Discovery of Novel Hybrids of Edaravone and 6-phenyl-4,5-dihydropyridazin-3(2H)-one with Antiplatelet Aggregation and Neuroprotection for Ischemic Stroke Treatment.

Drugs with anti-platelet aggregation and neuroprotection are of great significance for the treatment of ischemic stroke. A series of edaravone and 6-phenyl-4,5-dihydropyridazin-3(2H)-one hybrids were designed and synthesized. Among them, 6g showed the most effective cytoprotective effect against oxygen-glucose deprivation/reoxygenation-induced damage in BV2 cells and an excellent inhibitory effect on platelet aggregation induced by adenosine diphosphate and arachidonic acid. Additionally, 6g could prevent thrombosis caused by ferric chloride in rats and pose a lower risk of causing bleeding compared with aspirin. It provides better protection against ischemia/reperfusion injury in rats compared with edaravone and alleviates the oxidative stress related to cerebral ischemia/reperfusion by increasing the GSH and SOD levels and decreasing the MDA concentration. Finally, molecular docking results showed that 6g probably acts on PDE3 A and plays an anti-platelet aggregation effect. Overall, 6g could be a potential candidate compound for the treatment of ischemic stroke.

Effects of irrelevant unintelligible and intelligible background speech on spoken language production.

Earlier work has explored spoken word production during irrelevant background speech such as intelligible and unintelligible word lists. The present study compared how different types of irrelevant background speech (word lists vs. sentences) influenced spoken word production relative to a quiet control condition, and whether the influence depended on the intelligibility of the background speech. Experiment 1 presented native Dutch speakers with Chinese word lists and sentences. Experiment 2 presented a similar group with Dutch word lists and sentences. In both experiments, the lexical selection demands in speech production were manipulated by varying name agreement (high vs. low) of the to-be-named pictures. Results showed that background speech, regardless of its intelligibility, disrupted spoken word production relative to a quiet condition, but no effects of word lists versus sentences in either language were found. Moreover, the disruption by intelligible background speech compared with the quiet condition was eliminated when planning low name agreement pictures. These findings suggest that any speech, even unintelligible speech, interferes with production, which implies that the disruption of spoken word production is mainly phonological in nature. The disruption by intelligible background speech can be reduced or eliminated via top-down attentional engagement.

Retraction: Co3 O4 Polyhedron@MnO2 Nanotube Composite as Anode for High-Performance Lithium-Ion Batteries.

Small 2021, 17, 2008165 DOI: 10.1002/smll.202008165 The above article in Small, published online on 26 March 2021 in Wiley Online Library (https://onlinelibrary.wiley.com/doi/abs/10.1002/smll.202008165),[1] has been retracted by agreement between the authors, the Editor-in-Chief, José Oliveira, and Wiley-VCH GmbH. The retraction has been agreed following an investigation by the corresponding author. The electrochemical measurements on the anode were performed in a wrong manner and cannot reliably be reproduced. The conclusions of this article are considered to be invalid. The authors agree with the retraction but were not available to confirm the final wording of the retraction. [1] Z. Cao, Y. Yang, J. Qin, J. He, Z. Su, Small 2021, 17, 2008165.

Dissociation of Writing Processes: A Functional Magnetic Resonance Imaging Study on the Neural Substrates for the Handwritten Production of Chinese Characters.

Writing is an important way to communicate in everyday life because it can convey information over time and space, but its neural substrates remain poorly known. Although the neural basis of written language production has been investigated in alphabetic scripts, it has rarely been examined in nonalphabetic languages such as Chinese. The present functional magnetic resonance imaging study explored the neural substrates of handwritten word production in Chinese and identified the brain regions sensitive to the psycholinguistic factors of word frequency and syllable frequency. To capture this, we contrasted neural activation in "writing" with "speaking plus drawing" and "watching plus drawing." Word frequency (high, low) and syllable frequency (high, low) of the picture names were manipulated. Contrasts between the tasks showed that writing Chinese characters was mainly associated with brain activation in the left frontal and parietal cortex, whereas orthographic processing and the motor procedures necessary for handwritten production were also related to activation in the right frontal and parietal cortex as well as right putamen/thalamus. These results demonstrate that writing Chinese characters requires activation in bilateral cortical regions and the right putamen/thalamus. Our results also revealed no brain activation associated with the main effects of word frequency and syllable frequency as well as their interaction, which implies that word frequency and syllable frequency may not affect the writing of Chinese characters on a neural level.

[Mechanism of Liangfu Pills in treatment of functional dyspepsia: based on network pharmacology and experimental verification].

This study aims to explore the potential mechanism of Liangfu Pills in the treatment of functional dyspepsia(FD) based on network pharmacology and molecular docking, and verify the mechanism by animal experiment. The active components of Liangfu Pills were screened from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP), and the targets of Liangfu Pills were predicted by SwissTargetPrediction. The targets of FD were retrieved from GeneCards. On this basis, the common targets of the disease and the pills were yielded and the protein interaction was retrieved based on STRING. The core targets were screened out, followed by Gene Oncology(GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis with DAVID. Finally, molecular docking was carried out with the help of AutoDock Tools to predict the binding degree between the effective components of Liangfu Pills and core targets. A total of 19 active components of Liangfu Pills and 591 FD-related targets were screened out by network pharmacology, of which 253 were common targets of the disease and the prescription. Liangfu Pills was mainly involved in the biological processes of response to drug, negative regulation of transcription, positive regulation of apoptotic process, and cell surface receptor signaling pathway, and the KEGG pathways of hypoxia-inducible factor-1(HIF-1) signaling pathway, serotonergic synapse, tumor necrosis factor(TNF) signaling pathway, cyclic adenosine monophosphate(cAMP) signaling pathway, calcium signal pathway, and inflammatory mediator regulation of transient receptor potential(TRP) channels. The results of molecular docking showed that the key active components of Liangfu Pills had certain binding activity to the targets mitogen-activated protein kinase 1(MAPK1), protein kinase B(AKT1), transient receptor potential cation channel subfamily V member 1(TRPV1), 5-hydroxytryptamine receptor 1 A(HTR1 A), and 5-hydroxytryptamine receptor 2 A(HTR2 A). FD was induced in rats, and then Liangfu Pills was given to FD rats for 7 days. The results showed that Liangfu Pills could significantly relieve the symptoms of FD rats, significantly increase the expression of 5-hydroxytryptamine(5-HT), and down-regulate the expression of TRPV1. Through network pharmacology, molecular docking, and experimental verification, this study proved that Liangfu Pills improved FD through multiple components and multiple targets. The result lays a basis for further research on the mechanism and clinical application of Liangfu Pills in the treatment of FD.

Optimization Analysis of Two-Factor Continuous Variable between Thread Depth and Pitch of Microimplant under Toque Force.

Microimplant, an anchorage device, is widely applied in clinical orthodontic treatment. Since tooth torque is required to be controlled during orthodontic tooth movement, a novel microimplant needs to be developed to apply better torque force during orthodontic. In this study, the optimal value ranges of thread depth and pitch under toque force were studied for choosing microimplant with relevant value ranges in clinical design from biomechanical perspective. Finite element analysis (FEA) and optimization design technology were used for accessing the optimal value ranges of thread depth and pitch under toque force. Thread depth (D) (0.1 mm to 0.4 mm) and pitch (P) (0.4 mm to 1 mm) were used as continuous variables, with the other parameters as constant, and the optimal value ranges were obtained by analyzing the tangent slope and sensitivity of the response curve. When a torque force of 6 Nmm was applied on the microimplant, the maximum equivalent stress (Max EQV) of cortical bone and maximum displacements (Max DM) of microimplant were analysis indexes. When 0.55 mm ≤ P ≤ 1 mm, the Max EQV of cortical bone was relatively smaller with less variation range. When 0.1 mm ≤ D ≤ 0.35 mm, the Max DM of microimplant was relatively smaller with less variation range. So in conclusion, the initial stability of microimplants with pitch 0.55 mm ≤ P ≤ 1 mm and thread depth 0.1 mm ≤ D ≤ 0.35 mm was better with the torque force applied.

Proprioceptive Training with Visual Feedback Improves Upper Limb Function in Stroke Patients: A Pilot Study.

Proprioceptive deficit is one of the common sensory impairments following stroke and has a negative impact on motor performance. However, evidence-based training procedures and cost-efficient training setups for patients with poststroke are still limited. We compared the effects of proprioceptive training versus nonspecific sensory stimulation on upper limb proprioception and motor function rehabilitation. In this multicenter, single-blind, randomized controlled trial, 40 participants with poststroke hemiparesis were enrolled from 3 hospitals in China. Participants were assigned randomly to receive proprioceptive training involving passive and active movements with visual feedback (proprioceptive training group [PG]; n = 20) or nonspecific sensory stimulation (control group [CG]; n = 20) 20 times in four weeks. Each session lasted 30 minutes. A clinical assessor blinded to group assignment evaluated patients before and after the intervention. The primary outcome was the change in the motor subscale of the Fugl-Meyer assessment for upper extremity (FMA-UE-M). Secondary outcomes were changes in box and block test (BBT), thumb localization test (TLT), the sensory subscale of the Fugl-Meyer assessment for upper extremity (FMA-UE-S), and Barthel Index (BI). The results showed that the mean change scores of FMA-UE were significantly greater in the PG than in the CG (p = 0.010 for FMA-UE-M, p = 0.033 for FMA-UE-S). The PG group was improved significantly in TLT (p = 0.010) and BBT (p = 0.027), while there was no significant improvement in TLT (p = 0.083) and BBT (p = 0.107) for the CG group. The results showed that proprioceptive training was effective in improving proprioception and motor function of the upper extremity in patients with poststroke. This trial is registered in the Chinese Clinical Trial Registry (ChiCTR2000037808).

Exercise-induced neuroprotection against cerebral ischemia/reperfusion injury is mediated via alleviating inflammasome-induced pyroptosis.

As a primary nonpharmacological tool, exercise training is neuroprotective after experimental ischemic stroke by relieving neuroinflammation. However, the specific mechanism of which and anti-inflammatory effect of exercise at different intensities require in-depth investigations. To explore the issue, middle cerebral artery occlusion-reperfusion (MCAO-r) in mice were utilized, with subsequent exercise training at different intensities (high-intensity interval training versus moderate-intensity continuous training, i.e. HIIT vs. MICT) during an early phase post-modeling. The neurobehavioral assessment showed that MICT improved the performance of neurological deficit scores and rotarod test earlier, while HIIT appeared to be more efficacious to meliorate locomotor impairments and aerobic fitness at the end of intervention. Both exercise regimens inhibited the expressions of NLRP3 inflammasome components (NLRP3, ASC, and Cl.caspase-1) and pyroptosis-associated proteins (GSDMD, Cl.IL-1ß, and Cl.IL-18) as indicated by western blot and immunofluorescence co-staining. Multiplex assay panel revealed that both exercise regimens reduced the levels of pro-inflammatory cytokines and upregulated anti-inflammatory cytokine. Furthermore, an increased proportion of M2-like microglia and a diminished proportion of M1-like microglia in the peri-infarct zone were observed by colocalization analysis, which was jointly validated by western blot. Here, for the first time, our study demonstrated that HIIT elicited better improvements at functional and cardiovascular levels than MICT after ischemic stroke, and anti-inflammatory effect of exercise might result from suppression in inflammasome-mediated pyroptosis by shifting microglial polarization toward neuroprotective M2 phenotype.

Long-term Effectiveness and Adoption of a Cellphone Augmented Reality System on Patients with Stroke: Randomized Controlled Trial.

BACKGROUND: A serious game-based cellphone augmented reality system (CARS) was developed for rehabilitation of stroke survivors, which is portable, convenient, and suitable for self-training. OBJECTIVE: This study aims to examine the effectiveness of CARS in improving upper limb motor function and cognitive function of stroke survivors via conducting a long-term randomized controlled trial and analyze the patient's acceptance of the proposed system. METHODS: A double-blind randomized controlled trial was performed with 30 poststroke, subacute phase patients. All patients in both the experimental group (n=15) and the control group (n=15) performed a 1-hour session of therapy each day, 5 days per week for 2 weeks. Patients in the experimental group received 30 minutes of rehabilitation training with CARS and 30 minutes of conventional occupational therapy (OT) each session, while patients in the control group received conventional OT for the full 1 hour each session. The Fugl-Meyer Assessment of Upper Extremity (FMA-UE) subscale, Action Research Arm Test (ARAT), manual muscle test and Brunnstrom stage were used to assess motor function; the Mini-Mental State Examination, Add VS Sub, and Stroop Game were used to assess cognitive function; and the Barthel index was used to assess activities of daily living before and after the 2-week treatment period. In addition, the User Satisfaction Evaluation Questionnaire was used to reflect the patients' adoption of the system in the experimental group after the final intervention. RESULTS: All the assessment scores of the experimental group and control group were significantly improved after intervention. After the intervention. The experimental group's FMA-UE and ARAT scores increased by 11.47 and 5.86, respectively, and were both significantly higher than the increase of the control group. Similarly, the score of the Add VS Sub and Stroop Game in the experimental group increased by 7.53 and 6.83, respectively, after the intervention, which also represented a higher increase than that in the control group. The evaluation of the adoption of this system had 3 sub-dimensions. In terms of accessibility, the patients reported a mean score of 4.27 (SD 0.704) for the enjoyment of their experience with the system, a mean 4.33 (SD 0.816) for success in using the system, and a mean 4.67 (SD 0.617) for the ability to control the system. In terms of comfort, the patients reported a mean 4.40 (SD 0.737) for the clarity of information provided by the system and a mean 4.40 (SD 0.632) for comfort. In terms of acceptability, the patients reported a mean 4.27 (SD 0.884) for usefulness in their rehabilitation and a mean 4.67 (0.617) in agreeing that CARS is a suitable tool for home-based rehabilitation. CONCLUSIONS: The rehabilitation based on combined CARS and conventional OT was more effective in improving both upper limb motor function and cognitive function than was conventional OT. Due to the low cost and ease of use, CARS is also potentially suitable for home-based rehabilitation. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1800017568; https://tinyurl.com/xbkkyfyz.

Customizing Robot-Assisted Passive Neurorehabilitation Exercise Based on Teaching Training Mechanism.

Passive movement is an important mean of rehabilitation for stroke survivors in the early stage or with greater paralysis. The upper extremity robot is required to assist therapists with passive movement during clinical rehabilitation, while customizing is one of the crucial issues for robot-assisted upper extremity training, which fits the patient-centeredness. Robot-assisted teaching training could address the need well. However, the existing control strategies of teaching training are usually commanded by position merely, having trouble to achieve the efficacy of treatment by therapists. And deficiency of flexibility and compliance comes to the training trajectory. This research presents a novel motion control strategy for customized robot-assisted passive neurorehabilitation. The teaching training mechanism is developed to coordinate the movement of the shoulder and elbow, ensuring the training trajectory correspondence with human kinematics. Furthermore, the motion trajectory is adjusted by arm strength to realize dexterity and flexibility. Meanwhile, the torque sensor employed in the human-robot interactive system identifies movement intention of human. The goal-directed games and feedbacks promote the motor positivity of stroke survivors. In addition, functional experiments and clinical experiments are investigated with a healthy adult and five recruited stroke survivors, respectively. The experimental results present that the suggested control strategy not only serves with safety training but also presents rehabilitation efficacy.

Co3 O4 Polyhedron@MnO2 Nanotube Composite as Anode for High-Performance Lithium-Ion Batteries.

In this work, a novel lollipop nanostructure of Co3 O4 @MnO2 composite is prepared as anode material in lithium-ion batteries (LIBs). Cobalt metal-organic framework (ZIF-67) is grown on the open end of MnO2 nanotubes via a self-assembly process. The obtained ZIF-67@MnO2 is then converted to Co3 O4 @MnO2 by a simple annealing treatment in air. Scanning electron microscopy, transmission electron microscopy, and X-ray diffraction characterizations indicate that the prepared Co3 O4 @MnO2 takes a lollipop nanostructure with a stick of ≈100 nm in diameter, consisting of MnO2 nanotube, and a head part of ≈1 µm, consisting of Co3 O4 nanoparticles. The charge-discharge tests illustrate that this unique novel configuration endows the resulting Co3 O4 @MnO2 with excellent electrochemical performances, delivering a capacity of 1080 mAh g-1 at 300 mA g-1 after 160 cycles, and 696 mAh g-1 at 1 A g-1 after 210 cycles, compared with 404 mAh g-1 and 590 for pure Co3 O4 polyhedrons and pure MnO2 nanotubes at 300 mA g-1 after 160 cycles, respectively. The lollipop configuration consisting of porous Co3 O4 polyhedron and MnO2 nanotube shows excellent structural stability and facilitates lithium insertion/extraction, leading to excellent cyclic stability and rate capacity of Co3 O4 @MnO2 -based LIBs.