Targeting of KOR by famotidine promotes OPC maturation differentiation and CNS remyelination via STAT3 signaling pathway.

This study aims to identify FDA-approved drugs that can target the kappa-opioid receptor (KOR) for the treatment of demyelinating diseases. Demyelinating diseases are characterized by myelin sheath destruction or formation that results in severe neurological dysfunction. Remission of this disease is largely dependent on the differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLGs) in demyelinating lesions. KOR is an important regulatory protein and drug target for the treatment of demyelinating diseases. However, no drug targeting KOR has been developed due to the long clinical trials for drug discovery. Here, a structure-based virtual screening was applied to identify drugs targeting KOR among 1843 drugs of FDA-approved drug libraries, and famotidine was screen out by its high affinity cooperation with KOR as well as the clinical safety. We discovered that famotidine directly promoted OPC maturation and remyelination using the complementary in vitro and in vivo models. Administration of famotidine was not only effectively enhanced CNS myelinogenesis, but also promoted remyelination. Mechanically speaking, famotidine promoted myelinogenesis or remyelination through KOR/STAT3 signaling pathway. In general, our study provided evidence of new clinical applicability of famotidine for the treatment of demyelinating diseases for which there is currently no effective therapy.

Therapeutic effects and mechanisms of isoxanthohumol on DSS-induced colitis: regulating T cell development, restoring gut microbiota, and improving metabolic disorders.

Ulcerative colitis (UC) is a severe hazard to human health. Since pathogenesis of UC is still unclear, current therapy for UC treatment is far from optimal. Isoxanthohumol (IXN), a prenylflavonoid from hops and beer, possesses anti-microbial, anti-oxidant, anti-inflammatory, and anti-angiogenic properties. However, the potential effects of IXN on the alleviation of colitis and the action of the mechanism is rarely studied. Here, we found that administration of IXN (60 mg/kg/day, gavage) significantly attenuated dextran sodium sulfate (DSS)-induced colitis, evidenced by reduced DAI scores and histological improvements, as well as suppressed the pro-inflammatory Th17/Th1 cells but promoted the anti-inflammatory Treg cells. Mechanically, oral IXN regulated T cell development, including inhibiting CD4+ T cell proliferation, promoting apoptosis, and regulating Treg/Th17 balance. Furthermore, IXN relieved colitis by restoring gut microbiota disorder and increasing gut microbiota diversity, which was manifested by maintaining the ratio of Firmicutes/Bacteroidetes balance, promoting abundance of Bacteroidetes and Ruminococcus, and suppressing abundance of proteobacteria. At the same time, the untargeted metabolic analysis of serum samples showed that IXN promoted the upregulation of D-( +)-mannose and L-threonine and regulated pyruvate metabolic pathway. Collectively, our findings revealed that IXN could be applied as a functional food component and served as a therapeutic agent for the treatment of UC.

Engineering performance of tungsten network reinforced copper matrix composites synthesized by selective laser melting and infiltration.

To solve poor engineering performance of copper-tungsten alloys operated at high temperatures, 3D network tungsten frameworks were prepared using a selective laser melting (SLM) process, and then copper was melted and diffused into these tungsten network structures to form copper matrix composites with different copper contents (i.e. Cu-10vol%W and Cu-30vol%W). Their mechanical/electrical properties and arc ablation performance were characterized. Results showed the obtained CuW composites were dense with good interfacial bonding, and the connected Cu phases formed a heat conduction channel and improved electrical and thermal conductivities of the composites. Electrical conductivities of Cu-30W and Cu-10W composites were 44.7% and 80.3% IACS, and their thermal conductivities at 25°C were 247.5 and 375.4 W/(m·K), respectively. The W-skeleton grid structure in the composites showed enhanced effects on impact toughness and anti-friction/wear resistance. Tensile strengths of Cu-30W and Cu-10W composites measured at 300°C were 95 MPa and 135 MPa, and their impact toughness values were 11.25 and 15.25 J/cm2, respectively. For the arc ablation performance, the copper phase of CuW composite was identified as the key influencing phase, whereas the W skeleton effectively hindered the spread of arc spots, inhibited quick melting of copper phases, and played effective support and protection functions.

W network reinforced Cu matrix composites were prepared by combining 3D printing technology and fusion technology, which significantly improved the thermal and mechanical properties of Cu matrix composites. We find that the interconnected Cu phases improves the thermal properties of the composites, and the mesh W skeleton improves the mechanical properties.

Application of the 'online assessment + FOBT at home' to improve participation and the efficacy of opportunistic screening for colorectal cancer: a retrospective cohort study.

BACKGROUND: Colorectal cancer (CRC) screening faces two major challenges: insufficient screening coverage and poor adherence. A smartphone applet named "Early Screening Assistant (ESA)" was developed to create an online risk-assessment and fecal occult blood test (FOBT) at home. This retrospective study was designed to evaluate whether the new CRC screening strategy can improve the colonoscopy participation rate (PR) and lesion detection rate (DR). METHODS: In total, 6194 individuals who accepted normal health examinations and CRC screening based on the ESA from June 2020 to May 2022 were assigned to the ESA group. Accordingly, 7923 inhabitants who only accepted normal health examinations were assigned to the control group. The colonoscopy PR and neoplastic lesion DR were then compared between the two groups. RESULTS: Overall, a higher proportion of subjects in the ESA group (285 of 6194 [4.6%]) completed colonoscopy than in the control group (126 of 7923, [1.6%]), p < 0.01). The neoplastic lesion DR also significantly increased in the ESA group (76 of 6194 [1.22%]) compared with the control group (15 of 7923 [0.19%]) (p < 0.01). The adjusted diagnostic sensitivity and specificity of the "Online assessment + FOBT at home" were 41.5% and 62.6% for neoplastic lesions, respectively. CONCLUSIONS: This retrospective cohort study confirmed that the new CRC screening strategy based on the "Online assessment + FOBT at home" can improve colonoscopy participation and the neoplastic lesion detection rate and may represent a promising screening strategy for CRC. TRIAL REGISTRATION: This study was registered in China Clinical Trial Registry ( https://www.chictr.org.cn ) on 29/09/2022. REGISTRATION NUMBER: ChiCTR2200064186.

Fixed-Time Composite Neural Learning Control of Flexible Telerobotic Systems.

This article is devoted to the fixed-time synchronous control for a class of uncertain flexible telerobotic systems. The presence of unknown joint flexible coupling, time-varying system uncertainties, and external disturbances makes the system different from those in the related works. First, the lumped system dynamics uncertainties and external disturbances are estimated successfully by designing a new composite adaptive neural networks (CANNs) learning law skillfully. Moreover, the fast-transient, satisfactory robustness, and high-precision position/force synchronization are also realized by design of fixed-time impedance control strategies. Furthermore, the "complexity explosion" issue triggered by traditional backstepping technology is averted efficiently via a novel fixed-time command filter and filter compensation signals. And then, sufficient conditions of system controller parameters and fixed-time stability are theoretically given by establishing the Lyapunov stability theorem. Besides, the absolute stability of the two-port networked system under complex transmission time delays is rigorously proved. Finally, simulations are performed with 2-link flexible telerobotic systems under two cases, results are presented to realistically verify the proposed control algorithm available.

Peroxisom proliferator-activated receptor-γ coactivator-1α in neurodegenerative disorders: A promising therapeutic target.

Neurodegenerative disorders (NDDs) are characterized by progressive loss of selectively vulnerable neuronal populations and myelin sheath, leading to behavioral and cognitive dysfunction that adversely affect the quality of life. Identifying novel therapies that attenuate the progression of NDDs would be of significance. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a widely expressed transcriptional regulator, modulates the expression of genes engaged in mitochondrial biosynthesis, metabolic regulation, and oxidative stress (OS). Emerging evidences point to the strong connection between PGC-1α and NDDs, suggesting its positive impaction on the progression of NDDs. Therefore, it is urgent to gain a deeper and broader understanding between PGC-1α and NDDs. To this end, this review presents a comprehensive overview of PGC-1α, including its basic characteristics, the post-translational modulations, as well as the interacting transcription factors. Secondly, the pathogenesis of PGC-1α in various NDDs, such as Alzheimer's (AD), Parkinson's (PD), and Huntington's disease (HD) is briefly discussed. Additionally, this study summarizes the underlying mechanisms that PGC-1α is neuroprotective in NDDs via regulating neuroinflammation, OS, and mitochondrial dysfunction. Finally, we briefly outline the shortcomings of current NDDs drug therapy, and summarize the functions and potential applications of currently available PGC-1α modulators (activator or inhibitors). Generally, this review updates our insight of the important role of PGC-1α on the development of NDDs, and provides a promising therapeutic target/ drug for the treatment of NDDs.

Natural Compound 2,2',4'-Trihydroxychalcone Suppresses T Helper 17 Cell Differentiation and Disease Progression by Inhibiting Retinoid-Related Orphan Receptor Gamma T.

Retinoid-related orphan receptor γt (RORγt), a vital transcription factor for the differentiation of the pro-inflammatory Th17 cells, is essential to the inflammatory response and pathological process mediated by Th17 cells. Pharmacological inhibition of the nuclear receptor RORγt provides novel immunomodulators for treating Th17-driven autoimmune diseases and organ transplant rejection. Here, we identified 2,2',4'-trihydroxychalcone (TDC), a natural chalcone derivant, binds directly to the ligand binding domain (LBD) of RORγt and inhibited its transcriptional activation activity. Using three mice models of Th17-related diseases, it was found that the administration of TDC effectively alleviated the disease development of experimental autoimmune encephalomyelitis (EAE), experimental colitis, and skin allograft rejection. Collectively, these results demonstrated TDC targeting RORγt to suppress Th17 cell polarization, as well as its activity, thus, indicating the potential of this compound in treating of Th17-related autoimmune disorders and organ transplant rejection disorders.

A Tiny Model for Fast and Precise Ship Detection via Feature Channel Pruning.

It is of great significance to accurately detect ships on the ocean. To obtain higher detection performance, many researchers use deep learning to identify ships from images instead of traditional detection methods. Nevertheless, the marine environment is relatively complex, making it quite difficult to determine features of ship targets. In addition, many detection models contain a large amount of parameters, which is not suitable to deploy in devices with limited computing resources. The two problems restrict the application of ship detection. In this paper, firstly, an SAR ship detection dataset is built based on several databases, solving the problem of a small number of ship samples. Then, we integrate the SPP, ASFF, and DIOU-NMS module into original YOLOv3 to improve the ship detection performance. SPP and ASFF help enrich semantic information of ship targets. DIOU-NMS can lower the false alarm. The improved YOLOv3 has 93.37% mAP, 4.11% higher than YOLOv3 on the self-built dataset. Then, we use the MCP method to compress the improved YOLOv3. Under the pruning ratio of 80%, the obtained compressed model has only 6.7 M parameters. Experiments show that MCP outperforms NS and ThiNet. With the size of 26.8 MB, the compact model can run at 15 FPS on an NVIDIA TX2 embedded development board, 4.3 times faster than the baseline model. Our work will contribute to the development and application of ship detection on the sea.

2', 4'-Dihydroxy-2,3-dimethoxychalcone: A pharmacological inverse agonist of RORγt ameliorating Th17-driven inflammatory diseases by regulating Th17/Treg.

Multiple sclerosis, inflammatory bowel disease and organ transplant rejection are related to Th17 cell development and inflammatory respond. RORγt, a specific transcription factor regulating Th17 cell differentiation, is a pivotal target for the treatment of diseases. However, the clinical application of RORγt inverse agonists reported so far has been hindered due to limited efficacy and toxic side effects. Plant-derived natural products with drug-like properties and safety are wide and valuable resources for candidate drug discovery. Herein, structure-based virtual screening was used to find out 2',4'-Dihydroxy-2,3-dimethoxychalcone (DDC), a chalcone derivative rich in plants and food, located in the binding pocket of RORγt and targeted to inhibit RORγt activity. DDC repressed murine Th17 differentiation and promoted Treg differentiation remarkably in a dose-dependent manner. In addition, DDC treatment improved experimental autoimmune encephalomyelitis recovery, ameliorated experimental colitis severity, and prevented graft rejection significantly. Mechanically, DDC indirectly stabilized Foxp3 expression by inhibiting RORγt activity and the expression of its target gene profile in vitro and in vivo, which realized its regulation of Th17/Treg balance. In conclusion, our study provides a scientific basis that DDC, as an inverse agonist of RORγt with simple structure, rich sources, low cost, high efficiency, and low toxicity, has great potential for the development of a novel effective immunomodulator for the treatment of Th17-mediated inflammatory diseases.

Baicalin Promotes CNS Remyelination via PPARγ Signal Pathway.

BACKGROUND AND OBJECTIVES: Demyelinating diseases in the CNS are characterized by myelin sheath destruction or formation disorder that leads to severe neurologic dysfunction. Remission of such diseases is largely dependent on the differentiation of oligodendrocytes precursor cells (OPCs) into mature myelin-forming OLGs at the demyelinated lesions, which is defined as remyelination. We discover that baicalin (BA), a natural flavonoid, in addition to its well-known antiinflammatory effects, directly stimulates OLG maturation and CNS myelin repair. METHODS: To investigate the function of BA on CNS remyelination, we develop the complementary in vivo and in vitro models, including physiologic neonatal mouse CNS myelinogenesis model, pathologic cuprizone-induced (CPZ-induced) toxic demyelination model, and postnatal OLG maturation assay. Furthermore, molecular docking, pharmacologic regulation, and transgenic heterozygous mice were used to clarify the target and action of the mechanism of BA on myelin repair promotion. RESULTS: Administration of BA was not only merely effectively enhanced CNS myelinogenesis during postnatal development but also promoted remyelination and reversed the coordination movement disorder in the CPZ-induced toxic demyelination model. Of note, myelin-promoting effects of BA on myelination or regeneration is peroxisome proliferator-activated receptor γ (PPARγ) signaling-dependent. DISCUSSION: Our work demonstrated that BA promotes myelin production and regeneration by activating the PPARγ signal pathway and also confirmed that BA is an effective natural product for the treatment of demyelinating diseases.

Composite Adaptive Guaranteed Performances Synchronization Control for Bilateral Teleoperation System With Asymmetrical Time-Varying Delays.

This article studies the guaranteed performance synchronization control problem for networked bilateral teleoperation systems with system uncertainties. The communication channel connecting the master and the slave is subject to asymmetrical varying time delays with unknown upper bounds. The first result on prescribed performance synchronization control for the bilateral teleoperation system under such a weak assumption on the communication time delays is provided. Moreover, a novel composite adaptive control algorithm is proposed under a much weaker interval-excitation (IE) condition. More specifically, parameter adaptive estimation accuracy and speed are quantificationally ensured by employing a composite technique. Therefore, both steady-state performance and transient-state performance are achieved for the position synchronization and parameter estimation with the proposed control strategy. The Lyapunov function and the multidimensional small-gain framework are utilized to derive system stability criteria. It demonstrates that the allowable maximal derivatives of the transmission delays can be easily computed with the given parameters of the control algorithm and the nonlinear performance functions. Finally, both simulation and experimental results are provided to demonstrate the feasibility and superiority of the proposed composite adaptive strategy.

Discrete Sliding Mode Control Design for Bilateral Teleoperation System via Adaptive Extended State Observer.

The goal of this paper is to improve the synchronization control performance of nonlinear teleoperation systems with system uncertainties in the presence of time delays. In view of the nonlinear discrete states of the teleoperation system in packet-switched communication networks, a new discrete sliding mode control (DSMC) strategy is performed via a new reaching law in task space. The new reaching law is designed to reduce the chattering and improve control performance. Moreover, an adaptive extended state observer (AESO) is used to estimate the total system disturbances. The additional gain of AESO is adjusted in time to decrease the estimation errors of both system states and disturbances automatically and improve the estimation performances of the AESO. Finally, the validity of the designed control strategy is demonstrated by both simulation and experiments. Furthermore, the experimental comparison results indicate that the improvement is achievable with the proposed AESO and DSMC.

AIM2 promotes the development of non-small cell lung cancer by modulating mitochondrial dynamics.

Mitochondrial fusion and fission dynamics fine-tune cellular calcium homeostasis, ATP production capacity and ROS production and play important roles in cell proliferation and migration. Dysregulated mitochondrial dynamics is closely related to tumor development, but the mechanism of mitochondrial dynamics dysregulation and its role in the development of lung cancer remains unclear. Here, we demonstrate that the DNA sensor protein absent in melanoma 2 (AIM2) is highly expressed in non-small cell lung cancer (NSCLC) cells and that high AIM2 expression is associated with poor prognosis in patients with NSCLC. High expression of AIM2 contributes to tumor cell growth and proliferation independent of inflammasome activation in vitro and in vivo. Further studies have shown that AIM2 colocalizes with mitochondria in NSCLC cells and that AIM2 knockdown leads to enhanced mitochondrial fusion and decreased cell proliferation. Mechanistic studies have shown that AIM2 downregulation promotes MFN2 upregulation, thereby enhancing mitochondrial fusion. Moreover, we found that mitochondrial fusion driven by AIM2 knockdown leads to a decrease of cellular reactive oxygen species (ROS) production, which further causes inactivation of the MAPK/ERK signaling pathway. Together, we discovered a novel function of AIM2 in promoting NSCLC development by regulating mitochondrial dynamics and revealed its underlying mechanism. Our work provides new intervention targets for the treatment of NSCLC.

Finite Time Control Design for Bilateral Teleoperation System With Position Synchronization Error Constrained.

Due to the cognitive limitations of the human operator and lack of complete information about the remote environment, the work performance of such teleoperation systems cannot be guaranteed in most cases. However, some practical tasks conducted by the teleoperation system require high performances, such as tele-surgery needs satisfactory high speed and more precision control results to guarantee patient' health status. To obtain some satisfactory performances, the error constrained control is employed by applying the barrier Lyapunov function (BLF). With the constrained synchronization errors, some high performances, such as, high convergence speed, small overshoot, and an arbitrarily predefined small residual constrained synchronization error can be achieved simultaneously. Nevertheless, like many classical control schemes only the asymptotic/exponential convergence, i.e., the synchronization errors converge to zero as time goes infinity can be achieved with the error constrained control. It is clear that finite time convergence is more desirable. To obtain a finite-time synchronization performance, the terminal sliding mode (TSM)-based finite time control method is developed for teleoperation system with position error constrained in this paper. First, a new nonsingular fast terminal sliding mode (NFTSM) surface with new transformed synchronization errors is proposed. Second, adaptive neural network system is applied for dealing with the system uncertainties and the external disturbances. Third, the BLF is applied to prove the stability and the nonviolation of the synchronization errors constraints. Finally, some comparisons are conducted in simulation and experiment results are also presented to show the effectiveness of the proposed method.

A Disaster Response and Management Competency Mapping of Community Nurses in China.

BACKGROUND: It is widely accepted in many parts of the world thatcommunity nurses are of vital importance in various phases of disaster response and management. In China, however, it is not clear whether the Chinese community nurses are able to assume disaster-related duties due to the lack of a systematic assessment. METHODS: A pre-designed and well-tested questionnaire was employed to evaluate the competency in disaster response and management among 205 valid registered Chinese community nurses between September and October 2009. Statistical analyses were performed with SPSS Version 13.0 using one way ANOVA, Least Significant Difference (LSD) and multiple stepwise regression analysis. RESULTS: This group of Chinese community nurses scored at an intermediate level of competency (a score of 3.68 (SD 0.48) out of a perfect score of 5) in disaster response and management, suggesting that they have the basic ability to participate in disaster-related nursing. Four factors, namely, Experiences in Disaster Relief, Participation in Disaster Training, the Age and Duration in Job, were identified to be the predominant factors contributing significantly to the integrated competency in disaster response and management of an individual. CONCLUSION: Most of the Chinese community nurses have basic qualifications and competencies to undertake the responsibilities of disaster response and management. However, more targeted disaster training including virtual-reality based drills should be provided in order to improve their competency.