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Long noncoding RNAs (lncRNAs) play pivotal roles in the development of human malignancies, though their involvement in oral squamous cell carcinoma (OSCC) remains incompletely understood. Using The Cancer Genome Atlas (TCGA) dataset, we analyzed expression of 7840 lncRNAs in primary head and neck squamous cell carcinoma (HNSCC) and found that upregulation of LINC02154 is associated with a poorer prognosis. LINC02154 knockdown in OSCC cell lines induced cell cycle arrest and apoptosis, and significantly attenuated tumor growth in vitro and in vivo. Notably, depletion of LINC02154 downregulated FOXM1, a master regulator of cell cycle-related genes. RNA pulldown and mass spectrometry analyses identified a series of proteins that could potentially interact with LINC02154, including HNRNPK and LRPPRC. HNRNPK stabilizes FOXM1 expression by interacting with the 3'-UTR of FOXM1 mRNA, which suggests LINC02154 and HNRNPK promote cell cycling by regulating FOXM1 expression. Additionally, LINC02154 positively regulates HNRNPK expression by inhibiting microRNAs targeting HNRPNK. Moreover, LINC02154 affects mitochondrial function by interacting with LRPPRC. Depletion of LINC02154 suppressed expression of mitochondrial genes, including MTCO1 and MTCO2, and inhibited mitochondrial respiratory function in OSCC cells. These results suggest that LINC02154 exerts its oncogenic effects by modulating the cell cycle and oxidative phosphorylation in OSCC, highlighting LINC02154 as a potential therapeutic target., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Force steadiness can be impaired under dual-task conditions in older adults. Since this impairment is attributed to their limited attentional resources, we hypothesized that the degree of cortical activity involved in muscle contraction would affect force steadiness under dual-task conditions. To test this hypothesis, based on the premise that dorsiflexion requires more cortical resources than plantarflexion, we compared the effects of additional motor and cognitive task demands on force steadiness between dorsiflexion and plantarflexion contractions in young and older adults., Method: Eighteen young and eighteen older adults performed a force tracking task by applying either isometric dorsiflexion or plantarflexion force concurrently with and without (control) secondary upper-limb motor or cognitive task., Results: Force steadiness was impaired by both secondary upper-limb motor and cognitive tasks for the dorsiflexors and plantarflexors in older adults. While force steadiness was impaired similarly by additional task demands regardless of the secondary task type for the dorsiflexors, the impairment effect was larger in the secondary cognitive than motor task for the plantarflexors., Conclusion: The effects of dual-task demand on force steadiness could depend on the degree of cortical activity involved in muscle contraction in older adults.

Introduction: ACE cleaves angiotensin I (Ang I) to angiotensin II (Ang II) inducing vasoconstriction via Ang II type 1 (AT1) receptor, while ACE2 cleaves Ang II to Ang (1-7) causing vasodilatation by acting on the Mas receptor. In diabetic kidney disease (DKD), it is still unclear whether plasma or urine ACE2 levels predict renal outcomes or not., Research Design and Methods: Among 777 participants with diabetes enrolled in the Urinary biomarker for Continuous And Rapid progression of diabetic nEphropathy study, the 296 patients followed up for 9 years were investigated. Plasma and urinary ACE2 levels were measured by the ELISA. The primary end point was a composite of a decrease of estimated glomerular filtration rate (eGFR) by at least 30% from baseline or initiation of hemodialysis or peritoneal dialysis. The secondary end points were a 30% increase or a 30% decrease in albumin-to-creatinine ratio from baseline to 1 year., Results: The cumulative incidence of the renal composite outcome was significantly higher in group 1 with lowest tertile of plasma ACE2 (p=0.040). Group 2 with middle and highest tertile was associated with better renal outcomes in the crude Cox regression model adjusted by age and sex (HR 0.56, 95% CI 0.31 to 0.99, p=0.047). Plasma ACE2 levels demonstrated a significant association with 30% decrease in ACR (OR 1.46, 95% CI 1.044 to 2.035, p=0.027) after adjusting for age, sex, systolic blood pressure, hemoglobin A1c, and eGFR., Conclusions: Higher baseline plasma ACE2 levels in DKD were protective for development and progression of albuminuria and associated with fewer renal end points, suggesting plasma ACE2 may be used as a prognosis marker of DKD., Trial Registration Number: UMIN000011525., Competing Interests: Competing interests: JW receives speaker honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Kyowa Kirin, Novo Nordisk, and Mitsubishi Tanabe, and receives grant support from Bayer, Chugai, Kyowa Kirin, Otsuka, Shionogi, Sumitomo, and Mitsubishi Tanabe., (© 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.)

Asymmetrically impaired standing control is a prevalent disability among stroke patients; however, most of the neuromuscular characteristics are unclear. Therefore, the main purpose of this study was to investigate between-limb differences in intermuscular coherence during quiet standing. Consequently, 15 patients who had sub-acute stroke performed a quiet standing task without assistive devices, and electromyography was measured on the bilateral tibialis anterior (TA), soleus (SL), and medial gastrocnemius (MG). The intermuscular coherence of the unilateral synergistic (SL-MG) pair and unilateral antagonist (TA-SL and TA-MG) pairs in the delta (0-5 Hz) and beta (15-35 Hz) bands were calculated and compared between the paretic and non-paretic limbs. The unilateral synergistic SL-MG coherence in the beta band was significantly greater in the non-paretic limb than in the paretic limb ( p = 0.017), while unilateral antagonist TA-MG coherence in the delta band was significantly greater in the paretic limb than in the non-paretic limb ( p < 0.01). During quiet standing, stroke patients showed asymmetry in the cortical control of the plantar flexor muscles, and synchronous control between the antagonistic muscles was characteristic of the paretic limb. This study identified abnormal muscle activity patterns and asymmetrical cortical control underlying impaired standing balance in patients with sub-acute stroke using an intermuscular coherence analysis.

Objective: Gait disturbance lowers activities of daily living in patients with Parkinson's disease (PD) and related disorders. However, the effectiveness of pharmacological, surgical and rehabilitative treatments is limited. We recently developed a novel neuromodulation approach using gait-combined closed-loop transcranial electrical stimulation (tES) for healthy volunteers and patients who are post-stroke, and achieved significant entrainment of gait rhythm and an increase in gait speed. Here, we tested the efficacy of this intervention in patients with Parkinsonian gait disturbances., Methods: Twenty-three patients were randomly assigned to a real intervention group using gait-combined closed-loop oscillatory tES over the cerebellum at the frequency of individualised comfortable gait rhythm, and to a sham control group., Results: Ten intervention sessions were completed for all patients and showed that the gait speed ( F (1, 21) =13.0, p=0.002) and stride length ( F (1, 21) =8.9, p=0.007) were significantly increased after tES, but not after sham stimulation. Moreover, gait symmetry measured by swing phase time ( F (1, 21) =11.9, p=0.002) and subjective feelings about freezing ( F (1, 21) =14.9, p=0.001) were significantly improved during gait., Conclusions: These findings showed that gait-combined closed-loop tES over the cerebellum improved Parkinsonian gait disturbances, possibly through the modulation of brain networks generating gait rhythms. This new non-pharmacological and non-invasive intervention could be a breakthrough in restoring gait function in patients with PD and related disorders., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Aging is associated with impairment of multiple organs, including skeletal muscle and heart. In this study, we investigated whether resveratrol, an activator of an NAD + -dependent protein deacetylase Sirtuin-1 (SIRT1), attenuates age-related sarcopenia and cardiomyocyte hypertrophy in mice. Treatment of mice with resveratrol (0.4 g/kg diet) from 28 weeks of age for 32 weeks prevented aging-associated shortening of rotarod riding time. In the tibialis anterior (TA) muscle, histogram analysis showed that the atrophic muscle was increased in 60-week-old (wo) mice compared with 20-wo mice, which was attenuated by resveratrol. In the heart, resveratrol attenuated an aging-associated increase in the cardiomyocyte diameter. Acetylated proteins were increased and autophagic activity was reduced in the TA muscle of 60-wo mice compared with those of 20-wo mice. Resveratrol treatment reduced levels of acetylated proteins and restored autophagic activity in the TA muscle. Aging-related reduction in myocardial autophagy was also suppressed by resveratrol. Skeletal muscle-specific SIRT1 knockout mice showed increases in acetylated proteins and atrophic muscle fibers and reduced autophagic activity in the TA muscle. These results suggest that activation of SIRT1 by treatment with resveratrol suppresses sarcopenia and cardiomyocyte hypertrophy by restoration of autophagy in mice., Competing Interests: Competing interests The authors declare no competing interests., (Copyright © 2023 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Intra- or inter-muscular (EMG-EMG) coherence is a simple and non-invasive method for estimating central nervous system control during human standing tasks. Although this research area has developed, no systematic literature review has been conducted., Objectives: We aimed to map the current literature on EMG-EMG coherence during various standing tasks to identify the research gaps and summarize previous studies comparing EMG-EMG coherence between healthy young and elderly adults., Methods: Electronic databases (PubMed, Cochrane Library, and CINAHL) were searched for articles published from inception to December 2021. We incorporated studies that analyzed EMG-EMG coherence of the postural muscles in various standing tasks., Results: Finally, 25 articles fulfilled the inclusion criteria and involved 509 participants. Most participants were healthy young adults, while only one study included participants with medical conditions. There was some evidence that EMG-EMG coherence could identify differences in standing control between healthy young and elderly adults, although the methodology was highly heterogeneous., Conclusion: The present review indicates that EMG-EMG coherence may help elucidate changes in standing control with age. In future studies, this method should be used in participants with central nervous system disorders to understand better the characteristics of standing balance disabilities., 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 Yamanaka, Horiuchi and Nojima.)

This study aimed to investigate the relationship between heart rate variability (HRV), a parameter of the autonomic nervous system activity (ANSA), and postoperative delirium and postoperative events. This retrospective cohort study included elderly patients aged 65 years or older who were admitted to the intensive care unit (ICU) after cardiovascular surgery. ANSA was measured using HRV parameters for 1 h at daytime and 1 h at night-time before ICU discharge. The primary endpoint was the effect of HRV parameters and delirium on mortality and readmission rates within 1 year after discharge, and the secondary endpoint was the association between HRV parameters and delirium. Cox proportional hazards models were used to examine the association between HRV parameters and postoperative events by adjusting for delirium and pre and postoperative information. A total of 71 patients, 39 without delirium and 32 with delirium, met the inclusion criteria. The incidence of death and readmission within 1 year was significantly higher in the delirium group and in the group with higher daytime HF (high frequency power) and r-MSSD (square root of the squared mean of the difference of successive NN intervals), parameters of the parasympathetic nervous system activity (PNSA), than that in other groups. Furthermore, the delirium group had significantly higher HF and r-MSSD than the nondelirium group. Even after adjusting for confounding factors in the multivariate analysis, a trend of higher daytime HF and r-MSSD was observed, indicating a significant effect on the occurrence of combined events within 1 year of discharge. ICU delirium has been associated with higher daytime HF and r-MSSD, parameters of PNSA. ICU delirium was a prognostic factor, and increased daytime PNSA may worsen the prognosis of elderly patients after cardiovascular surgery., (© 2022. Springer Japan KK, part of Springer Nature.)

Metformin has been a long-standing prescribed drug for treatment of type 2 diabetes (T2D) and its beneficial effects on virus infection, autoimmune diseases, aging and cancers are also recognized. Metformin modulates the differentiation and activation of various immune-mediated cells such as CD4+ and CD+8 T cells. The activation of adenosine 5'-monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1) pathway may be involved in this process. Recent studies using Extracellular Flux Analyzer demonstrated that metformin alters the activities of glycolysis, oxidative phosphorylation (OXPHOS), lipid oxidation, and glutaminolysis, which tightly link to the modulation of cytokine production in CD4+ and CD+8 T cells in various disease states, such as virus infection, autoimmune diseases, aging and cancers.

Muscular dystrophies are inherited myopathic disorders characterized by progressive muscle weakness. Recently, several gene therapies have been developed; however, the treatment options are still limited. Resveratrol, an activator of SIRT1, ameliorates muscular function in muscular dystrophy patients and dystrophin-deficient mdx mice, although its mechanism is still not fully elucidated. Here, we investigated the effects of resveratrol on membrane resealing. We found that resveratrol promoted membrane repair in C2C12 cells via the activation of SIRT1. To elucidate the mechanism by which resveratrol promotes membrane resealing, we focused on the reorganization of the cytoskeleton, which occurs in the early phase of membrane repair. Treatment with resveratrol promoted actin accumulation at the injured site. We also examined the role of cortactin in membrane resealing. Cortactin accumulated at the injury site, and cortactin knockdown suppressed membrane resealing and reorganization of the cytoskeleton. Additionally, SIRT1 deacetylated cortactin and promoted the interaction between cortactin and F-actin, thus possibly enhancing the accumulation of cortactin at the injury site. Finally, we performed a membrane repair assay using single fiber myotubes from control and resveratrol-fed mice, where the oral treatment with resveratrol promoted membrane repair ex vivo. These findings suggest that resveratrol promotes membrane repair via the SIRT1/cortactin axis., (© 2022. The Author(s).)

Gamma-aminobutyric acid (GABA) activity within the primary motor cortex (M1) is essential for motor learning in cortical plasticity, and a recent study has suggested that real-time neurofeedback training (NFT) can self-regulate GABA activity. Therefore, this study aimed to investigate the effect of GABA activity strengthening via NFT on subsequent motor learning. Thirty-six healthy participants were randomly assigned to either an NFT group or control group, which received sham feedback. GABA activity was assessed for short intracortical inhibition (SICI) within the right M1 using paired-pulse transcranial magnetic stimulation. During the NFT intervention period, the participants tried to modulate the size of a circle, which was altered according to the degree of SICI in the NFT group. However, the size was altered independently of the degree of SICI in the control group. We measured the reaction time before, after (online learning), and 24 h after (offline learning) the finger-tapping task. Results showed the strengthening of GABA activity induced by the NFT intervention, and the suppression of the online but not the offline learning. These findings suggest that prior GABA activity modulation may affect online motor learning., 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 IBRO. Published by Elsevier Ltd. All rights reserved.)

Insulin-like growth factor (IGF)-binding proteins (IGFBPs) are secretory proteins that regulate IGF signaling. In this study, we investigated the role of IGFBP5 in replicative senescence in embryonic mouse fibroblasts (MEFs). During passages according to the 3T3 method, MEFs underwent senescence after the 5th passage (P5) based on cell growth arrest, an increase in the number of cells positive for senescence-associated β-galactosidase (SA-β-GAL) staining, and upregulation of p16 and p19. In P8 MEFs, IGFBP5 mRNA level was markedly reduced compared with that in P2 MEFs. Downregulation of IGFBP5 via siRNA in P2 MEFs increased the number of SA-β-GAL-positive cells, upregulated p16 and p19, and inhibited cell growth. Incubation of MEFs with IGFBP5 during serial passage increased the cumulative population doubling and decreased SA-β-GAL positivity compared with those in vehicle-treated cells. IGFBP5 knockdown in P2 MEFs increased phosphorylation levels of ERK1 and ERK2. Silencing of ERK2, but not that of ERK1, blocked the increase in the number of SA-β-GAL-positive cells in IGFBP5-knockdown cells. The reduction in the cell number and upregulation of p16 and p21 in IGFBP5-knockdown cells were attenuated by ERK2 knockdown. Our results suggest that downregulation of IGFBP5 during serial passage contributes to replicative senescence via ERK2 in MEFs.

Background: Glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) plays a crucial role in lipolytic processing. Previous studies have shown that GPIHBP1 mutations cause severe hypertriglyceridemia and that serum GPIHBP1 levels are marginally higher in patients with coronary heart disease; however, the role of GPIHBP1 in type 2 diabetes mellitus (T2DM) remains unknown., Objective: We investigated the association between circulating GPIHBP1 levels and the prevalence of microvascular complications in T2DM., Methods: A total of 237 subjects with T2DM and 235 non-diabetic control subjects were enrolled in this study. Their serum GPIHBP1 levels were evaluated using ELISA assays., Results: Circulating GPIHBP1 levels were higher in patients with T2DM (952.7 pg/mL [761.3-1234.6], p < 0.0001) than in non-diabetic subjects (700.6 [570.8-829.6]), but did not differ in T2DM patients with or without hypertriglyceridemia. Serum GPIHBP1 levels were significantly higher in patients with T2DM with diabetic retinopathy (DR), diabetic nephropathy (DN), and microvascular complications than in those without these complications. Multivariable logistic regression and receiver operating characteristic (ROC) curve analyses revealed that the presence of microvascular complications, but not macrovascular complications, was independently associated with serum GPIHBP1 levels, which could predict the presence of diabetic microvascular complications., Conclusions: Elevated GPIHBP1 levels are associated with microvascular complications in T2DM and may help to predict their progression., (Copyright © 2022 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: Brain-computer interface (BCI) is a procedure involving brain activity in which neural status is provided to the participants for self-regulation. The current review aims to evaluate the effect sizes of clinical studies investigating the use of BCI-based rehabilitation interventions in restoring upper extremity function and effective methods to detect brain activity for motor recovery., Methods: A computerized search of MEDLINE, CENTRAL, Web of Science, and PEDro was performed to identify relevant articles. We selected clinical trials that used BCI-based training for post-stroke patients and provided motor assessment scores before and after the intervention. The pooled standardized mean differences of BCI-based training were calculated using the random-effects model., Results: We initially identified 655 potentially relevant articles; finally, 16 articles fulfilled the inclusion criteria, involving 382 participants. A significant effect of neurofeedback intervention for the paretic upper limb was observed (standardized mean difference = .48, [.16-.80], P = .006). However, the effect estimates were moderately heterogeneous among the studies ( I 2 = 45%, P = .03). Subgroup analysis of the method of measurement of brain activity indicated the effectiveness of the algorithm focusing on sensorimotor rhythm., Conclusion: This meta-analysis suggested that BCI-based training was superior to conventional interventions for motor recovery of the upper limbs in patients with stroke. However, the results are not conclusive because of a high risk of bias and a large degree of heterogeneity due to the differences in the BCI interventions and the participants; therefore, further studies involving larger cohorts are required to confirm these results.

Consolidated memories become transiently labile after memory reactivation, allowing update through reconsolidation. Although previous reports have indicated that the effects of post-reactivation training depend on the type of practice, it is unclear whether post-reactivation motor skill training of one limb can enhance the performance of the opposite limb. The present study aimed to investigate whether post-reactivation training (performing an isometric pinch force task) under two different training conditions using the left limb would enhance motor skills of the right limb through reconsolidation. Motor skills were measured in 38 healthy right-handed young adults during three sessions (S): S1 (right-hand training), S2 (memory reactivation and left-hand training 6 h after S1), and S3 (right-hand motor skill test 24 h after S1). Participants were assigned to one of three groups according to the task performed during S2: untrained controls (no training), left-hand training (constant force conditions), or left-hand training (variable force conditions). Left-hand training after memory reactivation during S2 significantly enhanced the motor skills of the right hand. Notably, constant training conditions significantly increased performance compared to the control group. These findings suggest that post-reactivation training in one limb effectively enhances motor skills in the opposite limb, and the effects depend on the training strategy, which has important implications for motor rehabilitation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: Relationships between stress urinary incontinence (SUI) and physical function and spinal alignment have not been fully elucidated; therefore, we examined these relationships in older women., Methods: The participants of this cross-sectional study comprised 21 women with SUI (SUI group) and 41 continent women (continent group) aged >65 years who participated in a community-based health-check survey from 2018 to 2019. We examined age, body mass index, number of deliveries, age at first childbirth, and medical histories as participants' characteristics. SUI was evaluated using the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF). We also assessed spinal alignment and physical activity, grip strength, trunk and lower limb muscle mass, gait speed, and one-leg standing time as measures of participants' physical function., Results: Body mass index was significantly higher in the SUI group compared with continents (P = 0.04), and trunk muscle mass in the SUI group was significantly lower (P < 0.01). Additionally, the thoracic kyphosis angle in the SUI group was significantly larger (P = 0.02). In the logistic regression analysis, trunk muscle mass (odds ratio = 0.546, P = 0.03) and increased thoracic kyphosis angle (odds ratio = 1.066, P = 0.045) were independent factors affecting SUI. Furthermore, there was a negative weak correlation between total ICIQ-SF score and trunk muscle mass (r = -0.36, P < 0.01), and a positive weak correlation between total ICIQ-SF score and thoracic kyphosis angle (r = 0.27, P < 0.05)., Conclusion: Trunk muscle mass and thoracic kyphosis angle relate to SUI status and severity among Japanese community-dwelling older women., (© 2021 The Authors. LUTS: Lower Urinary Tract Symptoms published by John Wiley & Sons Australia, Ltd.)

Objective: We examined the association between social frailty and subjective sleep quality among community-dwelling adults., Methods: This cross-sectional study recruited Japanese adults over the age of 60 years from health check-ups held in a public townhall in a suburban area between 2018 and 2019. Social frailty was evaluated using five criteria (living alone, not visiting friends sometimes, going out less frequently than the last year, not feeling helpful to friends or family, and not talking to someone every day) and categorized into three groups: non-frailty, pre-frailty, and frailty. Sleep quality was assessed according to the Pittsburgh Sleep Quality Index (PSQI) by giving participants a self-reported questionnaire. We performed multivariable linear regression analysis, denoting social frailty as an independent variable, and the global PSQI score as a dependent variable., Results: Data from 300 older adults were analyzed, 51.0% of whom were female. The participants' mean age was 73.0 years (standard deviation = 5.8). Multivariable analysis revealed the notable association between social frailty and a high global PSQI score (compared with non-frailty, frailty: β = 0.94, 95% CI = 0.08 to 1.80, p = 0.033). Of the five determiners of social frailty, not talking with someone every day was especially associated with a high global PSQI score (β = 1.57, 95% CI = 0.49 to 2.66, p = 0.005)., Conclusion: The present study suggests that social frailty is associated with poor sleep quality among community-dwelling older adults. Our findings indicate the importance of social frailty on sleep quality among older adults., Competing Interests: The authors declare no conflicts of interest with respect to this research study and paper., (2021, JAPANESE PHYSICAL THERAPY ASSOCIATION.)

Resveratrol affords protection against reactive oxygen species (ROS)-related diseases via activation of SIRT1, an NAD + -dependent deacetylase. However, the low bioavailability of resveratrol limits its therapeutic applications. Since piceatannol is a hydroxyl analog of resveratrol with higher bioavailability, it could be an alternative to resveratrol. In this study, we compared the cytotoxicity, antioxidative activity, and mechanisms of cytoprotection of piceatannol with those of resveratrol. In C2C12 cells incubated with piceatannol, electrospray ionization mass spectrometry analysis showed that piceatannol was present in the intracellular fraction. A high concentration (50 μM) of piceatannol, but not resveratrol, induced mitochondrial depolarization and apoptosis. However, piceatannol at 10 μM inhibited the increase in mitochondrial ROS level induced by antimycin A, and this ROS reduction was greater than that by resveratrol. The reduction in hydrogen peroxide-induced ROS by piceatannol was also greater than that by resveratrol or vitamin C. Piceatannol reduced antimycin A-induced apoptosis more than did resveratrol. SIRT1 knockdown abolished the antiapoptotic activity of resveratrol, whereas it blocked only half of the antiapoptotic activity of piceatannol. Piceatannol, but not resveratrol, induced heme oxygenase-1 (HO1) expression, which was blocked by knockdown of the transcription factor NRF2, but not by SIRT1 knockdown. HO1 knockdown partially blocked the reduction of ROS by piceatannol. Furthermore, the antiapoptotic action of piceatannol was abolished by HO1 knockdown. Our results suggest that the therapeutic dose of piceatannol protects cells against mitochondrial ROS more than does resveratrol via SIRT1- and NRF2/HO1-dependent mechanisms. The activation of NRF2/HO1 could be an advantage of piceatannol compared with resveratrol for cytoprotection. SIGNIFICANCE STATEMENT: This study showed that piceatannol and resveratrol were different in cytotoxicity, oxidant-scavenging activities, and mechanisms of cytoprotection. Protection by piceatannol against apoptosis induced by reactive oxygen species was superior to that by resveratrol. In addition to the sirtuin 1-dependent pathway, piceatannol exerted nuclear factor erythroid 2-related factor 2/heme oxygenase-1-mediated antioxidative and antiapoptotic effects, which could be an advantage of piceatannol compared with resveratrol., Competing Interests: All authors have no conflicts of interest to declare., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Photodynamic therapy (PDT) using the photosensitizer talaporfin sodium (talaporfin) is a new mode of treatment for cancer. However, the metabolic mechanism of talaporfin has not been clarified. Thus, we investigated the uptake, transportation, and elimination mechanisms of talaporfin in carcinoma and sarcoma. The results showed that talaporfin co-localized in early endosomes and lysosomes. Talaporfin uptake was via clathrin- and caveolae-dependent endocytosis and a high amount of intracellular ATP was essential. Inhibition of lysosomal enzymes maintained intracellular talaporfin levels. Inhibition of K-Ras signaling reduced talaporfin uptake in carcinoma and sarcoma cell lines. Talaporfin was taken up by clathrin- and caveolae-dependent endocytosis, translocated from early endosomes to lysosomes, and finally degraded by lysosomes. We also demonstrated that ATP is essential for the uptake of talaporfin and that activation of K-Ras is involved as a regulatory mechanism. These results provide new insights into the metabolism of talaporfin in cancer cells for the enhancement of PDT for carcinoma and sarcoma., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Beta-band (15-30 ​Hz) corticomuscular and intermuscular coherences are important markers of the corticospinal interaction. The purpose of this study was to investigate whether amount of visual feedback during an isometric pinch grip contraction would influence these coherences in young and elderly adults. Thirty-three healthy young and elderly subjects performed pinch grip force-matching task with right thumb and index finger, while scalp electroencephalogram (EEG) and electromyogram (EMG) from the first dorsal interosseous (FDI) and abductor pollicis brevis (APB) muscles were recorded. The amount of visual feedback was altered by manipulation of visual gain (low and high). Beta-band corticomuscular coherence was computed between EEG over the sensorimotor cortex and EMG from the FDI muscle and between EEG and EMG from the APB muscle (EEG-FDI and EEG-APB coherences). Also, beta-band intermuscular coherence was computed between EMG signals from the FDI and APB muscles (EMG-EMG coherence). Task performance was quantified as standard deviation (SD) of force and mean force error (MFE). EEG-FDI coherence was larger at high than low visual gain in the elderly but not in the young subjects, whereas there was no effect of age or visual gain on EEG-APB coherence. EMG-EMG coherence was smaller at high than low visual gain in the young and elderly subjects. The MFE was smaller at high than low visual gain in the young and elderly subjects, but the SD of force was smaller at high than low visual gain only in the young subjects. These results suggest that the effect of aging on beta-band coherence depends on the amount of visual feedback and further that visual feedback modulates beta-band corticomuscular and intermuscular coherences differently., Competing Interests: Declaration of competing interest None., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Peptide-vaccination therapy targeting tumour-associated antigens can elicit immune responses, but cannot be used to eliminate large tumour burden. In this study, we developed a therapeutic single-chain variable-fragment (scFv) antibody that recognises the cancer stem-like cell/cancer-initiating cell (CSC/CIC) antigen, DNAJB8., Methods: We screened scFv clones reacting with HLA-A24:20/DNAJB8-derived peptide (DNAJB8&#95;143) complex using naive scFv phage-display libraries. Reactivity and affinity of scFv clones against the cognate antigen were quantified using FACS and surface plasmon resonance. Candidate scFv clones were engineered to human IgG1 (hIgG1) and T-cell-engaging bispecific antibody (CD3xJB8). Complement-dependent cytotoxicity (CDC) and bispecific antibody-dependent cellular cytotoxicity (BADCC) were assessed., Results: scFv clones A10 and B10 were isolated after bio-panning. Both A10-hIgG1 and B10-hIgG1 reacted with DNAJB8-143 peptide-pulsed antigen-presenting cells and HLA-A24(+)/DNAJB8(+) renal cell carcinoma and osteosarcoma cell lines. A10-hIgG1 and B10-hIgG1 showed strong affinity with the cognate HLA/peptide complex (K D  = 2.96 × 10 -9  M and 5.04 × 10 -9  M, respectively). A10-hIgG1 and B10-hIgG1 showed CDC against HLA-A24(+)/DNAJB8(+) cell lines. B10-(CD3xJB8) showed superior BADCC to A10-(CD3xJB8)., Conclusion: We isolated artificial scFv antibodies reactive to CSC/CIC antigen DNAJB8-derived peptide naturally present on renal cell carcinoma and sarcoma. Immunotherapy using these engineered antibodies could be promising.

The metabolic changes and dysfunction in CD8 + T cells may be involved in tumor progression and susceptibility to virus infection in type 2 diabetes (T2D). In C57BL/6JJcl mice fed with high fat-high sucrose chow (HFS), multifunctionality of CD8 + splenic and tumor-infiltrating lymphocytes (TILs) was impaired and associated with enhanced tumor growth, which were inhibited by metformin. In CD8 + splenic T cells from the HFS mice, glycolysis/basal respiration ratio was significantly reduced and reversed by metformin. In the patients with T2D (DM), multifunctionality of circulating CD8 + PD-1 + T cells stimulated with PMA/ionomycin as well as with HLA-A*24:02 CMV peptide was dampened, while metformin recovered multifunctionality. Both glycolysis and basal respiration were reduced in DM, and glycolysis was increased by metformin. The disturbance of the link between metabolism and immune function in CD8 + PD-1 + T cells in T2D was proved by recovery of antigen-specific and non-specific cytokine production via metformin-mediated increase in glycolytic activity.

Non-invasive brain stimulation (NIBS) techniques are extensively applied for the treatment of neuropsychiatric disorders and offer a powerful tool for addressing fundamental questions in neuroscience research. Recently, the use of static magnetic fields (SMFs) as a tool of NIBS has led to the development of a safe and promising method of neuromodulation called transcranial static magnetic stimulation (tSMS). However, the neurophysiological mechanisms regarding the effect of tSMS on the cortical elements are not yet fully understood. Here, we focus on the modulation of cortical excitability and oscillatory brain activity induced by tSMS. We believe that understanding the physiological mechanisms of this novel method is an important step for developing these techniques into potentially useful tools for the treatment of specific patient groups. Reviewing the neurophysiological evidence provided by human and animal studies suggests that tSMS may affect brain oscillations and alter behavioral parameters through the modulation of cortical excitability. In this review, we outline possible accounts and future directions to better understand the link between neural modification and accompanied behavioral changes., (Copyright © 2019 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.)

We aimed to investigate clinical parameters that affected the results of navigated repetitive transcranial magnetic stimulation (nrTMS) language mapping by comparing the results of preoperative nrTMS language mapping with those of direct cortical stimulation (DCS) mapping. In the prospective, non-randomized study, patients had to meet all of the following inclusion criteria: the presence of left- or right-side brain tumors in the vicinity of or inside the areas anatomically associated with language functions; awake brain surgery scheduled; and age >18 years. Sixty one patients were enrolled, and this study included 42 low-grade gliomas and 19 high-grade gliomas (39 men, 22 women; mean age, 41.1 years, range 18-72 years). The tumor was located in the left and right hemisphere in 50 (82.0%) and 11 (18.0%) patients, respectively. In the 50 patients with left-side gliomas, nrTMS language mapping showed 81.6% sensitivity, 59.6% specificity, 78.5% positive predictive value, and 64.1% negative predictive value when compared with the respective DCS values for detecting language sites in all regions. We then investigated how some parameters, including age, tumor type, tumor volume, and the involvement of anatomical language-related regions, affected different subpopulations. Based on the receiver operating curve statistics, subgroup analysis showed that the non-involvement of language-related regions afforded significantly better the area under the curve (AUC) values (AUC = 0.81, 95% confidence interval (CI): 0.74-0.88) than the involvement of language-related regions (AUC = 0.58, 95% CI: 0.50-0.67; p < 0.0001). Our findings suggest that nrTMS language mapping could be a reliable method, particularly in obtaining responses for cases without tumor-involvement of classical perisylvian language areas.

Age-induced decline in the ability to perform daily activities is associated with a deterioration of physical parameters. Changes occur in neuromuscular system with age; however, the relationship between these changes and physical parameters has not been fully elucidated. Therefore, in this study, we aimed to determine the relationship between neuromuscular system evaluated using a coherence analysis of the leg muscles and physical parameters in community-dwelling healthy elderly adults. The participants were required to stand still in bipedal and unipedal stances on a force plate. Then, electromyography (EMG) was recorded from the tibialis anterior (TA) and medial and lateral gastrocnemius (MG/LG) muscles, and intermuscular coherence was calculated between the following pairs: TA and MG (TA-MG), TA and LG (TA-LG), and MG and LG (MG-LG). Furthermore, gait speed, unipedal stance time, and muscle mass were measured. EMG-EMG coherence for the MG-LG pair was significantly greater in the unipedal stance task than in the bipedal one (p = .001). Multiple linear regression analysis revealed that the muscle mass of the leg was negatively correlated with the change in the β-band coherence for the MG-LG pair from bipedal to unipedal stance (R 2  = 0.067, standard β = -0.345, p = .044). As the β-band coherence could reflect the corticospinal activity, the increased β-band coherence may be a compensation for the smaller muscle mass, or alternatively may be a sign of changes in the nervous system resulting in the loss of muscle mass., Competing Interests: Declaration of Competing Interest No conflicts of interest, financial or otherwise, are declared by the authors., (Copyright © 2020 Elsevier B.V. All rights reserved.)

It has been suggested that resting-state functional connectivity (rs-FC) between the primary motor area (M1) region of the brain and other brain regions may be a predictor of motor learning, although this suggestion is still controversial. In the work reported here, we investigated the relationship between M1 seed-based rs-FC and motor learning. Fifty-three healthy volunteers undertook random button-press and sequential motor learning tasks. Five-minute resting-state data acquisition was performed between the two tasks. Oscillatory neural activities during the random task and the rest period were measured using magnetoencephalography. M1 seed-based rs-FC was calculated for the alpha and beta bands using amplitude envelope correlation, in which the seed location was defined as an M1 position with peak event-related desynchronization value. The relationship between rs-FC and the performance of motor learning was examined using whole brain correlation analysis. The results showed that beta-band resting-state cross-network connectivity between the sensorimotor network and the core network, particularly the theory of mind network, affected the performance of subsequent motor learning tasks. Good learners could be distinguished from poor learners by the strength of rs-FC between the M1 and the left superior temporal gyrus, a part of the theory of mind network. These results suggest that cross-network connectivity between the sensorimotor network and the theory of mind network can be used as a predictor of motor learning performance., Competing Interests: Declaration of competing interest None of the authors declares any conflict of interest. This work was supported by a grant for KAKENHI (16K16429, 18H03132) grants funded by the Japan Society for the Promotion of Science (JSPS)., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

There is evidence that social relationships may modify cognitive decline in older people. We examined the prospective association between social support and cognitive function among community-dwelling older people. Japanese adults recruited at health checkups in suburban towns were surveyed at baseline and one-year follow-up. Cognitive function was assessed using the Montreal Cognitive Assessment, Japanese version (MoCA-J). Social support from coresiding family, non-coresiding family, and neighbors/friends was assessed using self-administered questionnaires. Multivariable linear regression analysis was conducted to examine the effects of social support on MoCA-J scores at follow-up. Data were analyzed from 121 older people (mean age (standard deviation): 73.86 (4.95) years). There was a positive association between social support exchanges with neighbors and friends and MoCA-J scores at follow-up after covariate adjustment (unstandardized β = 1.23, p = 0.006). Social support exchanges with coresiding family and non-coresiding family and relatives were not associated with MoCA-J scores at follow-up (coresiding family: Unstandardized β = 0.28, p = 0.813, non-coresiding family and relatives: Unstandardized β = 0.51, p = 0.238). The provision of emotional support to neighbors and friends had the largest effect on MoCA-J scores. Our findings suggest that social support exchanges with neighbors and friends are protective against cognitive decline.

Recent non-invasive brain stimulation techniques in combination with motor training can enhance neuroplasticity and learning. It is reasonable to assume that such neuroplasticity-based interventions constitute a useful rehabilitative tool for patients with Parkinson's Disease (PD). Regarding motor skill training, many kinds of tasks that do not involve real motor movements have been applied to PD patients. The purpose of this study is to elucidate whether motor skill training using mirror visual feedback (MVF) is useful to patients with PD in order to improve untrained hand performance dependent on the time course of training; and whether MVF combined with anodal transcranial direct current stimulation (tDCS) over primary motor cortex (M1) causes an additional effect based on increased motor cortical excitability. Eighteen right-handed patients with PD in the off-medication state and 10 age-matched healthy subjects (HS) performed four sessions of right-hand ball rotation using MVF (intervention) on two separate days, 1 week apart (day 1 and day 2). HS subjects received only sham stimulation. The intervention included four sessions of motor-skill training using MVF for 20 min comprised of four sets of training for 30 s each. PD patients were randomly divided into two intervention groups without or with anodal tDCS over the right M1 contralateral to the untrained hand. As the behavior evaluation, the number of ball rotations of the left hand was counted before (pre) and immediately after (post) intervention on both days (pre day 1, post day 1, pre day 2, and post day 2). Motor evoked potential (MEP), input-output function, and cortical silent period were recorded to evaluate the motor cortical excitatory and inhibitory system in M1 pre day 1 and post day 2. The number of ball rotations of the left hand and the facilitation of MEP by intervention were significantly impaired in patients with PD compared to HS. In contrast, if anodal tDCS was applied to right M1 of patients with PD, the number of ball rotations in accordance with I-O function at 150% intensity was significantly increased after day 1 and retained until day 2. This finding may help provide a new strategy for neurorehabilitation improving task-specific motor memory without real motor movements in PD.

Transcranial static magnetic stimulation (tSMS) is a recently introduced noninvasive brain stimulation technique that can modulate brain excitability. Here, we investigated a hypothesis that motor learning would be altered by tSMS applied to the primary motor cortex (M1). For motor task, we chose a serial reaction time task consisting of sequential trials and random trials in which the visual cue doesn't play out a repeating pattern of positions to evaluate an implicit motor learning, where the M1 is a key structure for skill acquisition and early consolidation. Forty-four healthy right-handed volunteers participated in the present study. TSMS was placed over the right M1 or dorsolateral prefrontal cortex (DLPFC). The control group received Sham stimulation over the right M1. Reaction times (RTs) of left hand were analyzed before (Pre session) and after (Post session) practice to examine online learning, and were also assessed 24 h later to examine offline learning (Cons session). The results showed that the RTs became faster in Post than Pre session regardless of the stimulation location. Interestingly, the RTs were significantly faster with the M1 stimulation than the DLPFC or Sham stimulation in Cons session. There was not significant difference in error rate among sessions or stimulation locations. These findings suggest that the modulation of the M1 using tSMS can enhance offline motor learning in an implicit task., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Variability is an inherent feature of the motor output. Although low-frequency oscillations (<0.5 Hz) are the most important contributor to the variability of force during single-joint isolated force tasks, it remains unclear whether they contribute to the variability of a more complex task, such as a voluntary postural task., Research Question: Do low-frequency oscillations contribute to postural sway (center of pressure (COP) variability) when participants attempt to voluntarily maintain posture in a forward leaning position?, Methods: Fourteen healthy young adults performed two tasks: 1) stand quietly (control condition); 2) leaned their body forward to 60% of their maximum lean distance by dorsiflexing the ankle joint. We recorded the COP and electromyographic (EMG) activity from the medial gastrocnemius (MG) and soleus (SL) muscles. We quantified the following: 1) COP variability as the standard deviation (SD) of anteroposterior COP displacements; 2) modulation of COP as the power in COP displacements from 0 to 2 Hz; 3) modulation of EMG bursting as the power in the rectified and smoothed EMG from 0 to 2 Hz; 4) modulation of the interference EMG as the power in the EMG from 10 to 35 and 35-60 Hz., Results: The SD of COP displacements related to the COP oscillations <0.5 Hz in both quiet standing and lean tasks. However, only for the lean task, the <0.5 Hz COP oscillations related to the EMG burst oscillations <0.5 Hz of the MG muscle. The EMG burst oscillations <0.5 Hz of the MG muscle further related to the interference EMG oscillations from 35 to 60 Hz for the lean task., Significance: Voluntary control of forward leaning posture relates to low-frequency neural inputs to the MG muscle., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Plantar flexor muscles play a crucial role in maintaining balance during quiet standing. The purpose of this study was to investigate the effect of their fatigue on common input to these muscles, using a coherence analysis. Thirteen healthy young male adults stood quietly before and after a fatigue protocol consisting of a heel raise exercise. Center of pressure (COP) displacement and electromyograms (EMGs) from the bilateral medial gastrocnemius and soleus muscles were recorded. EMG-EMG coherences between the bilateral homologous muscles (bilateral coherence) and within the unilateral muscles (unilateral coherence) in the right leg were calculated. Anteroposterior and mediolateral COP speeds, mediolateral COP SD, and 95% confidence ellipse area were larger in post- than pre-fatigue condition. Bilateral and unilateral coherences in delta band, that reflect comodulation of muscle activation, and bilateral coherence in alpha band, that is supposedly associated with the subcortical inputs, were smaller in post- than pre-fatigue condition. Unilateral coherences in alpha and beta band, reflecting physiological tremor and corticospinal drive, respectively, were not different between pre- and post-fatigue conditions. It is suggested that the low-frequency common input to the plantar flexor muscles is reduced following the fatiguing contraction during quiet standing, likely by a change in the postural control strategy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aging can impair an ability to lean the body forward to the edge of the base of support. Here, we investigated, using a coherence analysis, common inputs to bilateral and unilateral plantar flexor muscles to test a hypothesis that the age-related impairment would be related to strong synchronous bilateral activation and reduced cortical control of these muscles. Healthy young ( n = 14) and elderly adults ( n = 19), who were all right-foot dominant, performed quiet standing task and tasks that required the subjects to lean their body forward to 35 and 75% of the maximum lean distance. The electromyogram was recorded from the bilateral medial gastrocnemius (MG) and soleus (SL) muscles. We analyzed delta-band coherence, that reflects comodulation of muscle activity, between the bilateral homologous muscles (MG-MG and SL-SL pairs). The origin of this bilateral comodulation is suggested to be the subcortical system. Also, we examined beta-band coherence, that is related to the corticospinal drive, between the unilateral muscles (MG-SL pair) in the right leg. Results indicated that the bilateral delta-band coherence for the MG-MG pair was significantly smaller in the 75% forward lean than quiet standing and 35% forward lean tasks for the young adults (quiet: p = 0.036; 35%: p = 0.0011). The bilateral delta-band coherence for the SL-SL pair was significantly smaller in the 75% forward lean than 35% forward lean task for the young adults ( p = 0.027). Furthermore, the unilateral beta-band coherence was larger in the forward lean than quiet standing task for the young adults (35%: p < 0.001; 75%: p = 0.029). Contrarily, the elderly adults did not demonstrate such changes. These findings suggest the importance of decreasing the synchronous bilateral activation and increasing the unilateral cortical control of the plantar flexor muscles for the successful forward postural lean performance, and that aging impairs this modulatory ability.

To investigate the effects of aging on coordination of plantar flexor muscles during bipedal and unipedal stances, we examined a relationship between the center of pressure sway and electromyographic activity of these muscles, and also the common neural input, using a coherence analysis. Healthy young and elderly adults were asked to perform bipedal and unipedal standing. The electromyograms were recorded unilaterally from the medial and lateral gastrocnemius (MG and LG) and soleus (SL) muscles, and the common input was analyzed for MG-LG, MG-SL, and LG-SL pairs in two frequency bands: a delta band, that is associated with force variability, and a beta band, that could reflect the corticospinal drive. Main results indicated that the MG and SL muscles worked for lateral sway, while the LG muscle worked for medial sway during the unipedal stance. The delta-band coherence for the MG-SL pair and the beta-band coherences for all the pairs were larger during the unipedal than bipedal stance for both groups. The delta-band coherence for the MG-SL pair was larger for the elderly than young adults during the unipedal stance. In addition, the beta-band coherence for the MG-SL pair was larger than the other pairs during the unipedal stance for the elderly. These findings suggest that the oscillatory activity between the MG and SL muscles is strongly involved in the control of unipedal stance, and aging would increase the cortical drive to these muscles to deal with the postural sway that could be affected by forces generated cooperatively by them.