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Background: Balance and mobility deficits are major concerns in stroke rehabilitation. Virtual reality (VR) training and Swiss-ball training are commonly used approaches to improve balance and mobility. However, no study has compared the efficacy of VR training, Swiss-ball training, and their combination in improving balance and mobility function or investigated cortical activation and connectivity in individuals with stroke., Methods: A prospective, single-blinded, parallel-armed, multi-center randomized controlled trial with factorial design will be conducted. Seventy-six participants aged 30-80 years with stroke will be recruited. Participants will be allocated to one of the four groups: (A) the VR training + Swiss-ball training + conventional physical therapy group; (B) the Swiss-ball training + conventional physical therapy group; (C) the VR training + conventional physical therapy group; or (D) the conventional physical therapy group. All participants will receive 50 min of training per day, 5 times per week, for a total of 4 weeks. The primary outcomes will be balance and mobility measures. Secondary outcomes will include the 10-min walk test, dynamic gait index, and cortical activation. Outcomes will be measured on three occasions: at baseline, after the training, and at the 4-week follow-up., Discussion: This trial will provide evidence to determine whether there are differences in clinical outcomes and cortical activation following two different types of exercise programs and their combination, and to elucidate the recovery mechanisms of balance and mobility function in individuals with stroke., Trial Registration: Chinese Clinical Trial Registry reference: www.chictr.org.cn (No. ChiCTR2400082135). Registered on May 24, 2024., (© 2024. The Author(s).)

Although the coronavirus disease 2019 (COVID-19) crisis has passed, there remains a necessity for continuous efforts toward developing more targeted drugs and preparing for potential future virus attacks. Currently, most of the drugs received authorization for the treatment of COVID-19 have exhibited several limitations, such as poor metabolic stability, formidable preparation, and uncertain effectiveness. It is still significant to develop novel, structurally diverse small-molecule antiviral drugs targeting SARS-CoV-2 3-chymotrypsin-like protease (3CL pro ). Herein, we report a class of alkynylamide-based nonpeptidic 3CL pro inhibitors that can be prepared conveniently by our previously developed one-pot synthetic method. The structure-activity relationships of alkynylamides as SARS-CoV-2 3CL pro inhibitors have been carefully investigated and discussed in this study. The two stereoisomers of the resulting molecules exhibit stereoselective interaction with 3CL pro , and the optimized compound ( S , R )- 4y inhibits 3CL pro with high potency (IC 50 = 0.43 μM), low cytotoxicity, and acceptable cell permeability. Compound ( S , R )- 4y presents as a noncovalent inhibitor of 3CL pro against SARS-CoV-2 by the time-dependent inhibition assay (TDI) and mass spectrometry analysis. The Lineweaver-Burk plots, binding energy, surface plasmon resonance, and molecular docking studies suggest that ( S , R )- 4y specifically binds to an allosteric pocket of the SARS-CoV-2 3CL pro . These findings provide a novel class of nonpeptidic alkynylamide-based allosteric inhibitors with high selectivity against SARS-CoV-2 3CL pro featured by a simplified one-pot synthesis at room temperature in air., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

Objectives: The objective of this study was to investigate whether skeletal muscle cystathionine γ-lyase (CTH) contributes to high-fat diet (HFD)-induced metabolic disorders using skeletal muscle Cth knockout ( Cth Δskm ) mice., Methods: The Cth Δskm mice and littermate Cth-floxed ( Cth f/f ) mice were fed with either HFD or chow diet for 13 weeks. Metabolomics and transcriptome analysis were used to assess the impact of CTH deficiency in skeletal muscle., Results: Metabolomics coupled with transcriptome showed that Cth Δskm mice displayed impaired energy metabolism and some signaling pathways linked to insulin resistance (IR) in skeletal muscle although the mice had normal insulin sensitivity. HFD led to reduced CTH expression and impaired energy metabolism in skeletal muscle in Cth f/f mice. CTH deficiency and HFD had some common pathways enriched in the aspects of amino acid metabolism, carbon metabolism, and fatty acid metabolism. Cth Δskm +HFD mice exhibited increased body weight gain, fasting blood glucose, plasma insulin, and IR, and reduced glucose transporter 4 and CD36 expression in skeletal muscle compared to Cth f/f +HFD mice. Impaired mitochondria and irregular arrangement in myofilament occurred in Cth Δskm +HFD mice. Omics analysis showed differential pathways enriched between Cth Δskm mice and Cth f/f mice upon HFD. More severity in impaired energy metabolism, reduced AMPK signaling, and increased oxidative stress and ferroptosis occurred in Cth Δskm +HFD mice compared to Cth f/f +HFD mice., Discussion: Our results indicate that skeletal muscle CTH expression dysregulation contributes to metabolism disorders upon HFD.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to pose a significant global public health threat, particularly to older adults, pregnant women, and individuals with underlying chronic conditions. Dysregulated immune responses to SARS-CoV-2 infection are believed to contribute to the progression of COVID-19 in severe cases. Previous studies indicates that a deficiency in type I interferon (IFN-I) immunity accounts for approximately 15 %-20 % of patients with severe pneumonia caused by COVID-19, highlighting the potential therapeutic importance of modulating IFN-I signals. Natural products and their derivatives, due to their structural diversity and novel scaffolds, play a crucial role in drug discovery. Some of these natural products targeting IFN-I have demonstrated applications in infectious diseases and inflammatory conditions. However, the immunomodulatory potential of IFN-I in critical COVID-19 pneumonia and the natural compounds regulating the related signal pathway remain not fully understood. In this review, we offer a comprehensive assessment of the association between IFN-I and severe COVID-19, exploring its mechanisms and integrating information on natural compounds effective for IFN-I regulation. Focusing on the primary targets of IFN-I, we also summarize the regulatory mechanisms of natural products, their impact on IFNs, and their therapeutic roles in viral infections. Collectively, by synthesizing these findings, our goal is to provide a valuable reference for future research and to inspire innovative treatment strategies for COVID-19., 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 Ltd. All rights reserved.)

A slow-wave structure improvement for enhancing the 2π-mode electronic efficiency is embodied in the validation of an extended interaction oscillator (EIO), which has an electronic efficiency of 6.52% at 0.22 THz from particle-in-cell (PIC) calculations. A 2π-mode bi-periodic slow-wave structure (BPSWS) with staggered long and short slots is utilized for optimizing the circuit performance. The proposed BPSWS has the capability of combining the respective advantages for both π and 2π-mode in terms of coupling performance and output performance, thus supporting a strongly-coupled 2π-mode with higher coupling capability. Compared with the typical mono-periodic SWS (MPSWS), the adopted strongly-coupled 2π-mode effectively improves the characteristic impedance M 2 R/Q by 103% to 66.79 Ω, the coupling coefficient by 66% to 0.497, and the normalized wave-amplitude by 22%. Accordingly, 503 W of average output power can be derived for the BPSWS-EIO with a 25.7 kV and 0.3 A sheet beam injected. Cold-test experiments were conducted, confirming that the 0.22 THz structure exhibits commendable fabrication precision and consistency and thus demonstrates the expected frequency response., (© 2024. The Author(s).)

Monitoring the long-term changes in antibody and cellular immunity following Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is crucial for understanding immune mechanisms that prevent reinfection. In March 2023, we recruited 167 participants from the Changning District, Shanghai, China. A subset of 66 participants that were infected between November 2022 and January 2023 was selected for longitudinal follow-up. The study aimed to investigate the dynamics of the immune response, including neutralizing antibodies (NAbs), anti-spike (S)-immunoglobulin G (IgG), anti-S-IgM, and lymphocyte profiles, by analyzing peripheral blood samples collected three to seven months post infection. A gradual decrease in NAbs and IgG levels were observed from three to seven months post infection. No significant differences in NAbs and IgG titers were found across various demographics, including age, sex, occupation, and symptomatic presentation, across five follow-up assessments. Additionally, a strong correlation between NAbs and IgG levels was identified. Lymphocyte profiles showed a slight change at five months but had returned to baseline levels by seven months post infection. Notably, healthcare workers exhibited lower B-cell levels compared to police officers. Our study demonstrated that the immune response to SARS-CoV-2 infection persisted for at least seven months. Similar patterns in the dynamics of antibody responses and cellular immunity were observed throughout this period.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been ongoing for more than three years and urgently needs to be addressed. Traditional Chinese medicine (TCM) prescriptions have played an important role in the clinical treatment of patients with COVID-19 in China. However, it is difficult to uncover the potential molecular mechanisms of the active ingredients in these TCM prescriptions. In this paper, we developed a new approach by integrating the experimental assay, virtual screening, and the experimental verification, exploring the rapid discovery of active ingredients from TCM prescriptions. To achieve this goal, 4 TCM prescriptions in clinical use for different indications were selected to find the antiviral active ingredients in TCMs. The 3-chymotrypsin-like protease (3CL pro ), an important target for fighting COVID-19, was utilized to determine the inhibitory activity of the TCM prescriptions and single herb. It was found that 10 single herbs had better inhibitory activity than other herbs by using a fluorescence resonance energy transfer (FRET) - based enzymatic assay of SARS-CoV-2 3CL pro . The ingredients contained in 10 herbs were thus virtually screened and the predicted active ingredients were experimentally validated. Thus, such a research strategy firstly removed many single herbs with no inhibitory activity against SARS-CoV-2 3CL pro at the very beginning by FRET-based assay, making our subsequent virtual screening more effective. Finally, 4 active components were found to have stronger inhibitory effects on SARS-CoV-2 3CL pro , and their inhibitory mechanism was subsequently investigated. Among of them, methyl rosmarinate as an allosteric inhibitor of SARS-CoV-2 3CL pro was confirmed and its ability to inhibit viral replication was demonstrated by the SARS-CoV-2 replicon system. To validate the binding mode via docking, the mutation experiment, circular dichroism (CD), enzymatic inhibition and surface plasmon resonance (SPR) assay were performed, demonstrating that methyl rosmarinate bound to the allosteric site of SARS-CoV-2 3CL pro . In conclusion, this paper provides the new ideas for the rapid discovery of active ingredients in TCM prescriptions based on a specific target, and methyl rosmarinate has the potential to be developed as an antiviral therapeutic candidate against SARS-CoV-2 infection., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The development of Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) inhibitors is a hot spot in the research and development of antitumor drugs, which may induce immunomodulatory effects in the tumor microenvironment and participate in anti-tumor immune responses. To date, several SHP2 inhibitors have made remarkable progress and entered clinical trials for the treatment of patients with advanced solid tumors. Multiple compounds derived from natural products have been proved to influence tumor cell proliferation, apoptosis, migration and other cellular functions, modulate cell cycle and immune cell activation by regulating the function of SHP2 and its mutants. However, there is a paucity of information about their diversity, biochemistry, and therapeutic potential of targeting SHP2 in tumors. This review will provide the structure, classification, inhibitory activities, experimental models, and antitumor effects of the natural products. Notably, this review summarizes recent advance in the efficacy and pharmacological mechanism of natural products targeting SHP2 in inhibiting the various signaling pathways that regulate different cancers and thus pave the way for further development of anticancer drugs targeting SHP2., (© 2024 John Wiley & Sons Ltd.)

Chemotherapy combining with surgical treatment has been the main strategy for osteosarcoma treatment in clinical. Due to unclear pathogenesis and unidentified drug targets, significant progress has not been made in the development of targeted drugs for osteosarcoma during the past 50 years. Our previous discovery reported compound R-8i with a high potency for the treatment of osteosarcoma by phenotypic screening. However, both the metabolic stability and bioavailability of R-8i are poor (T 1/2  = 5.36 min, mouse liver microsome; and bioavailability in vivo F = 52.1 %, intraperitoneal administration) which limits it use for further drug development. Here, we described an extensive structure-activity relationship study of thiazolidine-4-one sulfone inhibitors from R-8i, which led to the discovery of compound 68. Compound 68 had a potent cellular activity with an IC 50 value of 0.217 μM, much higher half-life (T 1/2  = 73.8 min, mouse liver microsome) and an excellent pharmacokinetic profile (in vivo bioavailability F = 115 %, intraperitoneal administration). Compound 68 also showed good antitumor effects and low toxicity in a xenograft model (44.6 % inhibition osteosarcoma growth in BALB/c mice). These results suggest that compound 68 is a potential drug candidate for the treatment of osteosarcoma., 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 Masson SAS. All rights reserved.)

Introduction: Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that modulates brain states by applying a weak electrical current to the brain cortex. Several studies have shown that anodal stimulation of the ipsilesional primary motor cortex (M1) may promote motor recovery of the affected upper limb in patients with stroke; however, a high-level clinical recommendation cannot be drawn in view of inconsistent findings. A priming brain stimulation protocol has been proposed to induce stable modulatory effects, in which an inhibitory stimulation is applied prior to excitatory stimulation to a brain area. Our recent work showed that priming theta burst magnetic stimulation demonstrated superior effects in improving upper limb motor function and neurophysiological outcomes. However, it remains unknown whether pairing a session of cathodal tDCS with a session of anodal tDCS will also capitalise on its therapeutic effects., Methods and Analysis: This will be a two-arm double-blind randomised controlled trial involving 134 patients 1-6 months after stroke onset. Eligible participants will be randomly allocated to receive 10 sessions of priming tDCS+robotic training, or 10 sessions of non-priming tDCS+robotic training for 2 weeks. The primary outcome is the Fugl-Meyer Assessment-upper extremity, and the secondary outcomes are the Wolf Motor Function Test and Modified Barthel Index. The motor-evoked potentials, regional oxyhaemoglobin level and resting-state functional connectivity between the bilateral M1 will be acquired and analysed to investigate the effects of priming tDCS on neuroplasticity., Ethics and Dissemination: The study has been approved by the Research Ethics Committee of the Shanghai Yangzhi Rehabilitation Center (reference number: Yangzhi2023-022) and will be conducted in accordance with the Declaration of Helsinki of 1964, as revised in 2013., Trial Registration Number: ChiCTR2300074681., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Nuclear Dbf2-related kinase 1 (NDR1) is a nuclear Dbf2-related (NDR) protein kinase family member, which regulates cell functions and participates in cell proliferation and differentiation through kinase activity. NDR1 regulates physiological functions by interacting with different proteins. Protein-protein interactions (PPIs) are crucial for regulating biological processes and controlling cell fate, and as a result, it is beneficial to study the actions of PPIs to elucidate the pathological mechanism of diseases. The previous studies also show that the expression of NDR1 is deregulated in numerous human cancer samples and it needs the context-specific targeting strategies for NDR1. Thus, a comprehensive understanding of the direct interaction between NDR1 and varieties of proteins may provide new insights into cancer therapies. In this review, we summarize recent studies of NDR1 in solid tumors, such as prostate cancer and breast cancer, and explore the mechanism of action of PPIs of NDR1 in tumors., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed a serious threat to human. Since there are still no effective treatment options against the new emerging variants of SARS-CoV-2, it is necessary to devote a continuous endeavor for more targeted drugs and the preparation for the next pandemic. Salvia miltiorrhiza and its active ingredients possess wide antiviral activities, including against SARS-CoV-2. Danshensu, as one of the most important active ingredients in Salvia miltiorrhiza, has been reported to inhibit the entry of SARS-CoV-2 into ACE2 (angiotensin-converting enzyme 2)-overexpressed HEK-293T cells and Vero-E6 cells. However, there is a paucity of information regarding its detailed target and mechanism against SARS-CoV-2. Here, we present Danshensu as a covalent inhibitor of 3-chymotrypsin-like protease (3CL pro ) against SARS-CoV-2 by the time-dependent inhibition assay (TDI) and mass spectrometry analysis. Further molecular docking, site-directed mutagenesis, circular dichroism (CD) and fluorescence spectra revealed that Danshensu covalently binds to C145 of SARS-CoV-2 3CL pro , meanwhile forming the hydrogen bonds with S144, H163 and E166 in the S1 site. Structure-based optimization of Danshensu led to the discovery of the promising compounds with good inhibitory activity and microsomal stability in vitro. Due to Danshensu inhibiting lung inflammation in the mouse model, we found that Danshensu derivatives also showed better anti-inflammatory activity than Danshensu in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. Thus, our study provides not only the clue of the efficacy of Salvia miltiorrhiza against SARS-CoV-2, but also a detailed mechanistic insight into the covalent mode of action of Danshensu for design of covalent inhibitors against SARS-CoV-2 3CL pro , highlighting its potential as a bifunctional molecule with antivirus and anti-inflammation., 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. Published by Elsevier B.V.)

Introduction: Findings based on the use of transcranial magnetic stimulation and electromyography (TMS-EMG) to determine the effects of motor lateralization and aging on intracortical excitation and inhibition in the primary motor cortex (M1) are inconsistent in the literature. TMS and electroencephalography (TMS-EEG) measures the excitability of excitatory and inhibitory circuits in the brain cortex without contamination from the spine and muscles. This study aimed to investigate the effects of motor lateralization (dominant and non-dominant hemispheres) and aging (young and older) and their interaction effects on intracortical excitation and inhibition within the M1 in healthy adults, measured using TMS-EMG and TMS-EEG., Methods: This study included 21 young (mean age = 28.1 ± 3.2 years) and 21 older healthy adults (mean age = 62.8 ± 4.2 years). A battery of TMS-EMG measurements and single-pulse TMS-EEG were recorded for the bilateral M1., Results: Two-way repeated-measures analysis of variance was used to investigate lateralization and aging and the lateralization-by-aging interaction effect on neurophysiological outcomes. The non-dominant M1 presented a longer cortical silent period and larger amplitudes of P60, N100, and P180. Corticospinal excitability in older participants was significantly reduced, as supported by a larger resting motor threshold and lower motor-evoked potential amplitudes. N100 amplitudes were significantly reduced in older participants, and the N100 and P180 latencies were significantly later than those in young participants. There was no significant lateralization-by-aging interaction effect in any outcome., Conclusion: Lateralization and aging have independent and significant effects on intracortical excitation and inhibition in healthy adults. The functional decline of excitatory and inhibitory circuits in the M1 is associated with aging., Competing Interests: The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Bai, Zhu, Lou, Zhang, Jin, Qin, Tang, Li, Lu, Lin, Jin, Qi and Fong.)

Introduction: The COVID-19 pandemic and subsequent quarantine measures have led to a significant impact on mental health worldwide. Medical staff, in particular, have been exposed to high levels of stress due to their frontline work during the crisis. However, there is still limited research on the psychological mechanism among medical staff after quarantine., Methods: In this cross-sectional observational study, 150 medical staff from Shanghai YangZhi Rehabilitation Hospital, Shanghai, China, were enrolled in October 2022. SPSS 26.0 and PROCESS 4.0 model 6 were used to analyze the chain mediating effect of perceived stress, anxiety, resilience and depression among medical staff after quarantine. Anxiety and depression were compared during and after the quarantine. All scales have high validity and reliability in a Chinese population., Results: Our findings revealed a positive correlation between perceived stress and anxiety (r = 0.60, p  < 0.001) and depression ( r  = 0.60, p  < 0.001) levels among medical staff. Conversely, resilience was found to have a negative correlation with perceived stress ( r  = -0.67, p  < 0.001), anxiety ( r  = -0.57, p  < 0.001) and depression ( r  = -0.61, p  < 0.001). The score of depression during the quarantine was higher than the score after the quarantine, but the p -value is only marginally significant ( p  = 0.067). The score of anxiety during the quarantine was significantly higher than the score after the quarantine ( p  < 0.05). Moreover, the chain mediation model suggested that anxiety and resilience could mediate the association between perceived stress and depression among medical staff following quarantine. Specifically, perceived stress had no direct effect on depression (β = 0.025, t  = 0.548, p  = 0.59) but positively predicted anxiety (β = 0.381, t  = 8.817, p  < 0.001) and resilience (β = -1.302, t  = -6.781, p  < 0.001), which influenced depression levels indirectly through multiple pathways. The three indirect paths: the mediating role of anxiety, the mediating role of resilience, and the chain mediating role of both anxiety and resilience., Discussion: This study emphasizes the importance of psychological interventions aimed at protecting medical staff's psychological resilience and promoting coping mechanisms to manage stress during and after crises such as the COVID-19 pandemic. Additionally, our findings suggest that both anxiety and resilience play critical roles in mitigating the detrimental effects of perceived stress on mental health and further highlight the need for continued research to better understand the complex interplay of these factors., 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 © 2023 Chen, Ni, Lu, Wang, Qi and Zhai.)

Alzheimer's disease (AD) is the most common neurodegenerative disorder, and is caused by multiple pathological factors, such as the overproduction of β-amyloid (Aβ) and the hyperphosphorylation of tau. However, there is limited knowledge of the mechanisms underlying AD pathogenesis and no effective biomarker for the early diagnosis of this disorder. Thus in this study, a quantitative phosphoproteomics analysis was performed to evaluate global protein phosphorylation in the hippocampus of Aβ overexpressing APP/PS1 transgenic mice and tau overexpressing MAPT×P301S transgenic mice, two in vivo AD model systems. These animals, up to ten weeks old, do not exhibit cognitive dysfunctions and are widely used to simulate early-stage AD patients. The number of differentially phosphorylated proteins (DPPs) was greater for APP/PS1 transgenic mice than for MAPT×P301S transgenic mice. The function of the DPPs in APP/PS1 transgenic mice was mainly related to synapses, while the function of the DPPs in MAPT×P301S transgenic mice was mainly related to microtubules. In addition, an AD core network was established including seven phosphoproteins differentially expressed in both animal models, and the function of this core network was related to synapses and oxidative stress. The results of this study suggest that Aβ and tau induce different protein phosphorylation profiles in the early stage of AD, leading to the dysfunctions in synapses and microtubule, respectively. And the detection of same DPPs in these animal models might be used for early AD diagnosis., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Farnesoid X receptor (FXR, NR1H4) is generally considered as a tumor suppressor of colorectal and liver cancers. The interaction between FXR, bile acids (BAs) and gut microbiota is closely associated with an increased risk of colorectal and liver cancers. Increasing evidence shows that FXR agonists may be potential therapeutic agents for colorectal and liver cancers. However, FXR agonists alone do not produce the desired results due to the complicated pathogenesis and single therapeutic mechanism, which suggests that effective treatments will require a multimodal approach. Based on the principle of improvingefficacy andreducingside effects, combination therapy is currently receiving considerable attention. In this review, colorectal and liver cancers are grouped together to discuss the effects of FXR agonists alone or in combination for combating the two cancers. We hope that this review will provide a theoretical basis for the clinical application of novel FXR agonists or combination with FXR agonists against colorectal and liver cancers., 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 Elsevier Inc. All rights reserved.)

Adverse psychological states are stimulated by multiple types of environmental factors in human being. However, only few animal models of adverse psychological states were established by applying multiple types of stressors to mimic real conditions. A multisensory stress simulation device was designed to apply a combination of stressors to animals. Selected types and intensity of stressors were stimulated by this multisensory stress simulation device to induce chronic multiple mild stress (CMMS) in rats, modeling sustained adverse psychological states caused by long-term exposure in relative extreme environments with limited social interaction in human being. Fourteen-day treatment of CMMS-induced anhedonia, anxiety, and the loss of body weight in rats, which were similar to those in human being with adverse psychological states. Moreover, CMMS treatment leads to decreased production of serotonin and increased expression of corticotropin-releasing factor receptor 1, adrenocorticotropic hormone, and glucocorticoid in the brain, which were prevented by paroxetine and sertraline, two clinical-used antidepressants. Furthermore, these antidepressants prevented the CMMS-induced inhibition of brain-derived neurotrophic factor/cAMP-response element binding protein pathway, reduction of synaptic protein expression, and the activation of microglia and astrocytes in the hippocampus and the prefrontal cortex of rats. In addition, 14-day CMMS-induced long-term depressive-like behaviors, even after 14 days of CMMS treatment. And sertraline reversed CMMS-induced behavioral and biochemical changes in rats. All these results suggested that CMMS protocol induced sustained adverse psychological states in rats. By adjusting the intensity and the type of stressors in the multisensory stress simulation device, it might be practicable to establish animal models with complicated and changeable environmental factors., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Multifunctional electrode materials with inherent conductivity have attracted extensive attention in recent years. Two-dimensional (2D) metal telluride nanomaterials are more promising owing to their strong metallic properties and unique physical/chemical merits. In this review, recent advancements in the preparation of 2D metal tellurides and their application in electrode materials are presented. First, the most available preparation methods, such as hydro/solvent thermal, chemical vapor deposition, and electrodeposition, are summarized. Then, the unique performance of metal telluride electrodes in capacitors, anode materials of Li/Na ion batteries, electrocatalysis, and lithium-sulfur batteries are discussed. Finally, significant challenges and opportunities in the preparation and application of 2D metal tellurides are proposed., 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 Guo, Gu, Xu, Lu, Wang and Zhou.)

A Zn 0.5 Cd 0.5 S (ZCS) solid solution was prepared using a hydrothermal method, in which CoP nanowires were added as a co-catalyst and co-deposited with multiwalled carbon nanotubes (MWNTs) on sponge to prepare a series of ZCS/CoP/MWNTs/sponge electrodes. The microstructures of catalysts were analyzed to confirm ZCS and CoP were successfully loaded in MWNTs/sponge. The CO 2 reduction products (formate and formaldehyde) produced via dielectric barrier discharge (DBD) using the different catalysts proved that the introduction of the CoP nanowires co-catalyst can enhance the catalytic activity of ZCS/MWNTs/sponge in the DBD system. Using 10% CoP and a ZCS/CoP concentration of 2.5 g·L -1 , the resulting ZCS/CoP/MWNTs/sponge catalyst exhibited the best catalytic of CO 2 reduction ability toward formate (7894.6 μmol·L -1 ) and formaldehyde (308.5 μmol·L -1 ) after 60 min of discharge, respectively. The proposed DBD catalytic mechanism for the reduction of CO 2 was analyzed according to the Tafel slope, density functional theory calculations, photocurrent density and plasma reaction process. Furthermore, the application of the DBD catalytic technology for CO 2 capture and reduction was shown to be efficient in a seawater system, and as such, it could be useful for marine CO 2 storage and conversion., 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 © 2022 Elsevier Inc. All rights reserved.)

Amyloid proteins, such as β-amyloid (Aβ) and α-synuclein (α-syn), could form neurotoxic aggregates during the progression of neurodegenerative disorders. Phloroglucinol, a clinical-used drug for treating spasmodic pain, was predicted to cross the blood brain-barrier and possesses neuroprotective potential. In this study, we have found, for the first time, that phloroglucinol inhibited the formation of amyloid aggregates, and degraded pre-formed amyloid aggregates with the similar efficacy as curcumin, a widely known amyloid aggregation inhibitor. Moreover, phloroglucinol decreased the seeding during aggregation process and inhibited the aggregation of Aβ 1 - 42 with homocysteine (Hcy) seeds. Molecular docking analysis further demonstrated hydrophobic interactions and hydrogen bonds between phloroglucinol and Aβ 1 - 42 /α-syn. Furthermore, phloroglucinol inhibited amyloid aggregates-induced cytotoxicity in neuronal cells and prevented Aβ 1 - 42  + Hcy aggregates-induced cognitive impairments in mice. All these results suggested that phloroglucinol possesses the ability to degrade pre-formed amyloid aggregates, to inhibit the seeding during amyloid aggregation, and to reduce the neurotoxicity, indicating the reposition possibility of phloroglucinol as a novel drug for treating neurodegenerative disorders., (Copyright © 2022. Published by Elsevier B.V.)

Objective: We created predictive models using machine learning algorithms for return-to-work (RTW) in patients with traumatic upper extremity injuries., Methods: Data were obtained immediately before patient discharge and patients were followed up for 1 year. K-nearest neighbor, logistic regression, support vector machine, and decision tree algorithms were used to create our predictive models for RTW., Results: In total, 163 patients with traumatic upper extremity injury were enrolled, and 107/163 (65.6%) had successfully returned to work at 1-year of follow-up. The decision tree model had a lower F1-score than any of the other models (t values: 7.93-8.67, p < 0.001), while the others had comparable F1-scores. Furthermore, the logistic regression and support vector machine models were significantly superior to the k-nearest neighbors and decision tree models in the area under the receiver operating characteristic curve (t values: 6.64-13.71, p < 0.001). Compared with the support vector machine, logistical regression selected only two essential factors, namely, the patient's expectation of RTW and carrying strength at the waist, suggesting its superior efficiency in the prediction of RTW., Conclusion: Our study demonstrated that high predictability for RTW can be achieved through use of machine learning models, which is helpful development of individualized vocational rehabilitation strategies and relevant policymaking., 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 Bai, Zhang, Tang, Wang, Xia, Qi, Lu, Fang, Fong and Niu.)

The vestibular system is critical for human locomotion. Any deteriorated vestibular system leads to gait instability. In the past decades, these alternations in gait patterns have been majorly measured by the spatial-temporal gait parameters and respective variabilities. However, measuring gait characteristics cannot capture the full aspect of motor controls. Thus, to further understand the effects of deteriorated vestibular system on gait performance, additional measurement needs to be taken into consideration. This study proposed using the margin of stability (MOS) to identify the patterns of dynamic control under different types of mastoid vibrations in walking. This study hypothesized that (1) using the MOS method could facilitate the understanding of another aspect of motor control induced by different types of mastoid vibrations, and (2) applying the mastoid vibrations could induce the asymmetric MOS. Twenty healthy young adults were recruited. Two electromechanical vibrotactile transducers were placed on the bilateral mastoid process to apply different types of vestibular vibrations (bilateral, unilateral, and no vibration). A motion capture system with eight cameras was used to measure the MOSap (margin of stability in the anterior-posterior direction), MOSml (margin of stability in the medial-lateral direction), and respective variabilities. The results were in line with the hypotheses that both bilateral and unilateral mastoid vibrations significantly increased MOSap ( p = 0.036, p < 0.001), MOSml ( p = 0.012, p < 0.001), and respective variabilities p = 0.001, p < 0.001; p = 0.001, p < 0.01 when compared to the no vibration condition. Also, significantly larger MOSml ( p = 0.001), MOSml variability ( p < 0.023), MOSap ( p < 0.001), and MOSap variability ( p = 0.002) were observed under the unilateral vibration condition than that observed under the bilateral vibration condition. The above-mentioned result found that different types of mastoid vibrations affected the MOS differently, suggesting different patterns of control mechanisms under different sensory-conflicted situations. Besides, a significant difference between the dominant and non-dominant legs was observed in MOSml. Moreover, applying the unilateral mastoid vibrations induced a greater symmetric index of MOSml, suggesting that more active control in balance was needed in the medial-lateral than in the anterior-posterior direction., 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 Lu, Xie and Chien.)

Objectives: To compare water-based treadmill walking training with land-based treadmill walking training following anterior cruciate ligament (ACL) reconstruction., Design: Prospective, randomised, single-blind clinical trial., Setting: Single-centre study., Participants: Sixty patients undergoing rehabilitation following ACL reconstruction were assigned at random into two groups., Interventions: Patients in the water-based training group (WBG) underwent treadmill training in water, and patients in the land-based training group (LBG) underwent treadmill training on land., Main Outcome Measures: Muscle strength was evaluated using the ratio of peak torque to body weight (PT/BW) before and after 3 weeks of training., Results: After 3 weeks of training, both groups had significantly higher PT/BW ratios, passive position sense (PAPS) and Lysholm scores compared with pre-treatment levels. In the affected leg, the PT/BW ratio for the knee extensor muscles, PAPS and Lysholm scores showed significantly greater improvement in the WBG than in the LBG. No significant differences in the PT/BW ratio, single leg balance index and stability limit index of the knee flexor muscles at different angular velocities were seen between the two groups., Conclusion: The results suggest that water-based walking exercise could lead to greater improvements in extensor muscle strength, proprioception and knee performance compared with land-based training following ACL reconstruction., Clinical Trial Registration Number: ChiCTR1900025930., (Copyright © 2021 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.)

MicroRNAs (miRNAs) are key epigenomic regulators of proliferation, differentiation, and secretion in cells involved in follicular development. We here studied the functional role of one such molecule, miR-130a-3p, in goat ovarian granulosa cells (GCs). High expression of this miRNA was evident in goat GCs by fluorescence in situ hybridization and suppressed estradiol and progesterone secretion from these cells, as determined by ELISA. miR-130a-3p was predicted to have a binding site for the 3' UTR of the prostate transmembrane protein androgen induced 1 gene (PMEPA1), and this was verified by a dual-luciferase reporter assay. PMEPA1 mRNA and protein expression were both found to be regulated by miR-130a-3p in GCs. Moreover, the overexpression or knockdown of PMEPA1 enhanced or suppressed estradiol and progesterone secretion from these cells, respectively. Furthermore, the secretion of estradiol and progesterone did not change significantly after the offsetting of PMEPA1 overexpression in GCs by miR-130a-3p. In summary, our present data indicate that miR-130a-3p inhibits the secretion of estradiol and progesterone in GCs by targeting PMEPA1. Our study thus provides seminal data and important new insights into the regulation of reproductive mechanisms in the nanny goat and other female mammals., Competing Interests: Declaration of competing interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Peripheral nerve injury can result in both sensory and motor deficits, and these impairments can last for a long period after nerve repair., Objective: To systematically review the effects of sensory re-education (SR) on facilitating hand function recovery after peripheral nerve repair., Methods: This systematic review was limited to articles published from 1970 to 20 December 2020. Electronic searching was performed in CINAHL, Embase, PubMed, Web of Science, and Medline databases to include trials investigating the effects of SR training on hand function recovery after peripheral nerve repair and included only those studies with controlled comparisons., Results: Sixteen articles were included in final data synthesis. We found that only four studies could be rated as having good quality and noted obvious methodological limitations in the remaining studies. The current evidence showed that early SR with mirror visual feedback and the combinational use of classic SR and topical temporary anesthetic seemed to have long- and short-term effects, respectively on improving the sensibility and reducing the disabilities of the hand. The evidence to support the effects of conventional classical SR on improving hand functions was not strong., Conclusions: Further well-designed trials are needed to evaluate the effects of different SR techniques on hand function after nerve repair over short- and long-term periods.

Pyruvate kinase M2 (PKM2) is not only a key rate-limiting enzyme that guides glycolysis, but also acts as a non-metabolic protein in regulating gene transcription. In recent years, a series of studies have confirmed that post-translational modification has become an important mechanism for regulating the function of PKM2, which in turn affects tumorigenesis. In this study, we found that K62 residues were deacetylated, which is related to the prognosis of HCC. Further studies indicate that HDAC8 binds and deacetylates the K62 residue of PKM2. Mechanistically, K62 deacetylation facilitate PKM2 transport into the nucleus and bind β-catenin, thereby promoting CCND1 gene transcription and cell cycle progression. In addition, the deacetylation of K62 affects the enzyme activity of PKM2 and the flux of glucose metabolism. Therefore, these results suggest that HDAC8 / PKM2 signaling may become a new target for the treatment of HCC.

Background: Chuanqing is an unrecognised ethnic group in Guizhou, southwest China. The genetic history of the Chuanqing people is hotly debated due to a lack of available genetic data., Aim: To infer the genetic structure and population history of the Chuanqing people and genetic relationships of the Chuanqing with other East Asians., Subjects and Methods: We collected samples from 14 Chuanqing individuals from Guizhou and genotyped about 690,000 genome-wide single nucleotide polymorphisms (SNPs). We used Principal Component Analysis (PCA), ADMIXTURE analysis, and f statistics to infer the population genetic structure and admixture., Results: Chuanqing people show a distinct genetic profile from indigenous Tai-Kadai and Tibeto-Burman speaking populations in southwest China, but they are genetically similar to southern Han Chinese, Miao, She and Tujia populations. The Han Chinese characteristic Y chromosomal lineages reach high frequencies in the Chuanqing., Conclusions: The genetic formation of the Chuanqing people has been greatly influenced by Han Chinese related populations.

Study Design: A systematic review and meta-analysis., Objective: To assess the measurement properties of the Functional Rating Index (FRI) and determine whether its measurement properties are comparable with other region-specific questionnaires., Summary of Background Data: In addition to low back pain (LBP) and neck pain (NP), multiregion spinal pain (SP) is a common problem with a considerable prevalence in the general population. The FRI was built to assess physical functioning in patients with SP. However, a systematic review assessing evidence of its measurement properties in separated populations and a comparison with other questionnaires regarding each measurement property is lacking., Methods: Articles concerning the FRI's measurement properties or head-to-head comparison with other questionnaires on measurement properties were obtained from MEDLINE, Embase, CINAHL, and PsycINFO. Two reviewers independently reviewed the articles, extracted data, and conducted the methodological quality assessment. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist was used to assess the methodological quality of the included studies., Results: A total of 18 studies evaluating the FRI's measurement properties, including seven that carried out head-to-head comparisons in at least one measurement property with other questionnaires, were included in the current review. Our findings show strong positive evidence for structural validity and internal consistency in patients with SP and LBP. Evidence for most of the FRI's measurement properties is limited, conflicting, or even unknown. The current evidence shows that the FRI is comparable with both the Oswestry Disability Index and the Neck Disability Index in responsiveness. However, relevant information about the majority of the other measurement properties is lacking., Conclusion: Our finding suggests that clinicians and researchers should use the FRI with caution until there are more studies with high methodological quality that support the view that it is positive in all measurement properties, especially in regard to patients with multiregion SP., Level of Evidence: 1.

The g-C3N4/TiO2-NTs electrodes were synthesized by a dip-coating procedure followed by high-temperature annealing used in photoelectrochemical process. From the results, a simultaneous and rapid reduction of Cr(VI) and degradation of phenol in Cr(VI)/phenol system was observed with photoelectrocatalytic activity under UV-visible light irradiation than photocatalytic and electrocatalytic activities. The different kinds of Cr(VI)/organic pollutants systems were also investigated systematically. In addition, different scavengers were also added in Cr(VI)/phenol and Cr(VI)/benzyl alcohol systems to indicate that the hydroxyl radicals and superoxide radicals were the most major active species for the denomination of Cr(VI) and organic pollutants. The intermediates of phenol and benzyl alcohol were also detected during the reaction in order to deduce the photoelectrocatalysis mechanism underg-C3N4/TiO2-NTs electrodes that the charge separation was improved and subsequently electron-transfer efficiency was higher., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Films of TiO2 nanotubes distributed over the inner surface of a discharge reactor cylinder (CTD) or adhered to a stainless steel electrode surface (PTD) in a discharge reactor were compared with a single-discharge (SD) system to investigate their efficiencies in phenol degradation. Morphology studies indicated that the TiO2 film was destroyed in the PTD system, but that there was no change in the CTD system after discharge. X-ray diffraction results revealed that the anatase phase of the original sample was preserved in the CTD system, but that an anatase-to-rutile phase transformation occurred in the PTD system after discharge. The highest efficiencies of phenol degradation and total organic carbon (TOC) mineralization were observed in the CTD system, and there was no decrease in phenol degradation efficiency upon reuse of a TiO2 film, indicating high catalysis activity and stability of the TiO2 photocatalysts in the combined treatment. TiO2 photocatalysts favored the formation of hydrogen peroxide and disfavored the formation of ozone. A greater degree of oxidation of intermediates and higher energy efficiency in phenol oxidation were observed with the TiO2-plasma systems, especially in the CTD system, compared to those with the SD system., (Copyright © 2013 Elsevier Inc. All rights reserved.)