Phase separation of Nur77 mediates XS561-induced apoptosis by promoting the formation of Nur77/Bcl-2 condensates.

The orphan nuclear receptor Nur77 is a critical regulator of the survival and death of tumor cells. The pro-death effect of Nur77 can be regulated by its interaction with Bcl-2, resulting in conversion of Bcl-2 from a survival to killer. As Bcl-2 is overexpressed in various cancers preventing them from apoptosis and promoting their resistance to chemotherapy, targeting the apoptotic pathway of Nur77/Bcl-2 may lead to new cancer therapeutics. Here, we report our identification of XS561 as a novel Nur77 ligand that induces apoptosis of tumor cells by activating the Nur77/Bcl-2 pathway. In vitro and animal studies revealed an apoptotic effect of XS561 in a range of tumor cell lines including MDA-MB-231 triple-negative breast cancer (TNBC) and MCF-7/LCC2 tamoxifen-resistant breast cancer (TAMR) in a Nur77-dependent manner. Mechanistic studies showed XS561 potently induced the translocation of Nur77 from the nucleus to mitochondria, resulting in mitochondria-related apoptosis. Interestingly, XS561-induced accumulation of Nur77 at mitochondria was associated with XS561 induction of Nur77 phase separation and the formation of Nur77/Bcl-2 condensates. Together, our studies identify XS561 as a new activator of the Nur77/Bcl-2 apoptotic pathway and reveal a role of phase separation in mediating the apoptotic effect of Nur77 at mitochondria.

Removal of methylene blue by acrylic polymer adsorbents loaded with magnetic iron manganese oxides: Synthesis, characterization, and adsorption mechanisms.

Dyes pose significant risks for aquatic environments and biological health in general owing to their non-biodegradable nature, carcinogenicity, and toxicity. The effective treatment of dye wastewater has become an important research topic. In this study, acrylic polymers (AP) loaded with magnetic iron manganese oxides (MIMO) (AP/MIMO) were prepared and used for the first time for the adsorption of methylene blue (MB). Carbon in AP/MIMO exists predominantly in the C-H and C-C forms, with its content reaching 50.7%. Oxygen and nitrogen in AP/MIMO exist mainly in the -CO- and -N-C forms, with contents of up to 41.5% and 73.3%, respectively. MB removal by AP/MIMO was consistent with the pseudo-second-order kinetic model (R2 = 0.99), equilibrium was achieved within 20 min, and the highest MB capacity of 2611.23 mg g-1 was predicted by the Langmuir isotherm model (R2 = 0.91-0.94). AP/MIMO exhibited excellent MB adsorption performance in the pH range of 4-10, with a removal efficiency higher than 99.0% (MB = 100 mL 1000 mg L-1; AP/MIMO = 50 mg). Thermodynamic indicators, such as positive entropy (ΔS0; 98.30 J⋅mol-1⋅K-1), negative Gibbs free energy (ΔG0; -29.40, -28.50, and -27.50 KJ⋅mol-1), and positive enthalpy (ΔH0; 2.30 KJ⋅mol-1), demonstrated that MB removal by AP/MIMO was autonomous, favorable, and endothermic. In addition, the integration of experimental results and theoretical calculations verified that electrostatic interactions were the primary mechanism for MB adsorption at carboxyl sites on AP/MIMO. The total interaction energy between AP and MB was -310.43 kJ⋅mol-1, and the electrostatic effect had a decisive contribution to the MB adsorption, with a value of up to -341.06 kJ⋅mol-1. AP and MB were most likely bound by -COO and S atoms. Overall, AP/MIMO exhibits high adsorption capacity and shows potential as a high-performance magnetic polymer for MB removal.

The role of IBV PL1pro in virus replication and suppression of host innate immune responses.

BACKGROUND: Coronavirus papain-like proteases (PLpros) play a crucial role in virus replication and the evasion of the host immune response. Infectious bronchitis virus (IBV) encodes a proteolytically defective remnant of PL1pro and an active PL2pro. However, the function of PL1pro in IBV remains largely unknown. This study aims to explore the effect of PL1pro on virus replication and underlying mechanisms. RESULTS: The recombinant viruses rIBV-ΔPL1pro and rIBV-ΔPL1pro-N were obtained using reverse genetic techniques through the deletion of the IBV PL1pro domain and the N-terminal conserved sequence of PL1pro (PL1pro-N). We observed significantly lower replication of rIBV-ΔPL1pro and rIBV-ΔPL1pro-N than wild-type IBV. Further investigation revealed that the lack of PL1pro-N in IBV decreased virus resistance to interferon (IFN) while also inducing host immune response by enhancing the production of IFN-ß and activating the downstream STAT1 signaling pathway of IFNs. In addition, the overexpression of PL1pro-N significantly suppressed type I IFN response by down-regulating the expressions of genes in the IFN pathway. CONCLUSIONS: Our data demonstrated that IBV PL1pro plays a crucial role in IBV replication and the suppression of host innate immune responses, suggesting that IBV PL1pro could serve as a promising molecular target for antiviral therapy.

A Lightweight Visual Simultaneous Localization and Mapping Method with a High Precision in Dynamic Scenes.

Currently, in most traditional VSLAM (visual SLAM) systems, static assumptions result in a low accuracy in dynamic environments, or result in a new and higher level of accuracy but at the cost of sacrificing the real-time property. In highly dynamic scenes, balancing a high accuracy and a low computational cost has become a pivotal requirement for VSLAM systems. This paper proposes a new VSLAM system, balancing the competitive demands between positioning accuracy and computational complexity and thereby further improving the overall system properties. From the perspective of accuracy, the system applies an improved lightweight target detection network to quickly detect dynamic feature points while extracting feature points at the front end of the system, and only feature points of static targets are applied for frame matching. Meanwhile, the attention mechanism is integrated into the target detection network to continuously and accurately capture dynamic factors to cope with more complex dynamic environments. From the perspective of computational expense, the lightweight network Ghostnet module is applied as the backbone network of the target detection network YOLOv5s, significantly reducing the number of model parameters and improving the overall inference speed of the algorithm. Experimental results on the TUM dynamic dataset indicate that in contrast with the ORB-SLAM3 system, the pose estimation accuracy of the system improved by 84.04%. In contrast with dynamic SLAM systems such as DS-SLAM and DVO SLAM, the system has a significantly improved positioning accuracy. In contrast with other VSLAM algorithms based on deep learning, the system has superior real-time properties while maintaining a similar accuracy index.

Feasibility study of on-line monitoring gadolinium based on neutron induced gamma activation.

Gadolinium is a soluble neutron poison for ensuring criticality safety of nuclear facility. A neutron induced gamma activation device was developed for the on-line measurement of gadolinium. The experimental device consisted of an 241Am-Be neutron source, six 3He detectors and a liquid scintillation detector. The size of sample container was optimized by using Monte Carlo simulations. Aqueous sample containing gadolinium nitrate were conducted with the device to obtain the calibration curve, and neutron self-shielding effect was also studied to correct the non-linear response. The results showed the minimum detectable concentration (MDC) of gadolinium was 0.426 mg/L. Two test samples were conducted to evaluate the performance of the device. The results demonstrated that the discrepancies were within 10%, which indicate the developed system can be successfully used for on-line monitoring of gadolinium.

Discovery of 5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1H-indole-2-carboxamide derivatives as novel anti-cancer agents targeting Nur77.

Encouraged by our previous findings and in continuation of our ongoing study project in designing and synthesis of novel Nur77-targeting anti-cancer agents, a series of 5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1H-indole-2-carboxamide derivatives were designed, synthesized and biologically evaluated as potent Nur77 modulators. Among synthesized compounds, 8b maintained good potency against different liver cancer cell lines and other types of cancer cell lines while exhibiting lower toxicity than the positive compound celastrol. Moreover, 8b displayed excellent Nur77-binding activity, superior to the lead compound 10g and comparable to the reference compound celastrol. The cytotoxic action of 8b towards cancer cells was associated with its induction of Nur77-mitochondrial targeting and Nur77-dependent apoptosis. Notably, 8b has good in vivo safety and anti-hepatocellular carcinoma (HCC) activity. Altogether, this study reveals that 8b is a novel Nur77 modulator with great promise for further research.

SAR study of oxidative DIMs analogs targeting the Nur77-mediated apoptotic pathway of cancer cells.

Nur77, an orphan nuclear receptor, is implicated in regulating diverse cellular biological processes including apoptosis and inflammation. We previously identified BI1071 (DIM-C-pPhCF3+MeSO3-), an oxidized methanesulfonate salt of (4-CF3-Ph-C-DIM), was a direct ligand of Nur77, which could activate the Nur77-Bcl-2 apoptotic pathway. To obtain more effective compounds targeting the Nur77-mediated apoptotic pathway, we designed and synthesized a series of BI1071 analogs by introducing various substituent groups in the indolyl-rings of BI1071. Structure-activity relationship study identified A11, B5 and B15 as improved analogs with stronger binding affinity to Nur77 and enhanced apoptotic activity compared to BI1071. Nur77-binding studies demonstrated that A11, B5 and B15 bind to Nur77 with a Kd of 34 nM, 19 nM and 16 nM, respectively. Furthermore, mechanism studies showed that A11, B5 and B15 induced apoptosis through utilizing the Nur77-Bcl-2 pathway.

Global trends in anesthetic research over the past decade: a bibliometric analysis.

Background: Anesthesia is the reversible inhibition of function of the central and/or peripheral nervous system using drugs or other means to ensure a successful operation. This inhibition is mainly manifested as a loss of sensation, especially pain. Methods: Bibliometric analysis was used to identify the characteristics, hotspots, and frontiers of global anesthesiology scientific output during the past 10 years. Literatures between 2011 and 2020 in the Web of Science Core Collection (WoSCC) were reviewed and analyzed. VOSviewer was used to visualize trends and hotspots in anesthesia research. Results: A total of 16,213 publications were retrieved and results showed that there was no significant correlation between the number of articles published each year and the year of publication. England had the most published papers, the greatest number of citations (NC), and the highest h-index. The University of London and the British Journal of Anesthesia were the richest affiliate and journal, respectively. The publication written by Heidenreich et al. had the highest global citation score (GCS). Conclusions: Our research found that global publications on anesthesia have raised. Recently, "surgery", "management", "propofol", and "analgesia" appeared most frequently, which were active areas of research. In the future research, pain management, pediatric anesthesia, safety, dexmedetomidine, et al. will be the hotspot and mainstream trend of research.

Extracellular vesicle-derived miR-1249-5p regulates influenza A virus-induced acute lung injury in RAW246.7 cells through targeting SLC4A1.

Acute lung injury (ALI) is characterized by tissue damage that leads to pulmonary epithelial membrane dysfunction and macrophage activation. Currently however, the exact mechanism by which the initial mediators of mouse lung epithelial (MLE-12) cells induce inflammation remines unclear. We constructed co-culture systems of MLE-12 cells with mouse macrophage cells RAW246.7 which were realized by the supernatant and Transwell chamber. In previous study, we successfully constructed an influenza A virus-induced MLE-12 cells model. Extracellular Vesicles (EVs) from cells supernatant were isolated by differential ultracentrifugation and confirmed by transmission electron microscopy. High-throughput sequencing results showed that MLE-12 cells stimulated by influenza A virus had higher level of miR-1249-5p. The results were validated by RT-qPCR analysis. The research aimed to investigate the roles and mechanisms of miR-1249-5p in ALI. RAW246.7 cells were transfected with miR-1249-5p mimic/inhibitor. The concentrations of TNF-α, IL-6 were determined by ELISA and the uptake of EVs was monitored by confocal laser scanning microscope. Western blotting detected changes in the SLC4A1 and NF-κB signaling pathway. The results indicated that miR-1249-5p played an important role in ALI, and further investigation of its target gene SLC4A1 and NF-κB signaling pathway provides ideas for new therapeutic targets and strategies for ALI.

Phase separation of Nur77 mediates celastrol-induced mitophagy by promoting the liquidity of p62/SQSTM1 condensates.

Liquid-liquid phase separation promotes the formation of membraneless condensates that mediate diverse cellular functions, including autophagy of misfolded proteins. However, how phase separation participates in autophagy of dysfunctional mitochondria (mitophagy) remains obscure. We previously discovered that nuclear receptor Nur77 (also called TR3, NGFI-B, or NR4A1) translocates from the nucleus to mitochondria to mediate celastrol-induced mitophagy through interaction with p62/SQSTM1. Here, we show that the ubiquitinated mitochondrial Nur77 forms membraneless condensates capable of sequestrating damaged mitochondria by interacting with the UBA domain of p62/SQSTM1. However, tethering clustered mitochondria to the autophagy machinery requires an additional interaction mediated by the N-terminal intrinsically disordered region (IDR) of Nur77 and the N-terminal PB1 domain of p62/SQSTM1, which confers Nur77-p62/SQSTM1 condensates with the magnitude and liquidity. Our results demonstrate how composite multivalent interaction between Nur77 and p62/SQSTM1 coordinates to sequester damaged mitochondria and to connect targeted cargo mitochondria for autophagy, providing mechanistic insight into mitophagy.

The clinical characteristics and underlying causes of liver damage in patients with COVID-19 infection: Retrospective analysis.

OBJECTIVES: 2019-nCoV has become a global threat to human health. The primary objective of this study was to examine the hepatic damage in 2019-nCoV infected patients and the associated underlying causes. METHODS: In this retrospective study, a total of 68 laboratory-confirmed and 20 suspected COVID-19 cases from 23rd January 2020 to 15th February 2020 were included. The study was conducted in The First People's Hospital of Jingzhou, Hubei. SPSS version 23.0. was used for Statistical analysis using the Student's t-test or Chi-square test. Data was analyzed for the clinical characteristics and underlying causes of liver damage. The outcomes were followed up until March 29, 2020. RESULTS: Out of the 68 COVID-19 confirmed cases, 51 had an abnormal liver function, of which 15 had an abnormal liver function at the time of hospital admission. The relationship between the liver function and clinical prognosis of patients showed that the abnormal liver function was positively correlated with the severity of the infection (100% vs.70.2%, p=0.036). The proportion of patients with an elevated level of ALT and a depleted level of Albumin (ALB) were significantly lower in the COVID-19 suspected group than the confirmed group (5% vs. 50.9%, p=0.000; 10% vs. 35.8%, p=0.030, respectively). Besides, the utilization rate of lopinavir/ritonavir, azithromycin, and methylprednisolone in COVID-19 suspected patients were significantly lower than the confirmed patients (25% vs. 62.3%, p=0.004; 35% vs. 62.3%, p=0.037; 25% vs. 64.2%, p=0.003, respectively). CONCLUSIONS: Liver function anomalies are one of the common symptoms associated with the COVID-19 infection, where virus-replication in the liver cells, virus-induced inflammatory response, and administration of clinical medication could be the plausible reason.

The spatial organization of microbial communities during range expansion.

Microbes in nature often live in dense and diverse communities exhibiting a variety of spatial structures. Microbial range expansion is a universal ecological process that enables populations to form spatial patterns. It can be driven by both passive and active processes, for example, mechanical forces from cell growth and bacterial motility. In this review, we provide a taste of recent creative and sophisticated efforts being made to address basic questions in spatial ecology and pattern formation during range expansion. We especially highlight the role of motility to shape community structures, and discuss the research challenges and future directions.

The complete chloroplast genome of an endangered species Apostasia ramifera (Orchidaceae).

Apostasia ramifera S. C. Chen & K. Y. Lang 1986 is a Chinese endemic and endangered orchid. Here, we report the complete chloroplast (cp) genome sequence and the cp genome features of A. ramifera. The cp genome was 157,518 bp in length with a typical quadripartite structure, which was comprised of one large single-copy region (LSC, 86,353 bp) and one small single-copy region (SSC, 16,445 bp) separated by two inverted repeat regions (IRs, 27,360 bp). The cp genome encoded 133 genes, which included 87 protein-coding genes, 38 tRNAs and eight rRNAs. The average GC content of the genome is 35.8%. The phylogenetic analysis showed that A. ramifera was sister with A. wallichii and then nested in the other Apostasia species.

Adaptive slip ratio estimation for active braking control of high-speed trains.

Active braking control systems in high-speed trains are vital to ensure safety and are intended to reduce brake distances and prevent the wheels from locking. The slip ratio, which represents the relative difference between the wheel speed and vehicle velocity, is crucial to the design and successful implementation of active braking control systems. Slip ratio estimation and active braking control are challenging owing to the uncertainties of wheel-rail adhesion and system nonlinearities. Therefore, this paper proposes a novel adaptive slip ratio estimation approach for the active braking control based on an improved extended state observer. The extended state observer is developed through the augmentation of the system state-space to estimate the unmeasured train states as well as the model uncertainty. The accurate slip ratio is estimated using the observed extended states. Furthermore, the adaptability of the observer is improved by introducing the beetle antennae search algorithm to determine the optimal observer parameters. Finally, a feedback linearization braking control law is established to stabilize the closed-loop system due to its potential in coping with nonlinearities, which benefits the proven theoretical bounded stability. Experimental results validate the effectiveness of the proposed method.

A Study on the Expression of SPRED1 and PBRM1 (Baf180) and their Clinical Significances in Patients with Gastric Cancer.

BACKGROUND: To evaluate SPRED1 and PBRMl expression in patients with gastric cancer and determine the biological relationships of SPRED1 and PBRM1 with the occurrence and development of gastric cancer. METHODS: Tissue specimens of patients with gastric cancer at Jingzhou First People's Hospital were gathered from April 2016 to August 2018. SPRED1 and PBRMl (Baf180) protein expression levels were detected in the excised cancerous tissues and normal tissues (control group) of 80 patients with gastric cancer by immunohistochemical methods. RESULTS: The positive rates of SPRED1 and PBRMl protein expression in gastric cancer tissues were 55% and 75%, respectively. The positive rates of SPRED1 and PBRMl protein expression in the normal tissues without cancer were 84.6% and 92.3%, respectively. The expression in gastric cancer tissues was significantly lower than that of the control group (p < 0.05). Positive SPRED1 and PBRMl protein expression was related to histological type, depth of infiltration, presence of lymphatic metastasis, pathological grade, and clinical TNM phase (p < 0.05). SPRED1 expression and PBRMl expression were positively correlated. CONCLUSIONS: The expression of SPRED1 and PBRMl in gastric cancer tissues is low, unrelated to age and declines with increasing pathological grade and clinical phase of the gastric cancer tissues. SPRED1 and PBRMl expression may be related to the biological behavior of tumors, and the two may have a synergistic effect.

Foreign Object Intrusion Detection on Metro Track Using Commodity WiFi Devices with the Fast Phase Calibration Algorithm.

With continuous development in the scales of cities, the role of the metro in urban transportation is becoming more and more important. When running at a high speed, the safety of the train in the tunnel is significantly affected by any foreign objects. To address this problem, we propose a foreign object intrusion detection method based on WiFi technology, which uses radio frequency (RF) signals to sense environmental changes and is suitable for lightless tunnel environments. Firstly, based on extensive experiments, the abnormal phase offset between the RF chains of the WiFi network card and its offset law was observed. Based on this observation, a fast phase calibration method is proposed. This method only needs the azimuth information between the transmitter and the receiver to calibrate the the phase offset rapidly through the compensation of the channel state information (CSI) data. The time complexity of the algorithm is lower than the existing algorithm. Secondly, a method combining the MUSIC algorithm and static clutter suppression is proposed. This method utilizes the incoherence of the dynamic reflection signal to improve the efficiency of foreign object detection and localization in the tunnel with a strong multipath effect. Finally, experiments were conducted using Intel 5300 NIC in the indoor environment that was close to the tunnel environment. The performance of the detection probability and localization accuracy of the proposed method is tested.

A Rescue-Assistance Navigation Method by Using the Underground Location of WSN after Disasters.

A challenging rescue task for the underground disaster is to guide survivors in getting away from the dangerous area quickly. To address the issue, an escape guidance path developing method is proposed based on anisotropic underground wireless sensor networks under the condition of sparse anchor nodes. Firstly, a hybrid channel model was constructed to reflect the relationship between distance and receiving signal strength, which incorporates the underground complex communication characteristics, including the analytical ray wave guide model, the Shadowing effect, the tunnel size, and the penetration effect of obstacles. Secondly, a trustable anchor node selection algorithm with node movement detection is proposed, which solves the problem of high-precision node location in anisotropic networks with sparse anchor nodes after the disaster. Consequently, according to the node location and the obstacles, the optimal guidance path is developed by using the modified minimum spanning tree algorithm. Finally, the simulations in the 3D scene are conducted to verify the performance of the proposed method on the localization accuracy, guidance path effectiveness, and scalability.

The complete chloroplast genome of Geodorum eulophioides (Orchidaceae).

Geodorum eulophioides Schltr., is a critically Endangered orchid (IUCN). In this study, we report the first complete chloroplast (cp) genome of G. eulophioides to provide the underlying information for genetic breeding and conservation studies of this species. The cp genome sequence of G. eulophioides is 149,466 bp in length, which contains one large single-copy region (LSC, 85,436 bp), one small single-copy region (SSC, 14,086 bp), and two inverted repeat regions (IRs, 24,972 bp). The cp genome encoded 177 genes, of which 106 were unique genes (78 protein-coding genes, 24 tRNAs, and 4 rRNAs). Phylogenetic analysis showed that G. eulophioides is closely related to the genera Eulophia.

Adhesive Bacteria in the Terminal Ileum of Children Correlates With Increasing Th17 Cell Activation.

Humans and symbiotic bacteria are interdependent and co-evolved for millions of years. These bacteria communicate with human hosts in the gut in a contact-independent metabolite. Because most intestinal bacteria are non-adhesive, they do not penetrate the mucus layer and are not directly in contact with epithelial cells (ECs). Here, we found that there are adhesive bacteria attached to the Children's terminal ileum. And we compared the immune factors of non-adhesive bacteria in the children ileum with adhesive bacteria as well. Stimulated Th17 cell associated with adherent bacteria in the ileum ECs. SIgA responses are similar to those roles in mouse experiments. Immunohistochemical analysis confirmed that the expression of SAA1, IL-2, IL-17A, foxp3, RORγt, TGFß, and protein increased in Th17 cells. Finally, we used 16S rRNA genes 454 pyrosequencing to analyze the differences in bacterial communities between adhesive and non-adhesive bacteria in the ileum. Ileum with adherent bacteria demonstrated increased mucosa-related bacteria, such as Clostridium, Ruminococcus, Veillonella, Butyricimonas, and Prevotella. We believe that adhesive bacteria in children's terminal ileum associated with an increased Th17 cell activation and luminal secretory IgA. Adhesive bacteria very closely adhere to terminal ileum of children. They may play important role in human gut immunity and Crohn's disease.

An evolutionarily stable strategy to colonize spatially extended habitats.

The ability of a species to colonize newly available habitats is crucial to its overall fitness1-3. In general, motility and fast expansion are expected to be beneficial for colonization and hence for the fitness of an organism4-7. Here we apply an evolution protocol to investigate phenotypical requirements for colonizing habitats of different sizes during range expansion by chemotaxing bacteria8. Contrary to the intuitive expectation that faster is better, we show that there is an optimal expansion speed for a given habitat size. Our analysis showed that this effect arises from interactions among pioneering cells at the front of the expanding population, and revealed a simple, evolutionarily stable strategy for colonizing a habitat of a specific size: to expand at a speed given by the product of the growth rate and the habitat size. These results illustrate stability-to-invasion as a powerful principle for the selection of phenotypes in complex ecological processes.