Naringin Alleviates Intestinal Fibrosis by Inhibiting ER Stress-Induced PAR2 Activation.

Fibrosis characterized by intestinal strictures is a common complication of Crohn's disease (CD), without specific antifibrotic drugs, which usually relies on surgical intervention. The transcription factor XBP1, a key component of endoplasmic reticulum (ER) stress, is required for degranulation of mast cells and linked to PAR2 activation and fibrosis. Many studies have confirmed that naringin (NAR) can inhibit ER stress and reduce organ fibrosis. We hypothesized that ER stress activated the PAR2-induced epithelial-mesenchymal transition process by stimulating mast cell degranulation to release tryptase and led to intestinal fibrosis in CD patients; NAR might play an antifibrotic role by inhibiting ER stress-induced PAR2 activation. We report that the expression levels of XBP1, mast cell tryptase, and PAR2 are upregulated in fibrotic strictures of CD patients. Molecular docking simulates the interaction of NAR and spliced XBP1. ER stress stimulates degranulation of mast cells to secrete tryptase, activates PAR2-induced epithelial-mesenchymal transition process, and promotes intestinal fibrosis in vitro and vivo experiments, which is inhibited by NAR. Moreover, F2rl1 (the coding gene of PAR2) deletion in intestinal epithelial cells decreases the antifibrotic effect of NAR. Hence, the ER stress-mast cell tryptase-PAR2 axis can promote intestinal fibrosis, and NAR administration can alleviate intestinal fibrosis by inhibiting ER stress-induced PAR2 activation.

Fibrosis characterized by intestinal strictures is a common complication of Crohn's disease. The endoplasmic reticulum stress­mast cell tryptase­PAR2 axis promotes intestinal fibrosis, and naringin administration alleviates intestinal fibrosis by inhibiting endoplasmic reticulum stress­induced PAR2 activation.

Mechanism of simulated lunar dust-induced lung injury in rats based on transcriptomics.

Lunar dust particles are an environmental threat to lunar astronauts, and inhalation of lunar dust can cause lung damage. The current study explored the mechanism of lunar dust simulant (CLDS-i) inducing inflammatory pulmonary injury. Wistar rats were exposed to CLDS-i for 4 h/d and 7d/week for 4 weeks. Pathological results showed that a large number of inflammatory cells gathered and infiltrated in the lung tissues of the simulated lunar dust group, and the alveolar structures were destroyed. Transcriptome analysis confirmed that CLDS-i was mainly involved in the regulation of activation and differentiation of immune inflammatory cells, activated signaling pathways related to inflammatory diseases, and promoted the occurrence and development of inflammatory injury in the lung. Combined with metabolomics analysis, the results of joint analysis of omics were found that the genes Kmo, Kynu, Nos3, Arg1 and Adh7 were involved in the regulation of amino acid metabolism in rat lung tissues, and these genes might be the key targets for the treatment of amino acid metabolic diseases. In addition, the imbalance of amino acid metabolism might be related to the activation of nuclear factor kappaB (NF-κB) signaling pathway. The results of quantitative real-time polymerase chain reaction and Western blot further confirmed that CLDS-i may promote the occurrence and development of lung inflammation and lead to abnormal amino acid metabolism by activating the B cell activation factor (BAFF)/ B cell activation factor receptor (BAFFR)-mediated NF-κB signaling pathway.

Exploring the mechanism of lung injury induced by lunar dust simulant in rats based on metabolomic analysis.

Inflammatory response and oxidative stress are considered to be important mechanisms of lung injury induced by lunar dust. However, the pulmonary toxicological mechanism remains unclear. In the present study, Wistar rats were exposed to CLDS-i 7 days/week, 4 h/day, for 4 weeks in the mouth and nose. Lung tissue samples were collected for histopathological analysis and ultra-performance liquid chromatography-mass spectrometry analysis. Enzyme activities and expression levels of key metabolic enzymes were detected by biochemical analysis and real-time PCR. The pathological features of lung tissue showed that CLDS-i caused congestion and inflammation in the lungs, and the lung structure was severely damaged. Metabolomics analysis showed that 141 metabolites were significantly changed in the lung tissue of the CLDS-i group compared with the control group. Combined with Kegg pathway analysis, it was found that the changes of amino acid metabolites were involved in these pathways, indicating that the simulated lunar dust exposure had the most obvious effect on amino acid metabolism in the lung tissue of rats. Real-time PCR analysis showed that the mRNA expression of six key enzymes related to amino acid metabolism was changed, and the enzyme activities of these key enzymes were also changed, which were consistent with the results of qPCR. These results suggest that changes in amino acid metabolism may be closely related to the pathogenesis of lung injury induced by lunar dust, and amino acid metabolism may be a potential biomarker of lung diseases related to lunar dust exposure.

PARs in the inflammation-cancer transformation of CRC

Colorectal cancer (CRC) is one of the common malignancies with a global trend of increasing incidence and mortality. There is an urgent need to identify new predictive markers and therapeutic targets for the treatment of CRC. Protease-activated receptors (PARs) are a class of G-protein-coupled receptors, with currently identified subtypes including PAR1, PAR2, PAR3 and PAR4. Increasingly, studies suggest that PARs play an important role in the growth and metastasis of CRC. By targeting multiple signaling pathways may contribute to the pathogenesis of CRC. In this review, we first describe recent studies on the role of PARs in CRC inflammation-cancer transformation, focusing on the important role of PARs in signaling pathways associated with inflammation-cancer transformation, and summarize the progress of research on PARs-targeted drugs (AU)

PARs in the inflammation-cancer transformation of CRC.

Colorectal cancer (CRC) is one of the common malignancies with a global trend of increasing incidence and mortality. There is an urgent need to identify new predictive markers and therapeutic targets for the treatment of CRC. Protease-activated receptors (PARs) are a class of G-protein-coupled receptors, with currently identified subtypes including PAR1, PAR2, PAR3 and PAR4. Increasingly, studies suggest that PARs play an important role in the growth and metastasis of CRC. By targeting multiple signaling pathways may contribute to the pathogenesis of CRC. In this review, we first describe recent studies on the role of PARs in CRC inflammation-cancer transformation, focusing on the important role of PARs in signaling pathways associated with inflammation-cancer transformation, and summarize the progress of research on PARs-targeted drugs.

Distributed Resilient Tracking of Multiagent Systems Under Actuator and Sensor Faults.

The distributed resilient tracking problem for multiagent systems (MASs) is investigated in the presence of actuator/sensor faults over directed topology. Both actuator fault and sensor fault are taken into account. Meanwhile, using the local information, the fault compensators are introduced. Then, based on the fuzzy-logic systems (FLSs) and modification technique of adaptive law, a novel distributed adaptive resilient control protocol is developed, which can compensate the effect of faults on the actuator and sensor. It turns out that all signals of MASs are bounded, while the tracking errors enter an adjustable bounded region around the origin. Toward the end, two simulations are provided to validate the effectiveness of the theoretical results.

Bioinspired Polyacrylamide/(polyvinyl alcohol-copper acetate) Hydrogel with Cooling-Triggered Shape Memory, Color Changing, and Self-Healing Behavior.

Inspired by many living creatures with adjustment of shape and color in an ever-changing environment, color changeable shape memory hydrogels are designed and expected to be potential candidates in the fields spanning from anti-counterfeiting to biomedical devices. However, they normally require complex synthesis, and more importantly, the cooling-induced shape recovery hydrogel is still rare and in its infancy so far. Herein, a unique color changeable shape memory hydrogel by simply incorporating polyvinylalcohol and copper acetate into covalent polyacrylamide network is developed. As core functional element, copper ions serve as reversible crosslinks after heating to achieve excellent cooling-triggered shape memory effect, color shifting and self-healing behavior, showing significant potential in diverse applications like grabbing, information encryption, and biomimetic designs. This work may guide the development of cooling-triggered smart hydrogels for practical applications.

Endoscopic resection for colorectal laterally spreading tumors in East Asian countries: a systematic review.

Background: To assess the efficacy and safety of different endoscopic resection methods for colorectal laterally spreading tumors (LSTs) in East Asian countries. Methods: A literature search was performed in PubMed, Embase, Cochrane Library and Web of Science databases. Colorectal LSTs of the included studies were resected with endoscopic mucosal resection (EMR) and/or endoscopic submucosal dissection (ESD). The main outcomes involved rates of en bloc resection, R0 resection, adverse events and recurrence. Results: A total of 20 studies were finally included in the present study. The total number of lesions were 3,903 (EMR: 1,230, ESD: 2,673). EMR-en bloc resection was obtained in 395/591 (66.8%), with ESD-en bloc resection reported in 2,020/2,265 (89.2%) [odds ratio (OR) 0.244, P<0.0001, 95% confidence interval (CI): 0.197-0.304]. EMR-R0 resection was achieved in 409/547 (74.8%), which was lower than that of ESD (1,895/2,241, 84.6%) (OR 0.541, P<0.0001, 95% CI: 0.432-0.677). Bleedings occurred more frequently in EMR than in ESD group (10.4% vs. 3.1%, OR 3.559, P<0.0001, 95% CI: 2.618-4.836). Rates of perforations in EMR and ESD were 0.4% and 4.1% (OR 0.099, P<0.0001, 95% CI: 0.036-0.27). Recurrence of EMR was higher than ESD group (6.3% vs. 1.0%, OR 6.732, P<0.0001, 95% CI: 3.751-12.082). Discussion: Endoscopic resections of colorectal LSTs are safe and effective. ESD leads to higher rates of en bloc and R0 resection, as well as lower rates of bleeding and recurrence, but it has a high risk of perforation, compared with EMR.

Log P analyzation-based discovery of GSH activated biotin-tagged fluorescence probe for selective colorectal cancer imaging.

Targeted activatable fluorescent probes could provide an effective approach for colorectal cancer imaging. In this study, F1 was found as an effective targeted activatable fluorescent probe based on log P analysis. In vitro experiments demonstrated that the initial fluorescence of the developed probe F1 was initially well quenched, and the fluorescence increased after the probe interacted with glutathione. Cell imaging results showed that the probe had good cell permeability and selectivity. Remarkably, F1 displayed enhanced tumor tissue fluorescence in MC-38 tumor-bearing mice. Notably, it showed selectivity in imaging clinical specimens of human colorectal cancer tissues. Accordingly, this study shows that log P analysis can facilitate the developing efficient of biotin-tagged activatable probes, and the identified F1 has a good potential in clinical colorectal cancer diagnosis.

Network Pharmacology-Based Strategy to Identify the Pharmacological Mechanisms of Pulsatilla Decoction against Crohn's Disease.

Purpose: To explore pharmacological mechanisms of Pulsatilla decoction (PD) against Crohn's disease (CD) via network pharmacology analysis followed by experimental validation. Methods: Public databases were searched to identify bioactive compounds and related targets of PD as well as related genes in patients with CD. Analyses using the drug-compound-target-disease network, the protein-protein interaction (PPI) network, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to predict the core targets and pathways of PD against CD. Colon tissue resected from patients with CD and tissue samples from a mouse model of CD fibrosis treated with PD were assessed to verify the major targets of PD in CD predicted by network pharmacologic analysis. Results: A search of the targets of bioactive compounds in PD and targets in CD identified 134 intersection targets. The target HSP90AA1, which was common to the drug-compound-target-disease and PPI networks, was used to simulate molecular docking with the corresponding bioactive compound. GO and KEGG enrichment analyses showed that multiple targets in the antifibrotic pathway were enriched and could be experimentally validated in CD patients and in a mouse model of CD fibrosis. Assays of colon tissues from CD patients showed that intestinal fibrosis was greater in stenoses than in nonstenoses, with upregulation of p-AKT, AKT, p-mTOR, mTOR, p-ERK1/2, ERK1/2, p-PKC, and PKC targets. Treatment of CD fibrosis mice with PD reduced the degree of fibrosis, with downregulation of the p-AKT, AKT, p-mTOR, mTOR, p-ERK1/2, ERK1/2, and PKC targets. Conclusion: Network pharmacology analysis was able to predict bioactive compounds in PD and their potential targets in CD. Several of these targets were validated experimentally, providing insight into the pharmacological mechanisms underlying the biological activities of PD in patients with CD.

Active Disturbance Rejection Control of Euler-Lagrange Systems Exploiting Internal Damping.

Active disturbance rejection control (ADRC) is an efficient control technique to accommodate both internal uncertainties and external disturbances. In the typical ADRC framework, however, the design philosophy is to "force" the system dynamics into a double-integral form by an extended state observer (ESO) and then the controller is designed. Especially, the systems' physical structure has been neglected in such a design paradigm. In this article, a new ADRC framework is proposed by incorporating at a fundamental level the physical structure of the Euler-Lagrange (EL) systems. In particular, the differential feedback gain can be selected considerably small or even 0, due to the effective exploitation of the system's internal damping. The design principle stems from an analysis of the energy balance of EL systems, yielding a physically interpretable design. Moreover, the exploitation of the system's internal damping is thoroughly discussed, which is of practical significance for applications of the proposed design. Besides, a sliding-mode ESO is designed to improve the estimation performance over traditional linear ESO. Finally, the proposed control framework is illustrated through tracking control of an omnidirectional mobile robot. Extensive experimental tests are conducted to verify the proposed design as well as the discussions.

Deep Temporal Model-Based Identity-Aware Hand Detection for Space Human-Robot Interaction.

Hand detection is a crucial technology for space human-robot interaction (SHRI), and the awareness of hand identities is particularly critical. However, most advanced works have three limitations: 1) the low detection accuracy of small-size objects; 2) insufficient temporal feature modeling between frames in videos; and 3) the inability of real-time detection. In the article, a temporal detector (called TA-RSSD) is proposed based on the SSD and spatiotemporal long short-term memory (ST-LSTM) for real-time detection in SHRI applications. Next, based on the online tubelet analysis, a real-time identity-awareness module is designed for multiple hand object identification. Several notable properties are described as follows: 1) the hybrid structure of the Resnet-101 and the SSD improves the detection accuracy of small objects; 2) three-level feature pyramidal structure retains rich semantic information without losing detailed information; 3) a group of the redesigned temporal attentional LSTM (TA-LSTM) is utilized for three-level feature map modeling, which effectively achieves background suppression and scale suppression; 4) low-level attention maps are used to eliminate in-class similarity between hand objects, which improves the accuracy of identity awareness; and 5) a novel association training scheme enhances the temporal coherence between frames. The proposed model is evaluated on the SHRI-VID dataset (collected according to the task requirements), the AU-AIR dataset, and the ImageNet-VID benchmark. Extensive ablation studies and comparisons on detection and identity-awareness capacities show the superiority of the proposed model. Finally, a set of actual testing is conducted on a space robot, and the results show that the proposed model achieves a real-time speed and high accuracy.

A Physics-Guided Coordinated Distributed MPC Method for Shape Control of an Antenna Reflector.

Active shape control for an antenna reflector is a significant procedure used to compensate for the impacts of a complicated space environment. In this article, a physics-guided distributed model predictive control (DMPC) framework for reflector shape control with input saturation is proposed. First, guided by the actual physical characteristics, an overall structural system is decomposed into multilevel subsystems with the help of a so-called substructuring technique. For each subsystem, a prediction model with information interaction is discretized by an explicit Newmark- ß method. Then, to improve the system-wide control performance, a coordinator among all the subsystems is designed in an iterative fashion. The input saturation constraints are addressed by transforming the original problem into a linear complementarity problem (LCP). Finally, by solving the LCP, the input trajectory can be obtained. The performance of the proposed DMPC algorithm is validated through an experiment on the shape control of an antenna reflector structure.

Prognostic and therapeutic implication of m6A methylation in Crohn disease.

BACKGROUND: N6-methyladenosine (m6A) methylation has been reported to participate in inflammatory bowel disease (including Crohn disease [CD]). However, the prognostic and therapeutic implication of m6A methylation modification in CD is still unclear. METHODS: Genomic information of CD patients was integrated to assess disease-related m6A regulators, and difference and correlation analyses of m6A regulators were explored by using the R packages. Next, CD patients were classified by the expression of differential and intersecting genes in m6A regulators, and difference and correlation analyses were conducted among immune infiltration and therapeutic responses. Finally, colon tissue resected from patients with CD were assessed to verify expression of Wilms tumor 1-associated protein (WTAP) and METTL14 from these m6A regulators. RESULTS: We identified 23 m6A regulators in CD patients. Difference analysis of these regulators showed that expression of METTL14, WTAP, RBM15 and YTHDF2/3 was upregulated in the treatment group compared with the control group, with expression of METTL3, YTHDF1, leucine-rich pentatricopeptide repeat motif-containing protein, HNRNPA2B1, IGF2BP1 and fat mass and obesity-associated protein downregulated. Moreover, RBM15, WTAP, leucine-rich pentatricopeptide repeat motif-containing protein, YTHDF1 and YTHDF3 were considered the characteristic genes of CD in m6A regulators. In addition, we identified 4 intersection genes of 3 m6A cluster patterns. Based on the expression of these intersection genes, difference analysis among m6A regulators indicated that the expression of 8 m6A regulators had statistical differences among the 3 geneCluster patterns. Assays of colon tissues from CD patients showed that expression of WTAP and METTL14 were higher in areas of stenosis than non-stenosis. CONCLUSION: m6A methylation modification might affect disease risk, immune infiltration and therapeutic responses in CD. Evaluating the expression of m6A regulators might provide insight into the prediction of disease prognosis and therapeutic responses.

Design and Experimental Study of Space Continuous Robots Applied to Space Non-Cooperative Target Capture.

Space capture actuators face problems such as insufficient flexibility and electrical components that are vulnerable to extreme space environments. To address these problems, a centralized-driven flexible continuous robot based on a multiple scissor mechanism units is proposed in this study. The continuous robot body is composed of two scissor mechanism units coupled in series, and the base container's three motors to drive the robot. The two scissor mechanism units ensure a wide range of flexible operations and the light weight of the robot. The centralized drive with three motors not only reduces the number of driving sources, but also ensures temperature control and protection of electrical components in the space environment. The kinematics and dynamics of the robot are analyzed, and the workspace and deformation performance of the robot are verified through experiments. Compared with other continuous robots, the proposed continuous robot retains the characteristics of continuous robots in a wide range of flexible operations. At the same time, the configuration is light and a small number of driving sources are used, which is suitable for extreme temperatures, vacuum, radiation, and strict resource-constrained environments in space.

Tropical Tensor Network for Ground States of Spin Glasses.

We present a unified exact tensor network approach to compute the ground state energy, identify the optimal configuration, and count the number of solutions for spin glasses. The method is based on tensor networks with the tropical algebra defined on the semiring of (R∪{-∞},⊕,⊙). Contracting the tropical tensor network gives the ground state energy; differentiating through the tensor network contraction gives the ground state configuration; mixing the tropical algebra and the ordinary algebra counts the ground state degeneracy. The approach brings together the concepts from graphical models, tensor networks, differentiable programming, and quantum circuit simulation, and easily utilizes the computational power of graphical processing units (GPUs). For applications, we compute the exact ground state energy of Ising spin glasses on square lattice up to 1024 spins, on cubic lattice up to 216 spins, and on three regular random graphs up to 220 spins, on a single GPU; we obtain exact ground state energy of ±J Ising spin glass on the chimera graph of D-Wave quantum annealer of 512 qubits in less than 100 s and investigate the exact value of the residual entropy of ±J spin glasses on the chimera graph; finally, we investigate ground-state energy and entropy of three-state Potts glasses on square lattices up to size 18×18. Our approach provides baselines and benchmarks for exact algorithms for spin glasses and combinatorial optimization problems, and for evaluating heuristic algorithms and mean-field theories.

Physical Human-Robot Collaboration: Robotic Systems, Learning Methods, Collaborative Strategies, Sensors, and Actuators.

This article presents a state-of-the-art survey on the robotic systems, sensors, actuators, and collaborative strategies for physical human-robot collaboration (pHRC). This article starts with an overview of some robotic systems with cutting-edge technologies (sensors and actuators) suitable for pHRC operations and the intelligent assist devices employed in pHRC. Sensors being among the essential components to establish communication between a human and a robotic system are surveyed. The sensor supplies the signal needed to drive the robotic actuators. The survey reveals that the design of new generation collaborative robots and other intelligent robotic systems has paved the way for sophisticated learning techniques and control algorithms to be deployed in pHRC. Furthermore, it revealed the relevant components needed to be considered for effective pHRC to be accomplished. Finally, a discussion of the major advances is made, some research directions, and future challenges are presented.

A transformed proportional-integral-derivative controller for a multi-vectored propeller aerostat with independent actuator magnitude and rate saturations.

The problem of designing a controller for a multi-vectored propeller airship with independent amplitude and rate saturations is addressed. First, a linear Proportional-Integral-Derivative (PID) controller is introduced for position control without considering the input saturations. Then, two design methods are applied to the traditional PID control output to satisfy the independent amplitude and rate constraints: the nested saturated PID controller (N-PID) and the transformed PID controller (T-PID). The bounded magnitudes and rate outputs of the modified controllers are given. Simulation results showed both controllers have good tracking performance while satisfying independent amplitude and rate saturations. However, the transformed PID controller has the advantage of expressing explicitly the relationship of the actuator magnitude and rate saturations with the parameters of the transformed function such that the actuator saturations are suppressed by calculation but not by trial and error.

Particulate matter exposure promotes Pseudomonas aeruginosa invasion into airway epithelia by upregulating PAFR via the ROS-mediated PI3K pathway.

Over exposure to particulate matter (PM) could irritate respiratory tract infection; while, Pseudomonas aeruginosa (P. aeruginosa) is one of the main common pathogens. Our study aims are to define whether PM exposure enhances the invasion of P. aeruginosa into the airway epithelia and to characterize the underlying mechanisms. Human bronchial epithelial cells (BEAS-2B) or BEAS-2B transfected by PAFR siRNA were challenged with PM and pretreated with N-acetylcysteine (NAC), LY294002 (PI3K inhibitor), BAY 11-7082 (NF-κB inhibitor), or CV-3988 (PAFR antagonist). P. aeruginosa invasion was evaluated using colony-forming units assay and confocal microscopy. Real-time RT-PCR, immunofluorescence, flow cytometry and western blotting were used to detect the genes or proteins expression. PM exposure promoted P. aeruginosa invasion into BEAS-2B cells through ROS-mediated PI3K pathway which enhanced the expression of PAFR, which could be alleviated by treatment with NAC, LY294002, and BAY 11-7082. Furthermore, NAC and PAFR siRNA attenuated PM-stimulated activation of PI3K pathway. Treatment with PAFR antagonist and siRNA also alleviated PM exposure-induced P. aeruginosa invasion into BEAS-2B cells. Our results demonstrated that PM exposure increased the PAFR expression and activated the PI3K pathway in a ROS-dependent manner. Upregulated PAFR and activated PI3K pathway formed a positive regulatory loop and promoted the invasion of P. aeruginosa into airway epithelia. These mechanisms may provide a novel approach against P.aeruginosa invasion.

Tough, Stretchable, Compressive Double Network Hydrogel Using Natural Glycyrrhizic Acid Tailored Low-Molecular-Weight Gelator Strategy: In Situ Spontaneous Formation of Au Nanoparticles To Generate a Continuous Flow Reactor.

Traditional solid supports of metal nanoparticles (MNPs) often suffer from the poor mechanical performance, the low recycling efficiency, and the mass loss in the regeneration process. To overcome this limit, in this work, we reported a natural triterpenoid-tailored low-molecular-weight gelator (LMWG) strategy to fabricate double network (DN) hydrogels with excellent mechanical properties for supporting MNPs. In this strategy, the supramolecular fibrillar structure of glycyrrhizic acid (GL) and the cross-linked polyacrylamide (PAAm) were used as the first physical network and the second chemical network, respectively. The resulting GL/PAAm DN gels possessed tough, stretchable, and compressive properties, as well as high fatigue resistance. In addition, the ice-templating technique has been used to recast the DN gel through the anisotropical growth of ice crystals for increasing the porosity and surface area. On account of the reductibility of the diglucuronic moiety of GL, gold nanoparticles (AuNPs) were in situ spontaneously reduced from Au(III) ions without external reducing reagents and anchored on the pore surface of Recast-GL/PAAm DN gel. This AuNP-anchored Recast-GL/PAAm DN gel can be used as a continuous flow reactor to catalyze the reduction of 4-nitrophenol to 4-aminophenol with high catalytic activity, good recyclability, and long-term stability. Our work provided an effective strategy to generate promising supports of MNPs with highly mechanical properties and excellent catalytic efficiencies.