The PandaX-III experiment uses high pressure Time Projection Chambers (TPCs) to search for Neutrinoless Double Beta Decay (NLDBD) of 136Xe, with high energy resolution and sensitivity at the China ...Jin-Ping underground Laboratory II (CJPL-II). Fine-pitch Microbulk Micromegas will be used for charge amplification and readout in order to reconstruct both the energy and track of the NLDBD event. In the first phase of the experiment, the detector, which contains 200 kg of 90% 136Xe enriched gas operated at 10 bar, will be immersed in a large water tank to ensure 5 m of water shielding. For the final phase, a ton-scale experiment with multiple TPCs will be constructed to improve the detection probability and sensitivity. A 20-kg scale prototype TPC with 7 Micromegas modules has been built to optimize the design of Micromegas readout modules, and to study the energy calibration of the gaseous TPC . The preliminary results of the PandaX-III prototype TPC will be also presented in this paper.
This paper proposed a new collision avoidance decision-making system designed for autonomous ship. The system outputs collision avoidance decisions based on the latest information at a certain ...frequency, which is suitable for real ship application. Front end and back end are two main components of this system. Front end provides preliminary information while back end generates collision avoidance decisions. Based on modified velocity obstacle method, the multistage optimization decision model is introduced and various constrains are considered including ship maneuverability, multi-ship, COLREGS, off-course and seamanship. Then the interactive actions taken by other ships during collision avoidance process are further analyzed. The modified velocity obstacle method incorporates a Finite State Machine (FSM) which can be used to handle the dynamic behavior of other ships. Finally, the case study is completed on the Electronic Chart System (ECS) to show that the proposed collision avoidance decision-making system is robust and effective under various marine scenarios. Therefore, the system has great potential to be equipped on board in the future.
•A novel collision avoidance decision-making system is proposed for autonomous ship.•The Multi-stage optimization model based on modified velocity obstacle method is developed.•The interactive actions taken by other ships are further analyzed.•Various simulation case study is conducted on the Electronic Chart System (ECS).
Urban expansion in China has its particularity, especially with regard to the role of the government. It plays not only dominant and medium roles in urban expansion but also a decisive role to a ...certain extent. In contrast, previous studies on urban expansion dynamics have largely ignored the role of government factors. Inevitably, this disregard will not reveal the innate character of the rapid urban expansion in China. Based on the above considerations, this article takes Shanghai as an example, to explore the spatial-temporal evolution of urban expansion. At the same time, systematically sort out the government behaviors at each stage, to reveal the particularity of urban expansion in China. Results found: urban expansion in Shanghai has gone through three stages. Construction of industrial district in suburbs led by the central government; construction of development zones and new towns under the competition between local governments; urban space restoration and infill with the collaboration of governments and markets.
•Urban expansion in China present obvious top-down government regulation attribute.•Urban expansion in Shanghai has gone through three stages.•The market and society will play an increasingly important role in the new round of urban expansion.
While immunosuppressive environments mediated by myeloid-derived suppressor cells (MDSCs) have been well documented in glioma patients, the mechanisms of MDSC development and activation have not been ...clearly defined. Here, we elucidated a role for glioma-derived exosomes (GDEs) in potentiating an MDSC pathway. We isolated normoxia-stimulated and hypoxia-stimulated GDEs and studied their MDSC induction abilities in vivo and in vitro. Analyses of spleen and bone marrow MDSC proportions (flow cytometry) and reactive oxygen species (ROS), arginase activity, nitric oxide (NO), T-cell proliferation and immunosuppressive cytokine (IL-10 and TGF-β, ELISA) levels were used to assess MDSC expansion and functional capacity. We also performed microRNA (miRNA) sequencing analysis of two types of GDEs to find miRNAs that potentially mediate the development and activation of MDSCs. GDE miRNA intracellular signaling in MDSCs was also studied. Hypoxia promoted the secretion of GDEs, and mouse MDSCs could uptake GDEs. Hypoxia-stimulated GDEs had a stronger ability to induce MDSCs than N-GDEs. The hypoxia-inducible expression of miR-10a and miR-21 in GDEs mediated GDE-induced MDSC expansion and activation by targeting RAR-related orphan receptor alpha (RORA) and phosphatase and tensin homolog (PTEN). Mice inoculated with miR-10a or miR-21 knockout glioma cells generated fewer MDSCs than those inoculated with normal glioma cells. These data elucidated a mechanism by which glioma cells influence the differentiation and activation of MDSCs via exosomes and demonstrated how local glioma hypoxia affects the entirety of tumor immune environments.
Japanese encephalitis virus (JEV), an arthropod-borne flavivirus, is a major cause of acute viral encephalitis in humans. No approved drug is available for the specific treatment of JEV infections, ...and the available vaccines are not effective against all clinical JEV isolates. In the study described here, a high-throughput screening of an FDA-approved drug library for inhibitors of JEV was performed. Five hit drugs that inhibited JEV infection with a selective index of >10 were identified. The antiviral activities of these five hit drugs against other flavivirus, including Zika virus, were also validated. As three of the five hit drugs were calcium inhibitors, additional types of calcium inhibitors that confirmed that calcium is essential for JEV infection, most likely during viral replication, were utilized. Adaptive mutant analysis uncovered that replacement of Q130, located in transmembrane domain 3 of the nonstructural NS4B protein, which is relatively conserved in flaviviruses, with R or K conferred JEV resistance to manidipine, a voltage-gated Ca
channel (VGCC) inhibitor, without an apparent loss of the viral growth profile. Furthermore, manidipine was indicated to protect mice against JEV-induced lethality by decreasing the viral load in the brain, while it abrogated the histopathological changes associated with JEV infection. This study provides five antiflavivirus candidates and identifies cytoplasmic calcium to be a novel antiviral target for the treatment of JEV infection. The findings reported here provide therapeutic possibilities for combating infections caused by flaviviruses.
No approved therapy for the treatment of Japanese encephalitis virus infection is currently available. Repurposing of approved drugs would accelerate the development of a therapeutic stratagem. In this study, we screened a library of FDA-approved drugs and identified five hit drugs, especially calcium inhibitors, exerting antiflavivirus activity that blocked viral replication. The
efficacy and toxicity of manidipine were investigated with a mouse model of JEV infection, and the viral target was identified by generating an adaptive mutant.
BMSC-secreted exosomes (BMSC-Exos) have shown potential for promoting behavioral recovery following spinal cord injury (SCI). However, its role in blocking astrocyte activation remains unclear. Thus, ...this study aimed to determine whether BMSC-Exos impair the function of astrocytes following SCI in mice and to seek the mechanism.
BMSC-Exos were collected by ultracentrifugation and identified. The SCI mice were developed by laminectomy combined with spinal cord shock, followed by BMSC-Exos or nerve growth factor (positive control) treatment. HE staining, Nissl staining, and TUNEL were conducted to analyze the pathological structural damage and neuronal damage in the mouse spinal cord. Bioinformatics was used to screen altered molecules under the BMSC-Exos treatment. Effects of BMSC-Exos and changes in ZBTB4 and ITIH3 expression on neuronal damage induced by activated astrocytes in the co-culture system were analyzed by CCK-8 and flow cytometry.
Nerve growth factor and BMSC-Exos promoted motor function recovery, alleviated nerve injury, and reduced apoptosis in mice with SCI. ZBTB4 was enriched in BMSC-Exos and lowly expressed in SCI. Downregulation of ZBTB4 diminished the therapeutic effects of BMSC-Exos against SCI. ITIH3 was a downstream target of ZBTB4. Neurotoxic activation of astrocytes induced neuronal injury, which was alleviated by BMSC-Exos. However, ZBTB4 knockdown overturned the effects of BMSC-Exos in vitro and combined ITIH3 knockdown alleviated the accentuating effects of ZBTB4 knockdown on neuronal injury.
BMSC-Exos protected against astrocyte-induced neuronal injury by delivering ZBTB4 to repress ITIH3, ultimately improving motor function in mice with SCI.
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•BMSC-Exos and NGF promote postoperative motor function recovery in SCI mice.•ZBTB4 is enriched in BMSC-Exos and lowly expressed in the spinal cord of SCI mice.•BMSC-Exos delivery of ZBTB4 promotes recovery of motor function in SCI mice.•ZBTB4 represses ITIH3 transcription through DNA methylation.•ITIH3 promotes activation of astrocytes and thus induces neurotoxicity.
Gliomas are the most common malignant primary brain tumours with a highly immunosuppressive tumour microenvironment (TME) and poor prognosis. Circular RNAs (circRNA), a newly found type of endogenous ...noncoding RNA, characterized by high stability, abundance, conservation, have been shown to play an important role in the pathophysiological processes and TME remodelling of various tumours.
CircRNA sequencing analysis was performed to explore circRNA expression profiles in normal and glioma tissues. The biological function of a novel circRNA, namely, circNEIL3, in glioma development was confirmed both in vitro and in vivo. Mechanistically, RNA pull-down, mass spectrum, RNA immunoprecipitation (RIP), luciferase reporter, and co-immunoprecipitation assays were conducted.
We identified circNEIL3, which could be cyclized by EWS RNA-binding protein 1(EWSR1), to be upregulated in glioma tissues and to correlate positively with glioma malignant progression. Functionally, we confirmed that circNEIL3 promotes tumorigenesis and carcinogenic progression of glioma in vitro and in vivo. Mechanistically, circNEIL3 stabilizes IGF2BP3 (insulin-like growth factor 2 mRNA binding protein 3) protein, a known oncogenic protein, by preventing HECTD4-mediated ubiquitination. Moreover, circNEIL3 overexpression glioma cells drives macrophage infiltration into the tumour microenvironment (TME). Finally, circNEIL3 is packaged into exosomes by hnRNPA2B1 and transmitted to infiltrated tumour associated macrophages (TAMs), enabling them to acquire immunosuppressive properties by stabilizing IGF2BP3 and in turn promoting glioma progression.
This work reveals that circNEIL3 plays a nonnegligible multifaceted role in promoting gliomagenesis, malignant progression and macrophage tumour-promoting phenotypes polarization, highlighting that circNEIL3 is a potential prognostic biomarker and therapeutic target in glioma.
Ship collisions often result in huge losses of life, cargo and ships, as well as serious pollution of the water environment. Meanwhile, it is estimated that between 75% and 86% of maritime accidents ...are related to human factors. Thus, it is necessary to enhance the intelligence of ships to partially or fully replace the traditional piloting mode and eventually achieve autonomous collision avoidance to reduce the influence of human factors. In this paper, we propose a multi-ship automatic collision avoidance method based on a double deep Q network (DDQN) with prioritized experience replay. Firstly, we vectorize the predicted hazardous areas as the observation states of the agent so that similar ship encounter scenarios can be clustered and the input dimension of the neural network can be fixed. The reward function is designed based on the International Regulations for Preventing Collision at Sea (COLREGs) and human experience. Different from the architecture of previous collision avoidance methods based on deep reinforcement learning (DRL), in this paper, the interaction between the agent and the environment occurs only in the collision avoidance decision-making phase, which greatly reduces the number of state transitions in the Markov decision process (MDP). The prioritized experience replay method is also used to make the model converge more quickly. Finally, 19 single-vessel collision avoidance scenarios were constructed based on the encounter situations classified by the COLREGs, which were arranged and combined as the training set for the agent. The effectiveness of the proposed method in close-quarters situation was verified using the Imazu problem. The simulation results show that the method can achieve multi-ship collision avoidance in crowded waters, and the decisions generated by this method conform to the COLREGs and are close to the level of human ship handling.
An integrated longitudinal-lateral control method is proposed for autonomous vehicle trajectory tracking and dynamic collision avoidance. A method of obstacle trajectory prediction is proposed, in ...which the trajectory of the obstacle is predicted and the dynamic solution of the reference trajectory is realized. Aiming at the lane changing scene of autonomous vehicles driving in the same direction and adjacent lanes, a trajectory re-planning motion controller with the penalty function is designed. The reference trajectory parameterized output of local reprogramming is realized by using the method of curve fitting. In the framework of integrated control, Fuzzy adaptive (proportional-integral) PI controller is proposed for longitudinal velocity tracking. The selection and control of controller and velocity are realized by logical threshold method; A model predictive control (MPC) with vehicle-to-vehicle (V2V) information interaction modular and the driver characteristics is proposed for direction control. According to the control target, the objective function and constraints of the controller are designed. The proposed method's performance in different scenarios is verified by simulation. The results show that the autonomous vehicles can avoid collision and have good stability.
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