書誌：   J Biol Chem ,2012

Lee AY, Chiba T, Truong LN, Cheng AN, Do J, Cho MJ, Chen L, Wu X. J Biol Chem. 2012, 287(4):2531-43.

Background: S-phase checkpoint is important for maintaining genome stability upon DNA damage in S-phase. Results: A replication essential protein Dbf4 is phosphorylated by checkpoint kinases when DNA is damaged. Conclusion: Dbf4 is a downstream target of the S-phase checkpoint to mediate DNA damage responses. Significance: These studies help understand how the genome is protected from DNA damage to prevent tumorigenesis.

Dbf4/Cdc7 (Dbf4-dependent kinase (DDK)) is activated at the onset of S-phase, and its kinase activity is required for DNA replication initiation from each origin. We showed that DDK is an important target for the S-phase checkpoint in mammalian cells to suppress replication initiation and to protect replication forks. We demonstrated that ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) proteins directly phosphorylate Dbf4 in response to ionizing radiation and replication stress. We identified novel ATM/ATR phosphorylation sites on Dbf4 and showed that ATM/ATR-mediated phosphorylation of Dbf4 is critical for the intra-S-phase checkpoint to inhibit DNA replication. The kinase activity of DDK, which is not suppressed upon DNA damage, is required for fork protection under replication stress. We further demonstrated that ATM/ATR-mediated phosphorylation of Dbf4 is important for preventing DNA rereplication upon loss of replication licensing through the activation of the S-phase checkpoint. These studies indicate that DDK is a direct substrate of ATM and ATR to mediate the intra-S-phase checkpoint in mammalian cells.  

書誌：日本臨床スポーツ医学会誌 ,2014

書誌： Experimental Brain Research ,2014

Kato K., Muraoka T., Higuchi T., Mizuguchi N. & Kanosue K. (2014). Experimental Brain Research, 232(1):181-189.

Abstract  We investigated the interaction between relaxation and contraction for remote, ipsilateral muscles of the hand and foot (wrist extensor/ankle dorsiflexor). Subjects sat in an armchair and were able to freely move their right hand and foot. They performed eight tasks: (1) wrist extension from a flexed (relaxed) position, (2) ankle dorsiflexion from a plantarflexed (relaxed) position, (3) wrist relaxation from an extended position, (4) ankle relaxation from a moderately dorsiflexed position. The remaining tasks involved (5) simultaneous performance of tasks 1 and 2, (6) 3 and 4, (7) 1 and 4, and (8) 2 and 3. Subjects performed each task as fast as possible after hearing a start signal. They were instructed not to activate antagonistic muscles in the tasks involving relaxation. When contraction of the wrist flexor/ankle dorsiflexor was concurrent with relaxation of the ipsilateral limb (ankle dorsiflexor/wrist extensor), the reaction time of contraction as observed in electromyography (EMG) activities in the wrist extensor/ankle dorsiflexor became longer and the EMG activities became smaller. Our findings suggest that muscle relaxation in one limb interferes with smooth movement of muscle contraction in the ipsilateral limb.

Keywords: Reaction time, Electromyography, Inhibition, Coordination

書誌：   Sensors , 2012

Chiba T, Tsuchiya T, Mori R, Shimokawa I. Sensors. 2012, 12:1648-1656.

Abstract: Recent drug discovery efforts have utilized high throughput screening (HTS) of large chemical libraries to identify compounds that modify the activity of discrete molecular targets. The molecular target approach to drug screening is widely used in the pharmaceutical and biotechnology industries, because of the amount of knowledge now available regarding protein structure that has been obtained by computer simulation. The molecular target approach requires that the structure of target molecules, and an understanding of their physiological functions, is known. This approach to drug discovery may, however, limit the identification of novel drugs. As an alternative, the phenotypic- or pathway-screening approach to drug discovery is gaining popularity, particularly in the academic sector. This approach not only provides the opportunity to identify promising drug candidates, but also enables novel information regarding biological pathways to be unveiled. Reporter assays are a powerful tool for the phenotypic screening of compound libraries. Of the various reporter genes that can be used in such assays, those encoding secreted proteins enable the screening of hit molecules in both living cells and animals. Cell- and animal-based screens enable simultaneous evaluation of drug metabolism or toxicity with biological activity. Therefore, drug candidates identified in these screens may have increased biological efficacy and a lower risk of side effects in humans. In this article, we review the reporter bioassay systems available for phenotypic drug discovery.

Keywords: drug development; high throughput screening; reporter mice; age-related disorders 

書誌：   Psychophysiology , 2014

Xu, L., Sommer, W., & Masaki, H. (2014). The structure of motor programming: Evidence from reaction times and lateralized readiness potentials. Psychophysiology, doi:10.1111/psyp.12296 (in press)

Abstract There is a widely accepted notion that movement elements are assembled prior to movement execution in a central motor programming stage. However, it is not clear how this stage is structured—whether it is a unitary stage allowing different motor parameters to cross talk or whether there are several independent processes dealing with each motor parameter.We addressed this question by orthogonally manipulating two movement-related factors: response sequence complexity and movement duration. Both factors yielded main effects on reaction time but no interaction. Additive effects of both factors on the onsets of response- but not stimulus-synchronized lateralized readiness potentials suggest separable motoric loci of sequence complexity and duration. These findings are at variance with the notion of a unitary movement programming stage.

Descriptors: Movement preparation, Mental chronometry, Lateralized readiness potential, Finger tapping, Kinematic parameter 

書誌： Frontiers in Neuroscience , 2014

Tsukahara S, Kanaya M, Yamanouchi K. (2014). Frontiers in Neuroscience, 8:299. doi: 10.3389/fnins.2014.00299.

Female sexual behavior in rodents, termed lordosis, is controlled by facilitatory and inhibitory systems in the brain. It has been well demonstrated that a neural pathway from the ventromedial hypothalamic nucleus (VMN) to the midbrain central gray (MCG) is essential for facilitatory regulation of lordosis. The neural pathway from the arcuate nucleus to the VMN, via the medial preoptic nucleus, in female rats mediates transient suppression of lordosis, until female sexual receptivity is induced. In addition to this pathway, other regions are involved in inhibitory regulation of lordosis in female rats. The lordosis-inhibiting systems exist not only in the female brain but also in the male brain. The systems contribute to suppression of heterotypical sexual behavior in male rats, although they have the potential ability to display lordosis. The lateral septum (LS) exerts an inhibitory influence on lordosis in both female and male rats. This review focuses on the neuroanatomy and sex differences of the lordosis-inhibiting system in the LS. The LS functionally and anatomically links to the MCG to exert suppression of lordosis. Neurons of the intermediate part of the LS (LSi) serve as lordosis-inhibiting neurons and project axons to the MCG. The LSi-MCG neural connection is sexually dimorphic, and formation of the male-like LSi-MCG neural connection is affected by aromatized testosterone originating from the testes in the postnatal period. The sexually dimorphic LSi-MCG neural connection may reflect the morphological basis of sex differences in the inhibitory regulation of lordosis in rats.

Keywords: lordosis, lateral septum, midbrain central gray, estradiol, sexual differentiation

書誌： 日本建築学会環境系論文集 ,2012

庄司 名奈恵，小 島 隆 矢 (2012). 日本建築学会環境系論文集 77(681), 829-836.

This study examines the negative image as use prevention factor of public library. To solve this problem, two questionnaire surveys were conducted. First survey was conducted to research conscious difference between the general user and well-informed person and Second survey was conducted for library user and non-user to analyze correlation or causality between impression in library, user's experience and attitude. The results are as followings:  1) There is a difference between the general user and well-informed person. Well-informed person doesn’t feel hard in library.  2) The hard impression of library makes non-user to avoid it. 

Keywords : public library, Structural Equation Modeling, Graphical Modeling, causality analysis, SD method, MANOVA 

書誌： Experimental Brain Research ,2013

Mizuguchi N, Umehara I., Nakata H. & Kanosue K. (2013). Experimental Brain Research, 230(2):243-249.

Abstract  Motor imagery is defined as the mental execution of a movement without any muscle activity. In the present study, corticospinal excitability was assessed by motor evoked potentials (MEPs) when the subjects imagined isometric elbow flexion at various force levels. Electromyography was recorded from the right brachioradialis, the biceps brachii and the triceps brachii muscles. First, the maximum voluntary contraction (MVC) of elbow flexion was recorded in each subject. Subjects practiced performing 10, 30 and 60 % MVC using visual feedback. After the practice, MEPs were recorded during the imagery of elbow flexion with the forces of 10, 30 and 60 % MVC without any feedback. After the MEPs recording, we assigned subjects to reproduce the actual elbow flexion force at 10, 30 and 60 % MVC. The MEPs amplitudes in the brachioradialis and biceps brachii in the 60 % MVC condition were significantly greater than those in the 10 % MVC condition (p < 0.05). These findings suggest that the enhancement of corticospinal excitability during motor imagery is associated with an increase in imagined force level. 

Keywords: Motor imagery, Force, Motor evoked potentials, Transcranial magnetic stimulation 

書誌： Scientific Reports,2014

Chiba T, Tamashiro Y, Park D, Kusudo T, Fujie R, Komatsu T, Kim SE, Park S, Hayashi H, Mori R, Yamashita H, Chung HY, Shimokawa I. Sci Rep. 2014, 4:4517. doi:10.1038/srep04517.

Knowledge of genes essential for the life-extending effect of dietary restriction (DR) in mammals is incomplete. In this study, we found that neuropeptide Y (Npy), which mediates physiological adaptations to energy deficits, is an essential link between DR and longevity in mice. The lifespan-prolonging effect of lifelong 30%DRwas attenuated in Npy-null mice, as was the effect on the occurrence of spontaneous tumors and oxidative stress responses in comparison to wild-type mice. In contrast, the physiological processes activated during adaptation to DR, including inhibition of anabolic signaling molecules (insulin and insulin-like growth factor-1), modulation of adipokine and corticosterone levels, and preferential fatty acid oxidation, were unaffected by the absence of Npy. These results suggest a key role for Npy in mediating the effects of DR. We also provide evidence that most of the physiological adaptations to DR could be achieved in mice without Npy.

書誌：   Journal of Ergonomics , 2013

Bae, S., Kamijo K., & Masaki, H. (2013). Journal of Ergonomics, S2:003. doi:10.4172/2165-7556.S2-003.

Abstract This study examined whether wearing a pair of core-supporting gym shorts influenced cognitive control and mood state following aerobic exercise in young adults. Cognitive performance and the event-related P3 potential were measured. Twenty-four adults were assigned to either the core-supporting shorts group or the normal shorts group. Participants completed 30 minutes of an acute treadmill exercise involving walking and/or running at an intensity of 70% HRmax. They next performed a modified Sternberg memory task, in which participants encoded a letter array and determine if a probe letter had been presented in the preceding set of memory items. Results indicated that the core-supporting shorts group exhibited greater response accuracy and larger P3 amplitudes as compared to the normal shorts group. In addition, the core-supporting shorts group reported more pleasantness and relaxation than the normal shorts group. These results suggest that wearing the core-supporting shorts improves the cognitive control associated with working memory and induces a positive affect as well.

Keywords: Acute aerobic exercise; Working memory; Cognitive control; Event-related potentials; P3; Positive mood; Core stability 

書誌： Neuroscience Letters , 2012

Hashimoto K, Ueda S, Ehara A, Sakakibara S, Yoshimoto K, Hirata K. (2012). Neurosci Lett. 506:79-83.

abstract Melatonin has ubiquitous actions, both as a direct free-radical scavenger and as an indirect anti-oxidant. The present study examined in vivo neuroprotective effects of melatonin on the nigrostriatal dopaminergic system in zitter (zi/zi) rat, which displays abnormal metabolism of superoxide leading to age-related degeneration of the dopaminergic system. For up to 9 months after weaning, zi/zi rats had ad libitum access to drinking water containing melatonin. Chronic treatment with melatonin attenuated the decreases of dopamine and its metabolite in zi/zi rat caudate-putamen (CPU). Immunohistochemistry for tyrosine hydroxylase (TH) was consistent with neurochemical data in the CPU and demonstrated substantial sparing of the reduction of TH-immunoreactive neurons in the substantia nigra pars compacta. Quantitative polymerase chain reaction (qPCR) was performed to analyze mRNA expressions of pro-inflammatory cytokines (IL-1ˇ and TNF-˛) and the anti-oxidant enzymes (catalase (CAT), superoxide dismutase (SOD) 1 and 2, and glutathione peroxidase (GPx1)) in the striatum and midbrain in order to examine the neuroprotective effect of melatonin. IL-1ˇ and TNF-˛ mRNA expressions were significantly increased in both areas of 3-month-old zi/zi rats, whereas there was a significant decrease in CAT mRNA expression in the striatum of 6-month-old zi/zi rat as compared to age-matched controls. With the exception of the high TNF-˛ mRNA expression in 3-month-old zi/zi midbrains, chronic treatment of melatonin attenuated expressional changes of IL-1ˇ, CAT, SOD1, and GPx1. These results suggest that besides its direct scavenger effects, chronic melatonin treatment provides a neuroprotective effect against dopaminergic degeneration by suppressing pro-inflammatory cytokines and up-regulating anti-oxidant enzyme expression. 

Keywords: Oxidative stress, Dopamine, Melatonin, Neuroprotection, Degeneration, PD model 

書誌： Progress in Neuro-Psychopharmacology and Biological Psychiatry ,2014

Nakano, M., Matsuo, K., Nakashima, M., Harada, K., Egashira, K., Masaki, H., Takahashi, K., & Watanabe, Y. (2014). Progress in Neuro-Psychopharmacology and Biological Psychiatry, 10.1016/j.pnpbp.2013.09.011, 48, 3, 51-56.

Abstract Background: Reduced motivation and blunted decision-making are key features of major depressive disorder (MDD). Patients with MDD show abnormal decision-making when given negative feedback regarding a reward. The brain mechanisms underpinning this behavior remain unclear. In the present study, we examined the association between rapid decision-making with negative feedback and brain volume in MDD. Methods: Thirty-six patients with MDD and 54 age-, sex- and IQ-matched healthy subjects were studied. Subjects performed a rapid decision-making monetary task in which participants could make high- or low-risk choices. We compared between the 2 groups the probability that a high-risk choice followed negative feedback. In addition, we used voxel-based morphometry (VBM) to compare between group differences in gray matter volume, and the correlation between the probability for high-risk choices and brain volume. Results: Compared to the healthy group, the MDD group showed significantly lower probabilities for high-risk choices following negative feedback. VBM analysis revealed that the MDD group had less gray matter volume in the right medial prefrontal cortex and orbitofrontal cortex (OFC) compared to the healthy group. The right OFC volume was negatively correlated with the probability that a high-risk choice followed negative feedback in patients with MDD. We did not observe these trends in healthy subjects. Conclusions: Patients with MDD show reduced motivation for monetary incentives when they were required to make rapid decisions following negative feedback. We observed a correlation between this reduced motivation and gray matter volume in the medial and ventral prefrontal cortex, which suggests that these brain regions are likely involved in the pathophysiology of aberrant decision-making in MDD.

Keywords: Decision-making, Depressive disorder, Negative feedback, Prefrontal cortex, Voxel-based morphometry 

書誌：   Keio J Med ,2011

Yamaguchi T, Tanabe S, Muraoka Y, Imai S, Masakado Y, Hase K, Kimura A, Liu M. (2011). Keio J Med. 60(3):90-5.  We evaluated the efficacy of a novel electromyogram (EMG)-controlled electrical stimulation system, called the integrated volitional control electrical stimulator (IVES), on the recovery of upper extremity motor functions in patients with chronic hemiparetic stroke. Ten participants in the chronic stage (more than 12 months post-stroke with partial paralysis of their wrist and fingers) received treatment with IVES to the extensor carpi radialis and extensor digitorum communis 6 h/day for 5 days. Before and after the intervention, participants were assessed using upper-extremity Fugl-Meyer motor assessment (FMA), the active range of motion (A-ROM), the nine-hole peg test (NHPT), and surface EMG recordings. The upper extremity FMA showed a statistically significant increase from 50.8 ± 5.8 to 56.8 ± 6.2 after the intervention (P < 0.01). The A-ROM of wrist extension was also significantly improved from 36.0° ± 15.4° to 45.0° ± 15.5° (P < 0.01). The NHPT significantly decreased from 85.3 ± 52.0 to 63.3 ± 29.7 (P = 0.04). EMG measurements demonstrated statistically significant improvements in the coactivation ratios for the wrist flexor and extensor muscles after the intervention. This study suggested that 5 days of IVES treatment yields a noticeable improvement in upper extremity motor functions in patients with chronic hemiparetic stroke. (Keio J Med 60 (3) : 90–95, September 2011) Keywords:  electric stimulation therapy, motor paralysis, neural plasticity, functional recovery, rehabilitation 

書誌： Neuromodulation ,2011

Kagaya H, Baba M, Saitoh E, Okada S, Yokoyama M, Muraoka Y. (2011). Neuromodulation. 14(3):278-83; discussion 283. doi: 10.1111/j.1525-1403.2011.00331.x. Objectives: This study aimed to determine the laryngeal elevation muscle motor points, evaluate the movement of hyoid bone and larynx during stimulation of the motor points, and examine the potential for treating severe dysphagia by functional electrical stimulation. Methods: The motor points of the laryngeal elevation muscles were anatomically determined from four cadavers. Those motor points in two healthy subjects and one lateral medullary syndrome patient were electrically stimulated by surface or implanted electrodes. Results: The movements elicited by electrical stimulation of the motor points were greater in implanted than in surface electrodes. Elevation of the hyoid bone and the larynx in a lateral medullary syndrome patient were achieved with the implanted electrodes, but the upper esophageal sphincter opening was not obtained unless an additional cricopharyngeus muscle block was provided. Conclusion: The hyoid bone and larynx were elevated by electrically stimulating the motor points of the laryngeal elevation muscles. Keywords: Dysphagia, functional electrical stimulation, hyoid bone, larynx, motor point

書誌：   Advanced Drug Delivery Reviews , 2010

Adv Drug Deliv Rev. 2010 Jul 31;62(9-10):918-27

Shibata S, Tahara Y, Hirao A.

Abstract

Daily restricted feeding entrains the circadian rhythm of mouse clock gene expression in the central nervous system, excluding the suprachiasmatic nucleus (SCN), as well as in the peripheral tissues such as the liver, lung, and heart. In addition to entrainment of the clock genes, daily restricted feeding induces a locomotor activity increase 2–3 h before the restricted feeding time initiates. The increase in activity is called the foodanticipatory activity (FAA). In addition to FAA, daily restricted feeding can also entrain peripheral circadian clocks in other organs such as liver, lung, and heart. This type of oscillator is called the food-entrainable peripheral oscillator (FEPO). At present, the mechanisms for restricted feeding-induced entrainment of locomotor activity (FAA) and/or peripheral clock (FEPO) are still unknown. In this review, we describe the role of the central nervous system and peripheral tissues in FAA performance and also in the entrainment of clock gene expression. In addition, the mechanism for entrainment of circadian oscillators by the abuse of drugs, such as methamphetamine, is discussed.

書誌： PLoS ONE ,2012

Masaki H, Murphy TI, Kamijo K, Yamazaki K, Sommer W (2012). PLoS ONE 7(5): e38006. doi:10.1371/journal.pone.0038006 Abstract Background: Recent studies employing stimulus-response compatibility tasks suggest that an increase in the amplitude of the positive deflection of the response-locked event-related potential (ERP) foreshadows errors on forthcoming trials. However, no studies have tested the generalizability of error-foreshadowing positivity to tasks without stimulus-response interference. Methodology/Principal Findings: The present study adopted an alternating-response task, in which the participants responded to the pointing direction of an arrowhead (up or down). Although the arrowhead direction alternated for the majority of trials (95%), occasionally this pattern was broken by a repeated stimulus, termed a lure trial. We compared the matched-reaction-time correct-preceding ERP with the error-preceding ERP on lure-preceding trials. There was no evidence that errors are foreshadowed by the increase of a positive electroencephalogram (EEG) deflection. To the contrary, analyses of ERPs time-locked to electromyogram (EMG) onset on the five consecutive lure-preceding trials showed larger positive deflections on correct-preceding than error-preceding trials. The post-response negativity did not differ between correct preceding and error-preceding trials. Conclusions/Significance: These results suggest that in minimal conflict tasks a decreased positivity may foreshadow incorrect performance several trials prior to the error, possibly reflecting the waning of task-related efforts. Therefore, error foreshadowing brain signals may be task-specific.

書誌： JPET,2012

JPET 340:698–705, 2012

Yuji Kubo, Yu Tahara, Akiko Hirao, and Shigenobu Shibata

Comprehensive gene expression profiling in mice in response to the inhalation of sevoflurane has revealed that circadian clock gene expression is affected strongly in the liver, heart, lung, and kidney, in this order, but moderately in the spleen and slightly in the brain. Therefore, we examined whether the administration of general anesthetics at different times of the day induces phase shifts of the liver clock in Per2::Luciferase knockin mice. One to 4 days of intraperitoneal injection of 2,2,2-tribromoethanol (240 mg/kg, anesthetic time 60 min) or 2,2,2-trichloroethanol (240 mg/kg, 60 min), common anesthetics in veterinary surgery, caused phase delays when injected during the daytime and phase advances when injected during the nighttime. Inhalation administration of isoflurane for 30 or 60 min during the daytime did not induce a phase delay. Injection of propofol (300 mg/kg, 17 min) during the daytime induced an insignificant phase delay of the Per2 bioluminescence rhythm. Injection of 2,2,2-tribromoethanol did not induce a phase shift in the suprachiasmatic nucleus, the main oscillator, or in behavioral locomotor rhythms, suggesting that 2,2,2-tribromoethanol induced phase shifts of the liver clock independent of the main suprachiasmatic clock. The expression of clock genes, such as Bmal1 and Clock, in mouse liver was decreased strongly 1 and 4 h after a single injection of 2,2,2- tribromoethanol. These results demonstrate that 2,2,2-tribromoethanol or 2,2,2-trichloroethanol produce phase shifts of the peripheral clock, independent of anesthetic activity. These anesthetics may cause circadian rhythm disorders in peripheral organs when administered as general anesthetics several times during the day.