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Lu Song,1,* Zhanzhao Zhang,2,* Rongguo Hu,1 Jie Cheng,1 Lin Li,1 Qinyi Fan,1 Na Wu,1 Jing Gan,1 Mingzhu Zhou,1 Zhenguo Liu11Department of Neurology, Xinhua Hospital, 2Department of Plastic and Reconstructive Surgery, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workAbstract: L-3,4-dihydroxyphenylalanine (L-dopa) remains the most effective therapy for Parkinson’s disease (PD), but its long-term administration is associated with the development of debilitating motor complications known as L-dopa-induced dyskinesia (LID). Enhanced function of dopamine D1 receptor (D1R) and N-methyl-d-aspartate receptor (NMDAR) is believed to participate in the pathogenesis of LID. Given the existence of physical and functional interactions between D1R and NMDAR, we explored the effects of uncoupling D1R and NMDA GluN1 (GluN1) interaction on LID by using the Tat-conjugated interfering peptide (Tat-D1-t2). In this study, we demonstrated in 6-hydroxydopamine (6-OHDA)-lesioned PD rat model that intrastriatal injection of Tat-D1-t2 alleviated dyskinetic behaviors and downregulated the phosphorylation of DARPP-32 at Thr34 induced by levodopa. Moreover, we also showed intrastriatal administration of Tat-D1-t2 elicited alterations in membranous GluN1 and D1R expression. These findings indicate that D1R/GluN1 complexes may be a molecular target with therapeutic potential for the treatment of dyskinesia in Parkinson’s patients.Keywords: 6-hydroxydopamine, Parkinson’s disease, dyskinesia, L-dopa, D1 receptor, NMDA, protein–protein interaction

Clarifying the dynamic relationship between carbon sources/sinks and urban development is crucial to achieving carbon neutrality and sustainable development in the region. This study used net ecosystem productivity （NEP） to evaluate the carbon sinks of the terrestrial ecosystem in the Yangtze River Delta （YRD） from 2005 to 2020. Geodetectors were used to explore the impact of urban expansion, socio-economic factors, and their interactions on carbon sources/sinks in the YRD and to evaluate the gap in achieving carbon neutrality in cities. The results showed that： ① In 2005-2020, the NEP contribution of the YRD was 69.13 Mt·a -1 and the loss of carbon sinks due to urban expansion was 1.97 Mt. The carbon emissions offset by carbon sinks were approximately 3% to 6%. ② The high carbon source areas were mainly distributed in the central and eastern YRD and the high carbon sink areas were primarily distributed in Zhejiang Province and southern Anhui Province. The forest-rich cities of Huangshan and Lishui, with smaller gaps between carbon emissions and carbon sinks, had the greatest potential for achieving carbon neutrality. Industrial or resource-based cities such as Xuzhou and Maanshan faced greater pressure to achieve carbon neutrality. Developed cities such as Shanghai and Suzhou had the largest carbon neutrality gap. ③ Urban expansion, economic and industrial agglomeration, high-density distribution of the population, and compact urban form were the key variables leading to the widening gap between carbon emissions and carbon sinks in the YRD. The increase in ecological space could effectively reduce carbon emissions. Urban expansion and socioeconomic development could be coupled with each other and have significant synergistic effects on carbon emissions.

Entropy during the dynamic structural evolution of catalysts has a non-trivial influence on chemical reactions. Confinement significantly affects the catalyst dynamics and thus impacts the reactivity. However, a full understanding has not been clearly established. To investigate catalyst dynamics under confinement, we utilize the active learning scheme to effectively train machine learning potentials for computing free energies of catalytic reactions. The scheme enables us to compute the reaction free energies and entropies of O 2 dissociation on Pt clusters with different sizes confined inside a carbon nanotube (CNT) at the timescale of tens of nanoseconds while keeping ab initio accuracy. We observe an entropic effect owing to liquid-to-solid phase transitions of clusters at finite temperatures. More importantly, the confinement effect enhances the structural dynamics of the cluster and leads to a lower melting temperature than those of the bare cluster and cluster outside the CNT, consequently facilitating the reaction to occur at lower temperatures and preventing the catalyst from forming unfavorable oxides. Our work reveals the important influence of confinement on structural dynamics, providing useful insight into entropy in dynamic catalysis., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Cervical cancer accounts for 10-15% of cancer-related mortality among women globally. Infection with high-risk human papillomavirus (HPV) types constitutes a significant etiological factor in the development of cervical carcinoma. The integration of HPV DNA into the host genome is considered a pivotal event in cervical carcinogenesis. Nevertheless, the precise mechanisms underlying HPV integration and its role in promoting cancer progression remain inadequately understood. Therefore, this study aims to identify potential common denominators at HPV DNA integration sites and to analyze the adjacent cellular sequences. We conducted whole-genome sequencing on 13 primary cervical cancer samples, employing the chromosomal coordinates of 537 breakpoints to assess the statistical overrepresentation of integration sites in relation to various chromatin features. Our analysis, which encompassed all chromosomes, identified several integration hotspots within the human genome, notably at 14q32.2, 10p15, and 2q37. Additionally, our findings indicated a preferential integration of HPV DNA into intragenic and gene-dense regions of human chromosomes. A substantial number of host cellular genes impacted by the integration sites were associated with cancer, including IKZF2, IL26, AHRR, and PDCD6. Furthermore, the cellular genes targeted by integration were enriched in tumor-related terms and pathways, as demonstrated by gene ontology and KEGG analysis. In conclusion, these findings enhance our understanding of HPV integration sites and provide deeper insights into the molecular mechanisms underlying the pathogenesis of cervical carcinoma., Competing Interests: None., (AJCR Copyright © 2024.)

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Pregnane X receptor (PXR), a xenobiotic-sensing nuclear receptor, plays a critical role in the metabolism of endogenous and exogenous substances in the liver. Here, we investigate whether PXR plays a role in pathogenesis of HCC. We show that liver tumors were developed in diethylnitrosamine (DEN)-treated in PXR knockout (KO) mice. Hepatic levels of prostaglandin F 2α (PGF 2α ) and aldo-keto reductase family 1 member C18 (Akr1c18), a prostaglandin synthase of catalyzing reduction of PGH 2 to PGF 2α , were significantly elevated in DEN-treated PXR KO mice. Hepatic mRNA levels of alpha fetoprotein (AFP), cyclin D1 (Ccnd1), fibroblast growth factor 21 (FGF21), and inflammatory cytokine interleukin 6 (IL-6) were significantly increased in DEN-treated PXR KO mice. Other members of Akr1c family, liver metabolizing enzymes including Cyp1a2, Cyp2b10 and Cyp3a11, and bile acid synthesis enzyme Cyp7a1 mRNA levels were significantly decreased in DEN-treated PXR KO mice. Our findings revealed that PXR deficiency promoted DEN-induced HCC in mice via induction of Akr1c18 expression and PGF 2α levels and the increased PGF 2α levels synthetized by Akr1c18 enhanced hepatocytes proliferation and induced inflammatory cytokine production, which accelerated liver tumor development after DEN treatment, suggesting that PXR deficiency may create a microenvironment that is more prone to DEN-induced liver tumors and targeting PXR and Akr1c18 to reduce PGF 2α biosynthesis may be a potential and novel therapeutic strategy for HCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

It is crucial to explore the impact of dietary interventions on depression and develop functional antidepressant foods, due to the significant side effects and poor treatment compliance of antidepressant drugs. Osmanthus fragrans flowers are edible and medicinal materials owing to their delightful floral aroma and significant health benefits. Here, we evaluated the antidepressant effects of the ethanolic extract of O. fragrans var. thunbergii flowers (OFE) and investigated the mechanisms of action on the serotonin system and neuroinflammation, and analyzed the main chemical components of OFE. A single administration of OFE significantly reduced the immobility duration in the forced swimming and tail suspension tests in mice without affecting locomotor activity. OFE exhibited selective enhancing effects on 5-HTergic function in vivo, as demonstrated by its potentiating effects on 5-hydroxytryptophan (5-HTP)-induced head-twitch behavior and alleviation effects on reserpine-induced ptosis deficits. In addition, OFE increased 5-hydroxytryptamine (5-HT) concentration and upregulated 5-HT 1A expression in reserpine-treated mice, further validating its effects on 5-HT transmission. Interestingly, OFE significantly alleviated microglia activation and the production of inflammatory mediators, both in reserpine-treated mice in vivo and lipopolysaccharide (LPS)-stimulated BV-2 cells in vitro. Additionally, 62 components in OFE were identified using ultra-performance liquid chromatography quadrupole time-of-flight high-resolution mass spectrometry, and glycoside derivatives were shown to be the major constituents of OFE. The present study showed that OFE can alleviate depressive-like behaviors by modulating the serotonin system and reducing neuroinflammation. These results suggest that OFE can be valuable dietary supplements with therapeutic effects on depression., Competing Interests: The authors declare that they have no conflict of interest., (© 2024 The Author(s). Food Science & Nutrition published by Wiley Periodicals LLC.)

Although deep deterministic policy gradient (DDPG) algorithm gets widespread attention as a result of its powerful functionality and applicability for large-scale continuous control, it cannot be denied that DDPG has problems such as low sample utilization efficiency and insufficient exploration. Therefore, an improved DDPG is presented to overcome these challenges in this article. Firstly, an optimizer based on fractional gradient is introduced into the algorithm network, which is conductive to increase the speed and accuracy of training convergence. On this basis, high-value experience replay based on weight-changed priority is proposed to improve sample utilization efficiency, and aiming to have a stronger exploration of the environment, an optimized exploration strategy for boundary action space is adopted. Finally, our proposed method is tested through the experiments of gym and pybullet platform. According to the results, our method speeds up the learning process, obtains higher average rewards in comparison with other algorithms.

Edible bird's nest (EBN), a most highly priced and valuable foodstuff, contains high percentage of proteins and carbohydrates. However, proteins adhering to these carbohydrates make the EBN hard and tough, which need to be boiled as the bird's nest soup to make the Chinese cuisine. To overcome the hard and tough texture of EBN and improve the digestion degrees, the present study screened and identified a probiotic strain Bacillus amyloliquefaciens YZW02 from 5-year stored EBN sample completely solubilizing EBN for the first time. The 24-h B. amyloliquefaciens fermented EBN contained 20.30-21.48 mg/mL of the soluble protein contents with a recovery rate of 98-100%, DPPH radical scavenging rate of 84.76% and ABTS radical scavenging capacity of 41.05%. The mixed fermentation of B. amyloliquefaciens YZW02 and Bacillus natto BN1 were further applied to improve the low-MW peptide percentages and antioxidant activities. The mixed-fermentation of B. natto BN1 with 4-h cultured B. amyloliquefaciens YZW02 had the lowest percentage (82.23%) of >12-kDa proteins/peptides and highest percentages of 3-12 kDa, 1-3 kDa and 0.1-1 kDa peptides of 8.6% ± 0.08, 7.57% ± 0.09, 1.77% ± 0.05 and 0.73% ± 0.05, with the highest DPPH, ABTS and • OH scavenging capacity of 90.23%, 46.45% and 49.12%, respectively. These findings would provide an efficient strategy for improving the solubility and antioxidant activities of EBNs., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Synthetic lethality is a phenomenon wherein the simultaneous deficiency of two or more genes results in cell death, while the deficiency of any individual gene does not lead to cell death. In recent years, synthetic lethality has emerged as a significant topic in the field of targeted cancer therapy, with certain drugs based on this concept exhibiting promising outcomes in clinical trials. Nevertheless, the presence of tumor heterogeneity and the intricate DNA repair mechanisms pose challenges to the effective implementation of synthetic lethality. This review aims to explore the concepts, development, and ethical quandaries surrounding synthetic lethality. Additionally, it will provide an in-depth analysis of the clinical application and underlying mechanism of synthetic lethality., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Aberrations in MYC underlie a large proportion of liver hepatocellular carcinoma (LIHC) cases; however, MYC is difficult to target because of its undruggable structure. We aimed to uncover MYC-associated molecular targets to provide new strategies for LIHC treatment., Methods: LIHC transcriptome datasets and clinical information were obtained from The Cancer Genome Atlas. A series of bioinformatics analyses were performed for 370 patients who were stratified based on the median MYC expression level (high-MYC group and low-MYC group). Correlation analysis was performed to determine relationships between the expression of key MYC-associated genes and prognosis, DNA promotor methylation, and immune cell infiltration. Gene ontology and Kyoto Encyclopedia of Genes and Genomes Pathway enrichment analyses were performed to elucidate the functions of these genes in LIHC. Their expression and functions in LIHC were further verified using transgenic mice overexpressing c-Myc under control of the hepatocyte-specific promoter (Alb-Cre)., Results: AURKB, CCNB2, and CDKN3 were overexpressed in LIHC patients with high MYC expression and were associated with poor prognosis. Upregulation of these 3 genes was significantly correlated with hypomethylated promoter status, advanced T stage, metastasis, and immune cell infiltration in LIHC patients. Functional enrichment analyses indicated that these genes participate in the "p53 signaling pathway" and "cell cycle". Furthermore, RT-PCR and IHC analysis revealed that their mRNA and protein expression levels were upregulated in an Alb-Cre;cMYC lsl/- mouse model. Drugs that target these 3 MYC-related genes were identified., Conclusion: Taken together, our results identify biomarkers of potential utility for managing liver cancer therapy owing to their significance in tumorigenesis, proliferation, and tumor immunity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Production and hosting by Elsevier B.V.)

Objectives: Endothelial cell-derived microparticles (EMPs) are directly indicative of endothelial cell activation or apoptosis, and may also reflect endothelial inflammation, increased coagulation, and vascular tone. The aim of this study is to investigate whether EMPs would be able to evaluate system involvement and be a new indicators of disease activity in Behçet's disease (BD)., Methods: Thirty-nine consecutive BD patients (who fulfilled the modified 1990 International Study Group on Behçet's disease or the 2006 International Criteria for Behçet's Disease) and 30 age- and sex-matched healthy controls were enrolled. The plasma levels of EMPs were measured by flow cytometry utilising specific labels for endothelial MPs (CD31+ and CD42b-)., Results: The levels of circulating EMPs (CD31+ and CD42b-) were significantly elevated in the case group compared with the healthy control group (p =0.000). Moreover, BD patients plasma EMPs were positively correlated with BD current activity form (r=0.802, p =0.000). Vascular and gastrointestinal involvement in BD patients were significantly increased (p=0.004 and p=0.011, respectively) with respect to patients without vascular and gastrointestinal EMPs., Conclusions: Levels of circulating EMPs are elevated in BD patients and correlate with the disease activity; the elevated EMPs may be a potential indicator to predict disease activity of BD. The plasma level of EMPs was increased, which indicated the increased risk of vascular and digestive tract involvement in BD.

Background: Large cell lung carcinoma (LCLC) is an exceptionally aggressive disease with a poor prognosis. At present, little is known about the molecular pathology of LCLC., Methods: Ultra-deep sequencing of cancer-related genes and exome sequencing were used to detect the LCLC mutational in 118 tumor-normal pairs. The cell function test was employed to confirm the potential carcinogenic mutation of PI3K pathway., Results: The mutation pattern is determined by the predominance of A > C mutations. Genes with a significant non-silent mutation frequency (FDR) < 0.05) include TP53 (47.5%), EGFR (13.6%) and PTEN (12.1%). Moreover, PI3K signaling (including EGFR, FGRG4, ITGA1, ITGA5, and ITGA2B) is the most mutated pathway, influencing 61.9% (73/118) of the LCLC samples. The cell function test confirmed that the potential carcinogenic mutation of PI3K pathway had a more malignant cell function phenotype. Multivariate analysis further revealed that patients with the PI3K signaling pathway mutations have a poor prognosis (P = 0.007)., Conclusions: These results initially identified frequent mutation of PI3K signaling pathways in LCLC and indicate potential targets for the treatment of this fatal type of LCLC., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

In this paper, the composite robust control problem of uncertain nonlinear systems with unmatched disturbances is investigated. In order to improve the robust control performance, the integral sliding mode control method is considered together with H ∞ control for nonlinear systems. By designing a disturbance observer with a new structure, the estimations of disturbances can be obtained with small errors, which are used to construct sliding mode control policy and avoid high gains. On the basis of ensuring the accessibility of specified sliding surface, the guaranteed cost control problem of nonlinear sliding mode dynamics is considered. To overcome the difficulty of robust control design caused by nonlinear characteristics, a modified policy iteration method based on sum of squares is proposed to solve the H ∞ control policy of the nonlinear sliding mode dynamics. Finally, the effectiveness of the proposed robust control method is verified by simulation tests., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 ISA. Published by Elsevier Ltd. All rights reserved.)

Excessive manganese (Mn) exposure produces neurotoxicity with mitochondrial damage. Mitophagy is a protective mechanism to eliminate damaged mitochondria to protect cells. The aim of this study was to determine the dose-response of Mn-induced mitochondria damage, the expression of mitophagy-mediated protein PINK1/Parkin and mitophagy in dopamine-producing SK-N-SH cells. Cells were exposed to 0, 300, 900, and 1500 μM Mn 2+ for 24 h, and ROS production, mitochondrial damage and mitophagy were examined. The levels of dopamine were detected by ELISA and neurotoxicity and mitophagy-related proteins (α-synuclein, PINK1, Parkin, Optineurin, and LC3II/I) were detected by western blot. Mn increased intracellular ROS and apoptosis and decreased mitochondrial membrane potential in a concentration-dependent manner. However, at the low dose of 300 μM Mn, autophagosome was increased 11-fold, but at the high dose of 1500 μM, autophagosome was attenuated to 4-fold, together with decreased mitophagy-mediated protein PINK1/Parkin and LC3II/I ratio and increased Optineurin expression, resulting in increased α-synuclein accumulation and decreased dopamine production. Thus, Mn-induced mitophagy exhibited a novel biphasic regulation: at the low dose, mitophagy is activated to eliminate damaged mitochondria, however, at the high dose, cells gradually loss the adaptive machinery, the PINK1/Parkin-mediated mitophagy weakened, resulting in neurotoxicity., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Background and Purpose: The constitutive androstane receptor (CAR), a known xenobiotic sensor, plays an important role in drug metabolism by regulating numerous genes. The polycyclic aromatic hydrocarbon pyrene, an environmental pollutant, is a CAR activator and induces mouse hepatotoxicity via CAR. Here, we investigate the molecular mechanisms of the inflammatory response in pyrene-caused mice liver injury., Experimental Approach: Effects of pyrene on the liver were investigated in wild-type and CAR knockout (KO) mice. Levels of pyrene and its urinary metabolite were analysed by high performance liquid chromatography (HPLC). Inflammatory responses were measured by qRT-PCR, western blotting, and ELISA for cytokines., Key Results: Serum amyloid A proteins (SAAs) were markedly increased in the liver and serum of pyrene-exposed wild-type mice. IL-17-producing helper T cells (Th17 cells) and IL-17 levels were increased in the liver of pyrene-exposed wild-type mice. Hepatic mRNA levels of inflammatory cytokines including IL-1β, IL-6 and TNFα, and serum IL-6 levels were significantly elevated in pyrene-treated wild-type mice. However, these changes were not observed in CAR KO mice., Conclusion and Implications: CAR plays a crucial role in pyrene-caused mice liver inflammatory response with increased SAAs and Th17 cells. Our results suggest that serum SAAs may be a convenient biomarker for early diagnosis of liver inflammatory response caused by polycyclic aromatic hydrocarbons, including pyrene. CAR and Th17 cells may be potential targets for novel therapeutic strategies for xenobiotic-induced liver inflammation., (© 2022 British Pharmacological Society.)

Background: Improvements in screening and imaging technologies and treatment of liver disease have influenced the trend in diagnosis for stage I liver cancer. In this article, recent trends in age, incidence, tumour size, and survival of different stages of liver cancer are analysed., Methods: Surveillance, Epidemiology, and end results data from the National Cancer Institute were used to analyse trends in age-adjusted incidence rate, mean tumour size at diagnosis, age at diagnosis, and 5-year survival probability for stage I liver cancer., Results: Stage I cases of liver cancer increased most tremendously over the study period, with a greater increase from 2004 to 2012 following a smaller increase from 2012 to 2015. Moreover, the mean age of stage I liver cancer increased by 1.72 years from 2004 to 2015. The 5-year-overall survival for stage I liver cases worsened from 97.9% to 83.7% from 2004 to 2011, whereas the 10-year survival probability for stage I cases worsened from 97.3% in 2004 to 79.6% in 2006. Comparing with higher stage cases, stage I liver cancer were more likely to be females, be married, live in metro areas, receive chemotherapy, and carry medical insurance., Conclusions: The incidence of stage I liver cancer has increased over the study period, with an increase in age of diagnosis, decrease in tumour size, and generally stable overall survival rate with slight decrease. These trends emphasized the importance of early detection of liver cancer and regular screening and better treatment for high-risk populations.RESEARCH HIGHLIGHTSImprovements in screening and imaging technologies and treatment of liver disease have influenced the trend in diagnosis for liver cancer.Stage I cases of liver cancer increased most tremendously over the study period, with a greater increase from 2004 to 2012 following a smaller increase from 2012 to 2015.These trends emphasized the importance of early detection of liver cancer and regular screening and better treatment for high-risk populations.

This article concentrates on the event-based collaborative design for strict-feedback systems with uncertain nonlinearities. The controller is designed based on neural network (NN) weights adaptive law. The controller and NN weights adaptive law are only updated at the triggering instants determined by a novel composite triggering threshold. Considering the conservativeness of event condition, the state-model error is integrated into constructing the composite condition and NN weights adaptive law. In the context of the proposed mechanism, the requirements of system information and the allowable range of event-triggering error are relaxed. The number of triggering instants is greatly reduced without deteriorating the system performance. Moreover, the stability of the closed-loop is proved by the Lyapunov method following time-interval and sampling instants. Simulation results show the effectiveness of the scheme proposed in this article.

Posttraumatic stress disorder (PTSD) is one of the most common psychiatric diseases, which is characterized by the typical symptoms such as re-experience, avoidance, and hyperarousal. However, there are few drugs for PTSD treatment. In this study, conditioned fear and single-prolonged stress were employed to establish PTSD mouse model, and we investigated the effects of Tanshinone IIA (TanIIA), a natural product isolated from traditional Chinese herbal Salvia miltiorrhiza, as well as the underlying mechanisms in mice. The results showed that the double stress exposure induced obvious PTSD-like symptoms, and TanIIA administration significantly decreased freezing time in contextual fear test and relieved anxiety-like behavior in open field and elevated plus maze tests. Moreover, TanIIA increased the spine density and upregulated synaptic plasticity-related proteins as well as activated CREB/BDNF/TrkB signaling pathway in the hippocampus. Blockage of CREB remarkably abolished the effects of TanIIA in PTSD model mice and reversed the upregulations of p-CREB, BDNF, TrkB, and synaptic plasticity-related protein induced by TanIIA. The molecular docking simulation indicated that TanIIA could interact with the CREB-binding protein. These findings indicate that TanIIA ameliorates PTSD-like behaviors in mice by activating the CREB/BDNF/TrkB pathway, which provides a basis for PTSD treatment., (© 2022 John Wiley & Sons Ltd.)

In this article, the problem of H ∞ codesign for nonlinear control systems with unmatched uncertainties and adjustable parameters is investigated. The main purpose is to solve the adjustable parameters and H ∞ controller simultaneously so that better robust control performance can be achieved. By introducing a bounded function and defining a special cost function, the problem of solving the Hamilton-Jacobi-Isaacs equation is transformed into an optimization problem with nonlinear inequality constraints. Based on the sum of squares technique, a novel policy iteration algorithm is proposed to solve the problem of the H ∞ codesign. Moreover, one modified algorithm for optimizing the robust performance index is given. The convergence and the performance improvement of new iteration policy algorithms are proved. Simulation results are presented to demonstrate the effectiveness of the proposed algorithms.

Introduction: Blepharospasm is uncommon in Parkinson's disease, especially in the peak-dose dyskinesia period., Case Presentation: We herein present the case of a patient with PD who developed blepharospasm in the peak-dose dyskinesia period. The symptom was improved by taking amantadine., Conclusion: The current report expands the phenomenology of peak-dose dykinesia in PD to include dystonic blepharospasm. This complication of levodopa therapy may respond to amantadine despite the dystonic appearance of movements., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fan, Zhang, Hu, Huang, Zhu, Chen, Zhang and Wang.)

Background: Chronic pain is defined as pain that persists typically for a period of over six months. Chronic pain is often accompanied by an anxiety disorder, and these two tend to exacerbate each other. This can make the treatment of these conditions more difficult. Glucose-dependent insulinotropic polypeptide (GIP) is a member of the incretin hormone family and plays a critical role in glucose metabolism. Previous research has demonstrated the multiple roles of GIP in both physiological and pathological processes. In the central nervous system (CNS), studies of GIP are mainly focused on neurodegenerative diseases; hence, little is known about the functions of GIP in chronic pain and pain-related anxiety disorders., Methods: The chronic inflammatory pain model was established by hind paw injection with complete Freund's adjuvant (CFA) in C57BL/6 mice. GIP receptor (GIPR) agonist (D-Ala 2 -GIP) and antagonist (Pro 3 -GIP) were given by intraperitoneal injection or anterior cingulate cortex (ACC) local microinjection. Von Frey filaments and radiant heat were employed to assess the mechanical and thermal hypersensitivity. Anxiety-like behaviors were detected by open field and elevated plus maze tests. The underlying mechanisms in the peripheral nervous system and CNS were explored by GIPR shRNA knockdown in the ACC, enzyme-linked immunosorbent assay, western blot analysis, whole-cell patch-clamp recording, immunofluorescence staining and quantitative real-time PCR., Results: In the present study, we found that hind paw injection with CFA induced pain sensitization and anxiety-like behaviors in mice. The expression of GIPR in the ACC was significantly higher in CFA-injected mice. D-Ala 2 -GIP administration by intraperitoneal or ACC local microinjection produced analgesic and anxiolytic effects; these were blocked by Pro 3 -GIP and GIPR shRNA knockdown in the ACC. Activation of GIPR inhibited neuroinflammation and activation of microglia, reversed the upregulation of NMDA and AMPA receptors, and suppressed the enhancement of excitatory neurotransmission in the ACC of model mice., Conclusions: GIPR activation was found to produce analgesic and anxiolytic effects, which were partially due to attenuation of neuroinflammation and inhibition of excitatory transmission in the ACC. GIPR may be a suitable target for treatment of chronic inflammatory pain and pain-related anxiety., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Jiang, Lu, Feng, Ma, Zhang, Guan, Yang, Fan, Zhu, Yang, Qi, Yang, Li, Zhao, Jiang, Tian and Liu.)

The dynamic evolution of catalyst structures greatly influences the reactivity, especially sub-nanometer clusters, exhibiting complex configurational fluctuation. In the present work, we study the structural dynamics of a Ru 19 cluster during the dissociation of N 2 and calculate the reaction free energies using ab initio molecular dynamics (AIMD). Our AIMD calculation predicts a peak-shaped reaction entropy curve due to the adsorption-induced phase transition of the Ru 19 cluster. The low melting points of sub-nanometer clusters make it possible to activate N 2 at low temperatures. This work demonstrates that the dynamic changes of cluster structures have a non-negligible effect on reaction free energy and offer an opportunity for achieving ammonia synthesis under mild conditions.

Loop-mediated isothermal amplification (LAMP) is a promising diagnostic tool for genetic amplification, which is known for its rapid process, simple operation, high amplification efficiency, and excellent sensitivity. However, most of the existing heating methods are external for completion of molecular amplification with possibility of contamination of specimens. The present research provided an internal heating method for LAMP using magnetic nanoparticles (MNPs), which is called nano-LAMP. Near-infrared light with an excitation wavelength of 808 nm was employed as the heating source; hydroxy naphthol blue (HNB) was used as an indicator to conduct methodological research. We demonstrate that the best temperature was controlled at a working power of 2 W and 4.8 µg/µL concentration of nanoparticles. The lowest limit for the detection of HPV by the nano-LAMP method is 10 2 copies/mL, which was confirmed by a gel electrophoresis assay. In the feasibility investigation of validated clinical samples, all 10 positive HPV-6 specimens amplified by nano-LAMP were consistent with conventional LAMP methods. Therefore, the nano-LAMP detection method using internal heating of MNPs may bring a new vision to the exploration of thermostatic detection in the future., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

The characterization and identification of the dynamics of cluster catalysis are crucial to unraveling the origin of catalytic activity. However, the dynamical catalytic effects during the reaction process remain unclear. Herein, we investigate the dynamic coupling effect of elementary reactions with the structural fluctuations of sub-nanometer Au clusters with different sizes using ab initio molecular dynamics and the free energy calculation method. It was found that the adsorption-induced solid-to-liquid phase transitions of the cluster catalysts give rise to abnormal entropy increase, facilitating the proceeding of reaction, and this phase transition catalysis exists in a range of clusters with different sizes. Moreover, clusters with different sizes show different transition temperatures, resulting in a non-trivial size effect. These results unveil the dynamic effect of catalysts and help understand cluster catalysis to design better catalysts rationally.

Occupational overexposure to manganese (Mn) produces Parkinson's disease-like manganism. Acute Mn intoxication in rats causes dopaminergic neuron loss, impairment of motor activity and reduction of the expression of Park2/Parkin. The expression of Park2/Parkin is also reduced. Whether these changes are reversible after cessation of Mn exposure is unknown, and is the goal of this investigation. Adult male rats were injected with Mn 2+ at doses 1 mg/kg and 5 mg/kg in the form of MnCl 2 ·4H 2 O, every other day for one-month to produce acute Mn neurotoxicity. For a half of rats Mn exposure was suspended for recovery for up to 5 months. Mn neurotoxicity was evaluated by the accumulation of Mn in blood and brain, behavioral activities, dopaminergic neuron loss, and the expression of Park2/Parkin in the blood cells and brain. Dose-dependent Mn neurotoxicity in rats was evidenced by Mn accumulation, rotarod impairments, reduction of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra, decreased level of Park2 mRNA in the blood and brain, and decreased Parkin protein in the brain. After cessation of Mn exposure, the amount of Park2 mRNA in the blood started to increase one month after the recovery. After 5-month of recovery, blood and brain Mn returned to normal, rotarod activity recovered, the reduction of TH-positive dopaminergic neurons ameliorated, and the level of Park2 mRNA in the blood and Park2/Parkin in the midbrain and striatum were returned to the normal. Mn neurotoxicity in rats is reversible after cessation of Mn exposure. The level of Park2 mRNA in the blood could be used as a novel biomarker for Mn exposure and recovery., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Our previous study showed that neuronal apoptosis was significantly increased upon treatment of conditioned medium (CM) from necroptotic astrocytes (NAS), leaving the underlying mechanism unclear. Considering the nutritive and supportive roles of astrocytes, we first examined the neurotrophic phenotype of necroptotic astrocytes with focus on glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), two important neurotrophic factors, and it was unexpectedly found that the expression of GDNF and BDNF were up-regulated in necroptotic astrocytes in vitro. A question was raised as to whether the functional secreted forms of neurotrophic factors were increased. Considering that extracellular vesicles (EVs) were carriers of secreted substances and their roles in cellular interaction, we isolated EVs from astrocytes and found EVs from normal and necroptotic astrocytes (EVs-NAS) had characteristics of exosomes. We then examined GDNF and BDNF in EVs-NAS, and BDNF was interestingly found as an immature form of pro-BDNF. The expression of pro-BDNF was found to be increased in EVs-NAS, and EVs-NAS had a negative effect on neuronal survival. To verify that whether pro-BDNF was involved in the detrimental effect of EVs-NAS, anti-pro-BDNF antibody was applied, and we found that neuronal apoptosis-induced by EVs-NAS could be significantly attenuated by blocking pro-BDNF, which suggested that necroptotic astrocytes induced neuronal apoptosis partially through EVs-derived pro-BDNF. The data expand our understanding in neurotrophic phenotype of necroptotic astrocytes, and may provide us new strategies targeting on EVs-NAS in treatment of neurological diseases., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Small cluster catalysts are highly size-dependent and exhibit complex structural dynamic effects during catalytic reactions. Understanding their structural dynamics is of great importance in tuning the catalytic performances of small clusters that widely exist in supported catalysts. However, very little is known about the size dependence of the dynamic effect of small clusters. In this work, we systematically study the free energies and barriers of catalytic dissociation of CO 2 at different temperatures on dynamical Cu clusters with different sizes by ab initio molecular dynamics. The reaction shows an abnormal entropic effect on Cu clusters, and more interestingly, it shows size sensitivity. On the Cu 7 cluster, the entropy curve shows a reverse peak shape with increasing temperature, and it is surprising to find that it has a complex pulse shape on the Cu 19 cluster. The detailed analysis shows that such temperature dependences can be attributable to the nontrivial behaviors of adsorption-induced phase transitions of the subnanometer Cu clusters during the dissociation of CO 2 . Our work not only demonstrates the complexity of the temperature dependence of the surface reaction on cluster sizes but also provides useful insight into the phase transition catalysis of dynamic clusters.

Electrified solid/liquid interfaces are the key to many physicochemical processes in a myriad of areas including electrochemistry and colloid science. With tremendous efforts devoted to this topic, it is unexpected that molecular-level understanding of electric double layers is still lacking. Particularly, it is perplexing why compact Helmholtz layers often show bell-shaped differential capacitances on metal electrodes, as this would suggest a negative capacitance in some layer of interface water. Here, we report state-of-the-art ab initio molecular dynamics simulations of electrified Pt(111)/water interfaces, aiming at unraveling the structure and capacitive behavior of interface water. Our calculation reproduces the bell-shaped differential Helmholtz capacitance and shows that the interface water follows the Frumkin adsorption isotherm when varying the electrode potential, leading to a peculiar negative capacitive response. Our work provides valuable insight into the structure and capacitance of interface water, which can help understand important processes in electrocatalysis and energy storage in supercapacitors., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Sub-nanometer metal clusters widely existing in catalysts have a large ensemble of metastable isomers that can interconvert during catalytic reactions, exhibiting complex dynamical catalytic effects. In this work, we systematically investigate the temperature dependent structural dynamics of the Cu 13 cluster in CO 2 dissociation using ab initio molecular dynamics and the free energy calculation method. We find an abnormal entropic effect due to adsorption-induced liquid-to-solid phase transition of the cluster during the course of the elementary dissociation step at transition temperatures. In the dissociation product, the formation of a rigid Cu 3 O unit decreases the dynamical fluidity of the cluster and increases the melting temperature, causing a decrease in the entropy of the dissociation product. Our work demonstrates the nontrivial effects of surface adsorption on phase transition behaviors of dynamic clusters and offers a new perspective to dynamic catalysis.

Subacute exposure to manganese (Mn) produced Parkinson's disease-like syndrome called Manganism. Chronic onset and progression are characteristics of Manganism, therefore, this study aimed to examine Mn toxicity following chronic exposures. Male Sprague-Dawley rats were injected Mn 2+ 1 and 5 mg/kg, every 10 days for 150 days (15 injections). Animal body weight and behavioral activities were recorded. At the end of experiments, the brain and liver were collected for morphological and molecular analysis. Chronic Mn exposure did not affect animal body weight gain, but the high dose of Mn treatment caused 20% mortality after 140 days of administration. Motor activity deficits were observed in a dose-dependent manner at 148 days of Mn administration. Immunofluorescence double staining of substantia nigra pars compacta (SNpc) revealed the activation of microglia and loss of dopaminergic neurons. The chronic neuroinflammation mediators TNFα, inflammasome Nlrp3, Fc fragment of IgG receptor IIb, and formyl peptide receptor-1 were increased, implicating chronic Mn-induced neuroinflammation. Chronic Mn exposure also produced liver injury, as evidenced by hepatocyte degeneration with pink, condensed nuclei, indicative of apoptotic lesions. The inflammatory cytokines TNFα, IL-1β, and IL-6 were increased, alone with stress-related genes heme oxygenase-1, NAD(P)H:quinone oxidoreductase-1 and metallothionein. Hepatic transporters, such as multidrug resistant proteins (Abcc1, Abcc2, and Abcc3) and solute carrier family proteins (Slc30a1, Slc39a8 and Slc39a14) were increased in attempt to eliminate Mn from the liver. In summary, chronic Mn exposure produced neuroinflammation and dopaminergic neuron loss in the brain, but also produced inflammation to the liver, with upregulation of hepatic transporters.

Purpose: To investigate whether arterial infundibular widening is a preaneurysmal lesion or not., Methods: Two hundred and nine patients with cerebral angiography were enrolled. The morphology, size and location of infundibula and cerebral aneurysms were studied in two-dimensional angiography and three-dimensional software space. Computational fluid dynamics (CFD) analysis was performed., Results: 234 infundibula and 129 infundibulum-like aneurysms (IFAs) were detected. In two-dimensional space, the typical morphology of an infundibulum was a symmetric dilatation at the arterial branch origin with a small vessel branch emanating from the tip and a wide base connecting the parent artery. In three-dimensional space, the infundibulum was dissymmetric with always one side longer than the other side. Furthermore, the infundibulum tilted upstream rather than downstream, with the longer side located downstream and the shorter side upstream in all cases. All the 129 IFAs occurred on the distal wall of the vessel branch origin, and no IFAs grew from the proximal wall of the branch origin. The possible development process of an infundibulum to an IFA was described in four development stages. The CFD analysis revealed that these lesions were associated with direct flow impingement in all cases. All the hemodynamic parameters on the distal wall of infundibula and IFAs were significantly (P<0.0001 or P<0.05) decreased compared with on the distal wall after virtual lesion removal., Conclusion: The infundibulum is a preaneurysmal lesion associated with high total pressure and high wall shear stress resulted from direct flow impingement and will progress to an aneurysm with time., (Copyright © 2020. Published by Elsevier Inc.)

Objective: To investigate the influences of urinary kallidinogenase on neuronal apoptosis in rats with cerebral infarction through the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) oxidative stress pathway., Materials and Methods: A total of 30 male rats were divided into group A (model control group), group B (rat model of cerebral infarction) and group C (rat model of cerebral infarction + medical treatment with urinary kallidinogenase). The percentage of cerebral infarct volume and the apoptosis of brain cells in the three groups of rats were detected via 2,3,5-Triphenyltetrazolium chloride (TTC) staining, the pathological morphology of brain tissues in the three groups of rats was observed via hematoxylin and eosin (HE) staining, and the protein levels of Nrf2 and superoxide dismutase 1 (SOD1) in the brain tissues in the three groups of rats were measured using the Western blotting assay., Results: The degree of neurological deficit in group B was remarkably higher than that in group A (p<0.05), and it was markedly decreased in group C compared to that in group B, displaying statistically significant differences (p<0.05). Compared to that in group A, the cell apoptosis was significantly aggravated in group B, while a remarkably alleviated cell apoptosis was observed in group C compared to that of group B, and the differences were statistically significant (p<0.05). The cerebral infarct volume accounted for 34.87% of the whole brain volume in group B, and a mild cerebral infarction was detected in group C, with a percentage of cerebral infarct volume of 21.14%. Group B showed a more evident increase in the cerebral infarct volume than in group C (p<0.05). Compared to those of group A, pyknotic nuclei and neuron staining of brain tissue cells were evidently increased, and the neuronal cell injury was aggravated in group B. Moreover, prominently decreased pyknotic nuclei and neuron staining (p<0.05) as well as mild neuronal cell injury (p<0.05) were detected in group C compared to those in group B. The levels of Nrf2 and SOD1 protein in the brain tissues in group B were remarkably lower than those of group C (p<0.05)., Conclusions: Urinary kallidinogenase can inhibit the neuronal apoptosis in rats and protect the rats from cerebral infarction, whose mechanism is associated with the activation of the Nrf2/ARE oxidative stress pathway.

Introduction: Level of serotonin is mainly regulated by the serotonin reuptake transporter encoded by SLC6A4 . The promoter region of SLC6A4 bears a repeat polymorphism 5-HTTLPR and a single nucleotide polymorphism rs25531. We have previously studied the association between these two variants and sporadic PD. The objective of the current study was to determine whether the SLC6A4 polymorphisms were associated with key motor and non-motor symptoms of PD. Methods: A total of 370 PD patients of Han Chinese were included. Associations between the SLC6A4 polymorphisms and PD symptoms including depression, intellectual impairment, tremor and rigidity were analyzed. Results: 5-HTTLPR was associated with depression in PD patients and presence of the LL genotype was protective against the depression risk. The rs25531 was associated with rest tremor in PD and the A allele serves as a recessive risk allele. No associations were found in the two polymorphisms with respect to intellectual impairment and rigidity in the cohort. Conclusion: The current study reveals two PD symptoms associated with SLC6A4 polymorphisms, and provides new insight into how serotonergic system genetically participates in the symptomatic progression of PD. Further study is warranted in additional populations.

Background: En bloc tumor resection followed by reconstruction is a widely used surgical treatment for malignant pelvic bone tumors. High rates of complications and mechanical instability often contribute to poor postoperative results. We attempted en bloc microwave ablation (MWA) in situ to improve the outcome. Methods: From May 1995 to December 2015, 104 patients with primary pelvic malignancy received radical MWA in our department. After careful dissection of the tumor-bearing bone from surrounding normal tissues with safe margins, a microwave antenna array was inserted into the tumor mass to emit electromagnetic energy, inducing tumor cellular death via thermocoagulation. The loose, devitalized tumor tissues were removed by cutting or curettage, leaving a defective bone scaffold. Re-strengthening by autograft or allograft was needed in most patients. Results: The over 3 years survival rate was 51.5% for high-grade malignancies (among them, 26.9% were osteosarcoma) and 94.8% for low-grade malignancies (chondrosarcoma). In most of the living patients, cosmetic and useful limbs were preserved. The mean functional score (Musculoskeletal Tumor Society) was 27 or 90% (range: 25-30, 75-100%). Among the 56 patients who belonged to the excellent function group, 11 were followed up for more than 10 years. The local recurrence rate was 8.6%. Among the 9 patients with recurrence, 5 died from disease, 2 were treated by hemipelvic amputation, and 2 underwent revision surgery with MWA and gained local control. The deep infection rate was 5.6%. All six patients with infection were healed by irrigation, debridement, and systemic antibiotic administration. Conclusion: Local, microwave-induced hyperthermia for treating malignant pelvic bone tumors is an effective alternative method. The oncological and functional results are encouraging. The use of MWA should be continued to evaluate and improve this new therapeutic system.

This study aimed to estimate the prevalence of chlamydial trachomatis (CT) infection and explore its risk factors among patients attending sexual and reproductive health clinics in Shenzhen, China. We collected demographic and clinical information from attendees (aged 18-49). CT and Neisseria gonorrhoeae (NG) infection was determined by nucleic acid amplification test (NAAT) on self-collected urine specimens. Of 1,938 participants recruited, 10.3% (95% confidence interval [CI]: 9.6%-11.0%) tested positive for CT. Prevalence was similar between men (10.6% [85/804]; 95% CI, 9.5%-11.7%) and women (10.1% [115/1134]; 95% CI: 9.2%-11.0%). Being 18-25 years old (adjusted odds ratio [aOR] = 2.52; 95%CI:1.35-4.71), never tested for CT before (aOR = 2.42; 95%CI: 1.05-5.61) and infected with NG(aOR = 3.87; 95%CI: 2.10-7.10) were independently associated with CT infection. We found that CT infection is prevalent among patients attending sexual and reproductive health clinics in Shenzhen, China. A comprehensive program including CT screening, surveillance and treatment is urgently needed., Competing Interests: The authors have declared that no competing interests exist.

Objective: This study was conducted to analyze the effect of miR-7 on the inflammatory response of microglia in vitro and in vivo by constructing an intracerebral hemorrhage model., Patients and Methods: In this study, we first established a model of cerebral hemorrhage in rat for in vivo experiments, and used lipoprotein (LPS) to induce an inflammatory response development in microglial cells, and constructed microglial inflammation models for in vitro experiments. Quantitative Real-time-polymerase chain reaction (qRT-PCR) was used to detect the expression of miR-7 in the rat model of cerebral hemorrhage and microglia with inflammation. The effect of miR-7 on the inflammation caused by intracerebral hemorrhage was evaluated through measuring the expression of IL-1β, IL-8 and TNF-α by enzyme-linked immunosorbent assay (ELISA). Dual luciferase reporter assay was used to detect the binding site of miR-7 to TLR4. Western blot was used to evaluate the level of TLR4 after overexpression and knockdown of miR-7 and to evaluate whether miR-7 alleviated the secondary inflammatory response of microglia after cerebral hemorrhage by inhibiting the expression of TLR4., Results: The expression of miR-7 in the rat cerebral hemorrhage model and microglial inflammation model tissue was significantly lower than that in the normal control group. Expression of inflammatory cytokines including IL-1β, IL-8 and TNF-α was significantly increased in rats with intracerebral hemorrhage and microglial inflammation in rats, and the expression of these inflammatory cytokines was partially reversed after overexpression of miR-7. Double luciferase reporter gene and ELISA results showed that miR-7 could inhibit the expression of TLR4 and relieve the secondary inflammatory response of microglia after cerebral hemorrhage., Conclusions: We demonstrated that, in in vivo and in vitro experiments, miR-7 could reduce the LPS-induced inflammatory response produced by microglial cells, and alleviate the inflammation in the brain of rats with cerebral hemorrhage.

Background: Diabetic neuropathic pain (DNP) is a common and distressing complication in patients with diabetes, and the underlying mechanism remains unclear. Tricyclic antidepressants (TCAs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are recommended as first-line drugs for DNP. Ammoxetine is a novel and potent SNRI that exhibited a strong analgesic effect on models of neuropathic pain, fibromyalgia-related pain, and inflammatory pain in our primary study. The present study was undertaken to investigate the chronic treatment properties of ammoxetine on DNP and the underlying mechanisms for its effects., Methods: The rat model of DNP was established by a single streptozocin (STZ) injection (60 mg/kg). Two weeks after STZ injection, the DNP rats were treated with ammoxetine (2.5, 5, and 10 mg/kg/day) for 4 weeks. The mechanical allodynia and locomotor activity were assayed to evaluate the therapeutic effect of ammoxetine. In mechanism study, the activation of microglia, astrocytes, the protein levels of pro-inflammatory cytokines, the mitogen-activated protein kinases (MAPK), and NF-κB were evaluated. Also, microglia culture was used to assess the direct effects of ammoxetine on microglial activation and the signal transduction mechanism., Results: Treatment with ammoxetine for 4 weeks significantly relieved the mechanical allodynia and ameliorated depressive-like behavior in DNP rats. In addition, DNP rats displayed increased activation of microglia in the spinal cord, but not astrocytes. Ammoxetine reduced the microglial activation, accumulation of pro-inflammatory cytokines, and activation of p38 and c-Jun N-terminal kinase (JNK) in the spinal cord of DNP rats. Furthermore, ammoxetine displayed anti-inflammatory effects upon challenge with LPS in BV-2 microglia cells., Conclusion: Our results suggest that ammoxetine may be an effective treatment for relieving DNP symptoms. Moreover, a reduction in microglial activation and pro-inflammatory release by inhibiting the p-p38 and p-JNK pathways is involved in the mechanism.

In this paper, the problem of adaptive actor-critic (AC) tracking control is investigated for a class of continuous-time nonlinear systems with unknown nonlinearities and quantized inputs. Different from the existing results based on reinforcement learning, the tracking error constraints are considered and new critic functions are constructed to improve the performance further. To ensure that the tracking errors keep within the predefined time-varying boundaries, a tracking error transformation technique is used to constitute an augmented error system. Specific critic functions, rather than the long-term cost function, are introduced to supervise the tracking performance and tune the weights of the AC neural networks (NNs). A novel adaptive controller with a special structure is designed to reduce the effect of the NN reconstruction errors, input quantization, and disturbances. Based on the Lyapunov stability theory, the boundedness of the closed-loop signals and the desired tracking performance can be guaranteed. Finally, simulations on two connected inverted pendulums are given to illustrate the effectiveness of the proposed method.

This study aimed to investigate the effects of SPAR signaling pathway on the restoration of motor function in ischemic stroke (IS). Sprague-Dawley male rats were separated into the control and sham groups, as well as the group for middle cerebral artery occlusion (MCAO) model establishment. Successfully established rat ischemic models were randomly divided into model, SNK MCAO-del and pcDNA3.1-SNK groups. The evaluation of motor function among the rats in each group was assessed using a balance beam, a screen test and the Garcia scoring method. CatWalk gait analysis was employed to evaluate the effect of the SNK signaling pathway on rat motor function. Triphenyltetrazolium chloride (TTC) and TUNEL staining were techniques were utilized for cerebral infarction (CI) area as well for hippocampal neuron apoptosis. The quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting methods were performed to detect mRNA and protein expressions of SNK and SPAR. When compared with the model group, the SNK MCAO-del group displayed decreased motor function score and CI area, while contrasting results were observed in the pcDNA3.1-SNK group. According to the results obtained from the CatWalk gait analysis, the SNK MCAO-del group showed a clear improvement compared to the model group whereas the pcDNA3.1-SNK group exhibited poorer results than the model group in the objective parameters of the study, such as movement, speed, running duration, print area, maximal contact area, maximal, mean intensity, and stride length. These findings suggested that SNK gene silencing promotes motor function by inhibiting the SNK-SPAR signaling pathway in rats with ischemic stroke., (© 2017 Wiley Periodicals, Inc.)

This paper is concerned with the problem of active complementary control design for affine nonlinear control systems with actuator faults. The outage and loss of effectiveness fault cases are considered. In order to achieve the performance enhancement of the faulty control system, the complementary control scheme is designed in two steps. Firstly, a novel fault estimation scheme is developed. Then, by using the fault estimations to reconstruct the faulty system dynamics and introducing a cost function as the optimization objective, a nearly optimal complementary control is obtained online based on the adaptive dynamic programming (ADP) method. Unlike most of the previous ADP methods with the addition of a probing signal, new adaptive weight update laws are derived to guarantee the convergence of neural network weights and the stability of the closed-loop system, which strongly supports the online implementation of the ADP method. Finally, two simulation examples are given to illustrate the performance and effectiveness of the proposed method.

This study aims to explore the effects of long non-coding RNA H19 (lncRNA H19) and microRNA let7a (miRNA let7a) expression on the prognosis of thyroid cancer (TC). This may aid in the discovery of more effective treatment and prognosis approaches for TC. Between January 2008 and January 2011, 131 TC tissues and adjacent tissues were obtained from TC patients. An additional 122 normal thyroid tissues were also collected as normal controls from patients with benign thyroid lesions. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect lncRNA H19 and miRNA let7a mRNA expression. Five-year follow-ups were conducted. A Receiver operating characteristic (ROC) curve was used to evaluate the diagnostic values of lncRNA H19 and miRNA let7a in TC. The Kaplan-Meier method was applied to analyze the 5-year survival rate of TC patients. Univariate and multivariate factor analyses were employed to analyze the prognostic factors of TC. The lncRNA H19 mRNA expression was higher while the miRNA let7a mRNA expression was lower in TC tissues than, in the normal thyroid tissues and adjacent tissues. The area under the ROC curve (AUC) of lncRNA H19 and miRNA let7a were 0.801 and 0.116, with sensitivity at 72.5% and 84%, as well as specificity 75.4% and 77%, respectively. In TC patients with tumor diameters≥1.0cm, lncRNA H19 mRNA expression was elevated, but miRNA let7a mRNA expression was reduced. This was also evident in TC patients with TNM stages III+IV and those with lymph node metastasis. TC patients with a lower 5-year survival rate showed upregulated levels of lncRNA H19 expression and, downregulated levels of miRNA let7a expression. LncRNA H19 and miRNA let7a expression, tumor diameter, TNM stage and lymph node metastasis were independent prognostic factors of TC. This study demonstrated that increased lncRNA H19 and decreased miRNA let7a expression levels are associated with poor prognosis in TC patients. An inverse relationship between lncRNA H19 and miRNA let7a expression levels was exhibited., (Copyright © 2017. Published by Elsevier Inc.)

Objective The aim of this study was to construct an in vivo carotid siphon model for testing neurovascular devices for endovascular interventions. Methods A model of a human carotid siphon was pre-shaped using a glass tube from a human cadaver and used to confine a segment of one side of the common carotid artery (CCA) in canines. This segment of CCA with the glass carotid siphon on was interposed end-to-end onto the contralateral CCA so as to simulate a human carotid artery siphon in vivo. Two weeks later, the siphon model was evaluated using computed tomography angiography and digital subtraction angiography, and the covered stent specially designed for intracranial vasculature was navigated through the siphon model for a longitudinal flexibility test. Results All dogs tolerated the procedures well, and the artificial siphon model in vivo provided realistic conditions for device testing. Two weeks later, the in vivo carotid siphon model remained patent with no thrombosis. Five covered stents were navigated to pass through five siphon models successfully, with vasospasm occurring in two siphons. Conclusion Construction of an in vivo siphon model in dogs with a glass tube is feasible and useful for the test of endovascular devices for treating neurovascular diseases.

Purpose: To quantitatively measure the morphology parameters of the right auricle with 256-slice multidetector computed tomography angiography (MDCTA) in healthy people., Materials and Methods: A retrospective analysis of 200 patients who had undergone coronary MDCTA with negative findings was performed. The raw imaging data were reconstructed and the right auricular volume, right atrial volume, right auricle height, base long and short axes, base perimeter and area, normal angle, and distance were quantitatively measured., Results: Men had significantly (P < 0.05) greater values than women in the right auricular volume (13.3 ± 4.0 vs. 11.7 ± 3.7 mL) and height (33.0 ± 5.0 vs. 30.5 ± 5.2 mm), the base long axis (34.4 ± 4.1 vs. 33.2 ± 3.9 mm), area (787.6 ± 177.6 vs. 771.0 ± 143.2 mm 2 ) and perimeter (119.2 ± 17.5 vs. 115.0 ± 13.0), and the normal distance (22.4 ± 6.6 vs. 20.2 ± 6.7 mm). The normal 95 % reference range for the right auricular parameters was put forward. The right auricular parameters had a good correlation with the right atrium volume, aortic diameter, the body weight, height, and body surface area but a bad correlation with the vertebral body height. Significantly (P < 0.05) greater values were found in the normal angle and distance in subjects below than over 40 years of age. No other significant (P > 0.05) difference existed in the other right auricular parameters., Conclusion: Quantitative measurements of the right auricle can help us get a good understanding of the right auricular morphology and its relationship with surrounding structures and are helpful for cardiac interventions of electrophysiology and radiofrequency ablation.

The treatment of malignant tumors following surgery is important in preventing relapse. Among all the post-surgery treatments, immunomodulators have demonstrated satisfactory effects on preventing recurrence according to recent studies. Ginsenoside is a compound isolated from panax ginseng, which is a famous traditional Chinese medicine. Ginsenoside aids in killing tumor cells through numerous processes, including the antitumor processes of ginsenoside Rh2 and Rg1, and also affects the inflammatory processes of the immune system. However, the role that ginsenoside serves in antitumor immunological activity remains to be elucidated. Therefore, the present study aimed to analyze the effect of ginsenoside Rh2 on the antitumor immunological response. With a melanoma mice model, ginsenoside Rh2 was demonstrated to inhibit tumor growth and improved the survival time of the mice. Ginsenoside Rh2 enhanced T-lymphocyte infiltration in the tumor and triggered cytotoxicity in spleen lymphocytes. In addition, the immunological response triggered by ginsenoside Rh2 could be transferred to other mice. In conclusion, the present study provides evidence that ginsenoside Rh2 treatment enhanced the antitumor immunological response, which may be a potential therapy for melanoma.

The state inequality constraints have been hardly considered in the literature on solving the nonlinear optimal control problem based the adaptive dynamic programming (ADP) method. In this paper, an actor-critic (AC) algorithm is developed to solve the optimal control problem with a discounted cost function for a class of state-constrained nonaffine nonlinear systems. To overcome the difficulties resulting from the inequality constraints and the nonaffine nonlinearities of the controlled systems, a novel transformation technique with redesigned slack functions and a pre-compensator method are introduced to convert the constrained optimal control problem into an unconstrained one for affine nonlinear systems. Then, based on the policy iteration (PI) algorithm, an online AC scheme is proposed to learn the nearly optimal control policy for the obtained affine nonlinear dynamics. Using the information of the nonlinear model, novel adaptive update laws are designed to guarantee the convergence of the neural network (NN) weights and the stability of the affine nonlinear dynamics without the requirement for the probing signal. Finally, the effectiveness of the proposed method is validated by simulation studies., (Copyright © 2016 ISA. Published by Elsevier Ltd. All rights reserved.)

Purpose: To quantitatively investigate left ventricular volume and function in middle-aged healthy subjects., Materials and Methods: Ninety healthy volunteers underwent cardiac 3 Tesla MRI. The left ventricular end-diastolic volume (EDV) and end-systolic volume (ESV), stroke volume (SV), ejection fraction (EF), cardiac output (CO), myocardial mass (MM), and their normalized indices (EDVI, ESVI, SVI, CI, and MI, respectively) after corrected with the body surface area (BSA) were analyzed and compared at different ages., Results: All subjects had successfully completed the 3-Tesla cardiac MR. Females had significantly smaller EDV (110.5 ± 9.2 versus 125.7 ± 8.3 mL), ESV (36.1 ± 3.5 versus 41.5 ± 3.8 mL), SV (74.3 ± 6.3 versus 84.2 ± 6.7 mL), CO (5.4 ± 0.8 versus 5.8 ± 0.9 l/min) and MM (73.0 ± 10.5 versus 94.8 ± 10.6 g) than males (P < 0.05). The EF had no significant (P = 0.47) difference between genders (67.3 ± 1.7 percent in females versus 66.9 ± 2.4 percent in males). After normalization with BSA, no significant (P > 0.05) difference was detected between the genders in EDVI (71.2 ± 4.3 versus 71.1 ± 4.2 mL/m 2 , P = 0.882), ESVI (23.3 ± 1.9 versus 23.5 ± 1.9 mL/m 2 , P = 0.733) and SVI (47.9 ± 2.9 versus 47.7 ± 3.7 mL/m 2 , P = 0.698) except for CI and MI. Females had significantly (P < 0.05) greater CI (3.5 ± 0.4 versus 3.3 ± 0.4) but smaller MI (46.9 ± 5.3 versus 53.6 ± 7.6) than males. EDV, EDVI, ESV, ESVI, SV, and SVI significantly (P < 0.05) decreased with age increase. BSA was positively correlated with EDV, ESV, SV, MM, and CO. No significance (P > 0.05) was detected in other parameters., Conclusion: The left ventricular volume and function differs in women compared with men in the middle-aged population, and these parameters have a tendency of decrease with ageing. J. Magn. Reson. Imaging 2016;44:1143-1150., (© 2016 International Society for Magnetic Resonance in Medicine.)

Aim: The selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors (SNRIs) are commonly used for the treatment of neuropathic pain and fibromyalgia. Ammoxetine ((±)-3-(benzo[d] [1,3]dioxol-4-yloxy)-N-methyl-3-(thiophen-2-yl)propan-1-amine) has been identified as a novel potent SNRI. In this study, we evaluated the acute analgesic properties of ammoxetine in different animal models of pain, and examined the involvement of monoamines in its analgesic actions., Methods: The analgesic effects of ammoxetine were assayed using models of acetic acid- and formalin-induced pain in mice, neuropathic pain induced by sciatic nerve injury (SNI), chronic constriction injury (CCI) and reserpine-induced fibromyalgia pain in rats. The contents of 5-HT and NE in brain regions of fibromyalgia rats were measured using HPLC-ECD. In all the experiments, duloxetine was used as a positive control drug., Results: Oral administration of ammoxetine (0.625-10 mg/kg) or duloxetine (2.5-40 mg/kg) dose-dependently decreased the number of acetic acid-induced writhing and formalin-induced first phase and second phase paw licking time in mice. Oral administration of ammoxetine (2.5-10 mg/kg) or duloxetine (10 mg/kg) alleviated mechanical allodynia in SNI and CCI rats and thermal hyperalgesia in CCI rats. The antiallodynic effect of ammoxetine in CCI rats was abolished by pretreatment with para-chlorophenylalanine methyl ester hydrochloride (PCPA, a 5-HT synthesis inhibitor) or α-methyl-para-tyrosine methylester (AMPT, a catecholamine synthesis inhibitor). Oral administration of ammoxetine (30 mg/kg) or duloxetine (50 mg/kg) significantly attenuated tactile allodynia in rats with reserpine-induced fibromyalgia. In the fibromyalgia rats, administration of ammoxetine (10, 30 mg/kg) or duloxetine (30, 50 mg/kg) dose-dependently increased the levels of 5-HT and NE, and decreased the metabolite ratio of 5-HT (5-HIAA/5-HT) in the spinal cord, hypothalamus, thalamus and prefrontal cortex., Conclusion: Ammoxetine effectively alleviates inflammatory, continuous, neuropathic and fibromyalgia-related pain in animal models, which can be attributed to enhanced neurotransmission of 5-HT and NE in the descending inhibitory systems.

Objectives: To evaluate the classification and diameter of left gastric vein (LGV) in healthy Chinese adults with multi-detector computed tomography (MDCT)., Methods: MDCT angiography was performed in 234 healthy adults for the portal venous system. CT cross-sectional thin-layer reconstruction combined with maximum intensity projection, volume rendering and multiplanar reconstruction were applied. The diameter of LGV was measured at the point within 2 cm from LGV origination., Results: Of 234 subjects, 11 subjects (4.70%) who did not have clear images were excluded, and 223 subjects (95.30%) with excellent images were included. The LGV was originated from the portal vein in 46.15%, splenic vein in 30.77%, portal splenic angle in 14.53%, and the left branch of the portal vein in 3.85%. The maximal diameter of LGV was 4.74 ± 0.84 mm with a 95% confidence interval of 4.63-4.85 mm, and the LGV diameter was positively correlated with the weight of patients (R = 0.26, P = 0.006). No significant difference existed in the maximal diameter of LGV at different origination sites (P = 0.35). The diameter of LGV was significantly greater in males than in females (4.90 ± 0.85 vs. 4.56 ± 0.80 mm, P = 0.002), and the maximal diameter of LGV was significantly (P = 0.02) greater in the age range of 30-39 and 40-49 years than in the range of >70 years. No statistical significance (P = 0.36) was detected in the other groups., Conclusion: MDCT can clearly display the detailed anatomy and variation of LGV in healthy adults, providing a normal range of LGV diameter for clinical reference for diagnosing possible portal hypertension and for possible intervention.