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Abstract Background Radiation-induced myelopathy (RM) is a significant complication of radiotherapy with its mechanisms still not fully understood and lacking effective treatments. Compound 7 (C7) is a newly identified, potent, and selective inhibitor of the Keap1-Nrf2 interaction. This study aimed to explore the protective effects and mechanisms of C7 on RM in vitro and in vivo. Methods Western blotting, quantitative real‐time polymerase chain reaction (qRT‐PCR), reactive oxygen species (ROS) and mitochondrial polarization, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, genetic editing techniques, locomotor functions, and tissue staining were employed to explore the protective effects and underlying mechanisms of C7 in radiation-induced primary rat microglia and BV2 cells, as well as RM rat models. Results In this study, we found that C7 inhibited the production of pro-inflammation cytokines and oxidative stress induced by irradiation in vitro. Further, the data revealed that radiation worsened the locomotor functions in rats, and C7 significantly improved histological and functional recovery in RM rats. Mechanically, C7 activated Nrf2 signaling and promoted the microglia transformation from M1 to M2 phenotype. Conclusion C7 could ameliorate RM by boosting Nrf2 signaling and promoting M2 phenotype microglia polarization in vitro and in vivo.

Abstract Background/Purpose Risk factors for re-bleeding and death after acute variceal bleeding (AVB) in cirrhotic HCC patients are not fully understood.We aimed to (1) explore how the combination of high-risk esophageal varices, HCC status, and portal vein tumor thrombus (i.e., HCC Portal Hypertension Imaging Score [HCCPHTIS]) helps predict increased risk of variceal re-bleeding and mortality; (2) assess predictability and reproducibility of the identified variceal re-bleeding rules. Methods This prospective study included 195 HCC patients with first-time AVB and liver cirrhosis, and conducted multivariable Cox regression analysis and Kaplan-Meier analysis. Receiver operating characteristic curve analysis was calculated to find the optimal sensitivity, specificity, and cutoff values of the variables. The reproducibility of the results obtained was verified in a different but related group of patients. Results 56 patients (28.7%) had re-bleeding within 6 weeks; HCCPHTIS was an independent risk factor for variceal re-bleeding after AVB (Odd ratio, 2.330; 95% confidence interval: 1.728–3.142, p 3 was 66.2%, sensitivity 83.9%, and specificity 82.3%. HCCPHTIS area under the curve was higher than Child-Pugh score (89% vs. 75%, p 4 was associated with increased risk of death within 6 weeks after AVB (p 3 is a strong predictor of variceal re-bleeding within the first 6 weeks. However, patients with HCCPHTIS > 4 were at increased risk of death within 6 weeks.

Geographic knowledge graph representation learning embeds entities and relationships in geographic knowledge graphs into a low-dimensional continuous vector space, which serves as a basic method that bridges geographic knowledge graphs and geographic applications. Previous geographic knowledge graph representation methods primarily learn the vectors of entities and their relationships from their spatial attributes and relationships, which ignores various semantics of entities, resulting in poor embeddings on geographic knowledge graphs. This study proposes a two-stage multimodal geographic knowledge graph representation (MGKGR) model that integrates multiple kinds of semantics to improve the embedding learning of geographic knowledge graph representation. Specifically, in the first stage, a spatial feature fusion method for modality enhancement is proposed to combine the structural features of geographic knowledge graphs with two modal semantic features. In the second stage, a multi-level modality feature fusion method is proposed to integrate heterogeneous features from different modalities. By fusing the semantics of text and images, the performance of geographic knowledge graph representation is improved, providing accurate representations for downstream geographic intelligence tasks. Extensive experiments on two datasets show that the proposed MGKGR model outperforms the baselines. Moreover, the results demonstrate that integrating textual and image data into geographic knowledge graphs can effectively enhance the model’s performance.

Purposes With the continuous access of distributed generator (DG) in the traditional distribution network, it has brought serious challenges to the distribution network protection configuration. Based on the analysis of the amplitude and phase characteristics of different types of DG fault current in distribution network line fault, this paper proposes a distribution network pilot protection scheme based on the amplitude and phase characteristics of fault sequence current. Methods The scheme uses the amplitude and phase difference characteristics of each sequence fault current at both ends of the line to construct the protection action amount and braking amount respectively. By setting the protection parameters reasonably, the selectivity and sensitivity of complex distribution network protection with different types of DG can be taken into account. Findings The protection scheme setting is simple, real-time adjustment is not required at the operation stage, and the computational power of the protection equipment is low. Finally, the effectiveness of the protection scheme is verified by a simulation example built by RTDS.

Background & Aims: Sphingosine kinase 1 (SphK1) has distinct roles in the activation of Kupffer cells and hepatic stellate cells in liver fibrosis. Here, we aim to investigate the roles of SphK1 on hepatic macrophage recruitment and polarization in liver fibrosis. Methods: Liver fibrosis was induced by carbon tetrachloride in wild-type and SphK1-/- mice to study the recruitment and polarization of macrophages. The effects of SphK1 originated from macrophages or other liver cell types on liver fibrosis were further strengthened by bone marrow transplantation. The direct effects of SphK1 on macrophage polarization were also investigated in vitro. Expression analysis of SphK1 and macrophage polarization index was conducted with human liver samples. Results: SphK1 deletion attenuated the recruitment of hepatic macrophages along with reduced M1 and M2 polarization in mice induced by carbon tetrachloride. SphK1 deficiency in endogenous liver cells attenuated macrophage recruitment via C-C motif chemokine ligand 2. Macrophage SphK1 activated the ASK1-JNK1/2-p38 signaling pathway to promote M1 polarization. Furthermore, macrophage SphK1 downregulated small ubiquitin-like modifier-specific peptidase1 to decrease de-SUMOylation of Kruppel-like factor 4 to promote M2 polarization. Finally, we confirmed that SphK1 expression was elevated and positively correlated with macrophage M1 and M2 polarization in human fibrosis livers. Conclusions: Our findings demonstrated that SphK1 aggravated liver fibrosis by promoting macrophage recruitment and M1/M2 polarization. SphK1 in macrophages is a potential therapeutic target for the treatment of liver fibrosis.

Objective: Discogenic low back pain (LBP) is associated with nociceptive nerve fibers that grow into degenerated intervertebral discs (IVD) but the etiopathogenesis of disease is not fully understood. The purpose of this study was to clarify the role of Netrin-1 in causing discogenic LBP. Methods: The level of nociceptive nerve innervation was examined in disc degenerative patients and rat needle-punctured models by immunohistochemistry. Nucleus pulposus (NP) cells were isolated from IVD tissues of rats and induced degeneration by interleukin-1β (IL-1β) or tumor necrosis factor α (TNFα). The candidate genes related to neuron outgrowth and migration were selected by Next-generation sequencing (NGS). CRISPR/Cas9 was used to knockdown Netrin-1 in NP cells. The impact of Netrin-1 on nerve innervation were evaluated with P2X2、NF200 staining and microfluidics assay. Meanwhile the CD31 staining and transwell assay were used to evaluate the impact of Netrin-1 in angiogenesis. The proteins and RNA extracted from NP cells related to catabolism and anabolism were examined by western blot assay and RT-qPCR experiment. ChIP and luciferase experiments were used to assess the intracellular transcriptional regulation of Netrin-1. Further, a needle-punctured rat model followed by histomorphometry and immunofluorescence histochemistry was used to explore the potential effect of Netrin-1 on LBP in vivo. Results: The level of nerve innervation was increased in severe disc degenerative patients while the expression of Netrin-1 was upregulated. The supernatants of NP cells stimulated with IL-1β or TNFα containing more Netrin-1 could promote axon growth and vascular endothelial cells migration. Knocking down Netrin-1 or overexpressing transcription factor TCF3 as a negative regulator of Netrin-1 attenuated this effect. The needle-punctured rat model brought significant spinal hypersensitivity, nerve innervation and angiogenesis, nevertheless knocking down Netrin-1 effectively prevented disc degeneration-induced adverse impacts. Conclusion: Discogenic LBP was induced by Netrin-1, which mediated nerve innervation and angiogenesis in disc degeneration. Knocking down Netrin-1 by CRISPR/Cas9 or negatively regulating Netrin1 by transcription factor TCF3 could alleviate spinal hypersensitivity. The translational potential of this article: This study on Netrin-1 could provide a new target and theoretical basis for the prevention and treatment for discogenic back pain.

Personalized recommender systems have been widely deployed in various scenarios to enhance user experience in response to the challenge of information explosion. Especially, personalized recommendation models based on graph structure have advanced greatly in predicting user preferences. However, geographical region entities that reflect the geographical context of the items is not being utilized in previous works, leaving room for the improvement of personalized recommendation. This study proposes a region-aware neural graph collaborative filtering (RA-NGCF) model, which introduces the geographical regions for improving the prediction of user preference. The approach first characterizes the relationships between items and users with a user-item-region graph. And, a neural network model for the region-aware graph is derived to capture the higher-order interaction among users, items, and regions. Finally, the model fuses region and item vectors to infer user preferences. Experiments on real-world dataset results show that introducing region entities improves the accuracy of personalized recommendations. This study provides a new approach for optimizing personalized recommendation as well as a methodological reference for facilitating geographical regions for optimizing spatial applications.

Abstract Formamidinium lead triiodide (α‐FAPbI3) has been widely used in high‐efficiency perovskite solar cells due to its small band gap and excellent charge‐transport properties. Recently, some additives show facet selectivity to generate a (001) facet‐dominant film during crystallization. However, the mechanism to realize such (001) facet selectivity is not fully understood. Here, the authors attempted to use three ammonia salts NH4X (X are pseudohalide anions) to achieve better (001) facet selectivity in perovskite crystallization and improved crystallinity. After addition, the (001) facet dominance is generally increased with the best effect from SCN− anions. The theoretical calculation revealed three mechanisms of such improvements. First, pseudohalide anions have larger binding energy than the iodine ion to bind the facets including (110), (210), and (111), slowing down the growth of these facets. The large binding energy also reduces nucleation density and improves crystallinity. Second, pseudohalide ions improve phase purity by increasing the formation energies of the δ‐phase and other hexagonal polytypes, retarding the α‐ to δ‐phase transition. Third, the strong binding of these anions can also effectively passivate the iodine vacancies and suppress nonradiative recombination. As a result, the devices show a power conversion efficiency of 24.11% with a Voc of 1.181 V.

Background and aim: Liver fibrosis resulting from persistent liver injury represents a major healthcare problem globally. Traditional Chinese medicine has played an essential role in the treatment of liver fibrosis in recent years. Thus, this study aims to assess the effect of Longhu Rendan (LHRD), a Chinese traditional patent medicine, on liver fibrosis and its potential mechanism. Methods: The liver fibrosis in mice was induced via the intraperitoneal injection of carbon tetrachloride (CCl4) for 6 weeks or bile duct ligation for 15 days. Various methods were used to judge the therapeutic effect of LHRD. Results: LHRD significantly suppressed the activity of serum index of abnormal liver function, liver cell apoptosis, and necrosis, attenuating liver injury. Moreover, LHRD treatment alleviated liver fibrotic features, such as the reduction of collagen deposition and hepatic stellate cell activation as well as profibrotic gene expression. Mechanistically, LHRD treatment inhibited nuclear transcription factor-kappa B signaling and inflammatory gene expression and diminished the production of reactive oxygen species and 4-hydroxynonenal, along with the downregulation of NADPH oxidase 4. Conclusions: Overall, the present study demonstrates that LHRD ameliorates liver injury and fibrosis via the inhibition of inflammation and oxidative stress in mice, indicating that LHRD is a potential medicine for the treatment of liver fibrosis.

Background and purposeTraumatic brain injury (TBI), especially the severe TBI are often followed by persistent cognitive sequalae, including decision-making difficulties, reduced neural processing speed and memory deficits. Diffuse axonal injury (DAI) is classified as one of the severe types of TBI. Part of DAI patients are marginalized from social life due to cognitive impairment, even if they are rated as favorable outcome. The purpose of this study was to elucidate the specific type and severity of cognitive impairment in DAI patients with favorable outcome.MethodsThe neurocognition of 46 DAI patients with favorable outcome was evaluated by the Chinese version of the Montreal Cognitive Assessment Basic (MoCA-BC), and the differences in the domains of cognitive impairment caused by different grades of DAI were analyzed after data conversion of scores of nine cognitive domains of MoCA-BC by Pearson correlation analysis.ResultsAmong the 46 DAI patients with favorable outcome, eight had normal cognitive function (MoCA-BC ≥ 26), and 38 had cognitive impairment (MoCA-BC < 26). The MoCA-BC scores were positively correlated with pupillary light reflex (r = 0.361, p = 0.014), admission Glasgow Coma Scale (GCS) (r = 0.402, p = 0.006), and years of education (r = 0.581, p < 0.001). Return of consciousness (r = −0.753, p < 0.001), Marshall CT (r = −0.328, p = 0.026), age (r = −0.654, p < 0.001), and DAI grade (r = −0.403, p = 0.006) were found to be negatively correlated with the MoCA-BC scores. In patients with DAI grade 1, the actually deducted scores (Ads) of memory (r = 0.838, p < 0.001), abstraction (r = 0.843, p < 0.001), and calculation (r = 0.782, p < 0.001) were most related to the Ads of MoCA-BC. The Ads of nine cognitive domains and MoCA-BC were all proved to be correlated, among patients with DAI grade 2. However, In the DAI grade 3 patients, the highest correlation with the Ads of MoCA-BC were the Ads of memory (r = 0.904, p < 0.001), calculation (r = 0.799, p = 0.006), orientation (r = 0.801, p = 0.005), and executive function (r = 0.869, p = 0.001).ConclusionDAI patients with favorable outcome may still be plagued by cognitive impairment, and different grades of DAI cause different domains of cognitive impairment.

High-Speed Rail (HSR) has increasingly become an important mode of inter-city transportation between large cities. Inter-city interaction facilitated by HSR tends to play a more prominent role in promoting urban and regional economic integration and development. Quantifying the impact of HSR’s interaction on cities and people is therefore crucial for long-term urban and regional development planning and policy making. We develop an evaluation framework using toponym information from social media as a proxy to estimate the dynamics of such impact. This paper adopts two types of spatial information: toponyms from social media posts, and the geographical location information embedded in social media posts. The framework highlights the asymmetric nature of social interaction among cities, and proposes a series of metrics to quantify such impact from multiple perspectives – including interaction strength, spatial decay, and channel effect. The results show that HSRs not only greatly expand the uneven distribution of inter-city connections, but also significantly reshape the interactions that occur along HSR routes through the channel effect.

Back pain: overactive protein causes disc breakdown Treatments targeting a protein that is overexpressed in damaged spinal cartilage could ease degenerative conditions associated with lower back pain. The intervertebral discs are complex cartilage tissues that absorb forces while allowing the motion of our spines. An immune-promoting enzyme called calcineurin is important in maintaining the supple, gel-like structure of the central part of each disc, the nucleus pulposus (NP). Fendong Zhao and Jian Chen at Zhejiang University School of Medicine Hangzhou, China and co-workers showed that RCAN1.4, a protein known to suppress calcineurin, is overexpressed in damaged human NPs. The team further revealed how a signaling pathway starting with RCAN1.4 suppresses key genes involved in forming the collagen fibers that hold the NP together. They therefore suggest that therapies targeting this protein could benefit patients suffering from disc degeneration diseases.

Abstract Objective To investigate the relationship between Modic changes (MCs) and recurrent lumbar disc herniation (rLDH) and that between the herniated disc component and rLDH following percutaneous endoscopic lumbar discectomy (PELD). Methods We included 102 (65 males, 37 females, aged 20–66 years) inpatients who underwent PELD from August 2013 to August 2016. All patients underwent CT and MRI preoperatively. The presence and type of Modic changes were assessed. During surgery, the herniated disc component of each patient was classified into two groups: nucleus pulposus group and hyaline cartilage group. The association of herniated disc component with Modic changes was investigated. The incidence of rLDH was assessed based on a more than 2-year follow-up. Results In total, 11 patients were lost to follow-up; the other 91 were followed up during 24–60 months. Of the 91 patients, 99 discs underwent PELD; 28/99 (28.3%) had MCs. Type I and II MCs were seen in 9 (9.1%) and 19 (19.2%), respectively; no type III MCs were found. Among 28 endplates with MCs, according to the herniated disc component, 18/28 (64.3%) showed evidence of hyaline cartilage in the intraoperative specimens, including 6/9 and 12/19 endplates with type I and II MCs, respectively. Among 71 endplates without MCs, 14/71 (19.7%) showed evidence of hyaline cartilage in the intraoperative specimens. Hyaline cartilage was more common in patients with MCs (P < 0.05). We found 2 cases of rLDH in the non-MC group (n = 71); 6 cases of rLDH were found in the MC group (n = 28), including 2 and 4 cases for types I and II, respectively. There was no significant difference between types I and II (P > 0.05). rLDH was more common in patients with MCs (P < 0.05). We found 5 rLDH cases in the hyaline cartilage group (n = 32); 3 rLDH cases were found in the nucleus pulposus group (n = 67). rLDH was more common in the hyaline cartilage group (P < 0.05). Conclusions rLDH following PELD preferentially occurs when MCs or herniated cartilage are present.

The interaction between the slipstream of the propellers and the wing of an aircraft with distributed electric propulsion (DEP) could benefit aerodynamics. A conceptual design and optimization are carried out in order to increase the range of an electric general aviation aircraft without affecting its takeoff and landing velocity in the same fuselage condition. Propellers are modelled using the actuator disk (AD) theory, and the aircraft is modelled using the vortex lattice method (VLM) to obtain DEP aircraft’s aerodynamics in conceptual design. The DIRECT method is used for global optimization. To concentrate on the layout of the propellers and wing, a propeller with the same chord distribution, twist distribution, and number of blades is selected. The design and optimization of DEP aircraft’s range is carried out with the objective of achieving the maximum product of the lift–drag ratio with propeller efficiency under force balance constrains. Additionally, to decrease the takeoff and landing distance, the DEP aircraft’s takeoff and landing performance are optimized with the objective of the smallest velocity at an angle near the tail down angle under the constrains of acceleration bigger than 0 and a Mach number at the tip of blades smaller than 0.7. The CFD simulation was used to confirm the DEP aircraft’s pretty accurate aerodynamics. Compared to the reference aircraft, the improved DEP aircraft with 10 high-lift propellers on the leading edge of the wing and 2 wing-tip propellers may boost cruise performance by 6% while maintaining takeoff and landing velocity. Furthermore, it has been shown that the stall speed of DEP aircraft with smaller wings would rise proportionally when compared to conventional design aircraft, and the power need of DEP aircraft will be increased as a result of the operation of high-lift propellers. The conceptual design and optimal approach suggested in this work has some reference value for the design and research of the fixed-wing DEP general aviation aircraft.

Ileal neobladder construction is a common treatment for patients with bladder cancer after radical cystectomy. However, metabolic disorders caused by transposed bowel segments occur frequently. Bladder tissue engineering is a promising alternative approach. Although numerous studies have reported bladder reconstruction using acellular and cellular scaffolds, there are also disadvantages associated with these methods, such as immunogenicity of synthetic grafts and incompatible mechanical properties of the biomaterials. Here, we engineered an autologous peritoneal graft consisting of a peritoneal sheet and the seromuscular layer from the ileum. Three months after the surgery, compared with the neobladder made from the ileum, the reconstructed neobladder using our new method showed normal function and better gross morphological characteristics. Moreover, histopathological and transcriptomic analysis revealed urothelium-like cells expressing urothelial biomarkers appeared in the neobladder, while no such changes were observed in the control group. Overall, our study provides a new strategy for bladder tissue engineering and informs a variety of future research prospects.

Building instances extraction is an essential task for surveying and mapping. Challenges still exist in extracting building instances from high-resolution remote sensing imagery mainly because of complex structures, variety of scales, and interconnected buildings. This study proposes a coarse-to-fine contour optimization network to improve the performance of building instance extraction. Specifically, the network contains two special sub-networks: attention-based feature pyramid sub-network (AFPN) and coarse-to-fine contour sub-network. The former sub-network introduces channel attention into each layer of the original feature pyramid network (FPN) to improve the identification of small buildings, and the latter is designed to accurately extract building contours via two cascaded contour optimization learning. Furthermore, the whole network is jointly optimized by multiple losses, that is, a contour loss, a classification loss, a box regression loss and a general mask loss. Experimental results on three challenging building extraction datasets demonstrated that the proposed method outperformed the state-of-the-art methods’ accuracy and quality of building contours.

Splenectomy in an animal model requires a standardized technique utilizing best practice to avoid variability which can result in adverse impact to the animal resulting in flawed physiologic responses simply due to technique rather than to the studied variables. In the case of the spleen, often investigators are analyzing the animal immune or inflammatory responses. Surgical splenectomy involves many variables from the training and expertise of the surgeon, which directly correlates to surgical technique to the length of operation and ease of the procedure. This operation, in turn, impacts blood loss and insensible fluid losses, sterile technique, unintended trauma to the spleen and surrounding organs, the length of the incision and the duration of the operation with more prolonged exposure to anesthetic agents. All these variables ultimately play a significant role in the experiment since they directly affect the response of the model in terms of inflammation, immune activation, or even suppression. Undesired variables such as these go unnoticed and lead to inaccurate and misleading data.