholestasis (OC) or primary biliary cholangitis (PBC). Tnfrsf12a knockout (KO) mice were generated. Cholestasis was induced by bile-duct ligation (BDL) or 0.1% 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-feeding. Human hepatoma PLC/PRF/5-ASBT and THP1 cell lines or primary mouse hepatocytes were used for mechanistic studies. Hepatic TNFRSF12A expression was markedly increased in OC or PBC patients. Genetic ablation of Tnfrsf12a in BDL- and 0.1%DDC-induced cholestatic mice significantly attenuated cholestatic liver injury with remarkable reduction of hepatocyte pyroptosis but without changing scores of necroptosis and apoptosis. Morphological features of hepatocyte pyroptosis and increased levels of pyroptosis-related proteins, NLRP3, cleaved-Caspase-1, and cleaved-GSDMD in OC patients and BDL-mice confirmed this observation. Further mechanistic studies revealed that bile acids (BAs) induced TNFRSF12A expression by enhancing the transcription factor c-JUN binding to the TNFRSF12A promoter and subsequently initiated hepatocyte pyroptosis by the NFκB/Caspase-1/GSDMD signaling. Interestingly, TWEAK, a typical ligand of TNFRSF12A, secreted by infiltrated macrophages in cholestatic livers, enhanced TNFRSF12A-induced hepatocyte pyroptosis. Taken together, we report, for the first time, that hepatic TNFRSF12A is dramatically increased in human cholestasis. Deletion of TNFRSF12A inhibits BAs-induced hepatocyte pyroptosis through the NFκB/Caspase-1/GSDMD signaling and thereby ameliorates cholestatic liver injury. As such, targeting TNFRSF12A could be a promising approach to treating cholestasis.