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Background and Aim: Ustekinumab, a new anti-interleukin-12/23 antibody, is an effective treatment for ulcerative colitis; however, data regarding predictive factors of its efficacy are limited. Predicting treatment efficacy in advance would be useful for selecting a therapeutic agent. This study aimed to identify biomarkers that can predict the long-term outcome of ustekinumab treatment., Materials and Methods: We retrospectively reviewed the records of patients with active ulcerative colitis treated with ustekinumab at Osaka Medical and Pharmaceutical University Hospital from June 2020 to January 2023. We divided patients into non-remission and remission groups, and examined whether baseline biomarkers, including C-reactive protein-to-lymphocyte ratio, and early treatment response could predict clinical remission at week 48 of ustekinumab treatment., Results: Of the 33 patients included in the study, 21 (63.6%) were in clinical remission at week 48 of ustekinumab treatment. Baseline C-reactive protein-to-lymphocyte ratio values were significantly higher in the non-remission than in the remission group. The baseline C-reactive protein-to-lymphocyte ratio value was identified as an independent prognostic factor for clinical remission at week 48 (odds ratio: 10, 95% confidence interval: 1.6-62.4, p = 0.014), with the cutoff value of 3.353 showing excellent prognostic performance (sensitivity: 71.4%, specificity: 83.3%). Furthermore, the clinical response at week 4 (odds ratio: 10, confidence interval: 1.78-56.1, p = 0.009) and that at week 8 (odds ratio: 12, confidence interval: 2.16-66.5, p = 0.005) were significantly associated with clinical remission at week 48., Conclusions: The baseline C-reactive protein-to-lymphocyte ratio value and early treatment response are useful biomarkers to predict the long-term efficacy of ustekinumab treatment., Competing Interests: Shiro Nakamura reports receiving speaking fees from AbbVie GK, EA Pharma Co., Ltd., Mitsubishi Tanabe Pharma Corporation., Mochida Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd, and Janssen Pharmaceutical K.K. Dr., (Copyright: © 2024 Koshiba et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Non-thermal atmospheric-pressure plasma (NTAPP) has been widely studied for clinical applications, e.g., disinfection, wound healing, cancer therapy, hemostasis, and bone regeneration. It is being revealed that the physical and chemical actions of plasma have enabled these clinical applications. Based on our previous report regarding plasma-stimulated bone regeneration, this study focused on Achilles tendon repair by NTAPP. This is the first study to reveal that exposure to NTAPP can accelerate Achilles tendon repair using a well-established Achilles tendon injury rat model. Histological evaluation using the Stoll's and histological scores showed a significant improvement at 2 and 4 weeks, with type I collagen content being substantial at the early time point of 2 weeks post-surgery. Notably, the replacement of type III collagen with type I collagen occurred more frequently in the plasma-treated groups at the early stage of repair. Tensile strength test results showed that the maximum breaking strength in the plasma-treated group at two weeks was significantly higher than that in the untreated group. Overall, our results indicate that a single event of NTAPP treatment during the surgery can contribute to an early recovery of an injured tendon., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Nakazawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Emotion affects postural control during quiet standing. Emotional states can be defined as two-dimensional models comprising valence (pleasant/unpleasant) and arousal (aroused/calm). Most previous studies have investigated the effects of valence on postural control without considering arousal. In addition, studies have focused on the center of pressure (COP) trajectory to examine emotional effects on the quiet standing control; however, the relationship between neuromuscular mechanisms and the emotionally affected quiet standing control is largely unknown. This study aimed to investigate the effects of arousal and valence on the COP trajectory and ankle muscle activity during quiet standing. Twenty-two participants were instructed to stand on a force platform and look at affective pictures for 72 seconds. The tasks were repeated six times, according to the picture conditions composed of arousal (High and Low) and valence (Pleasant, Neutral, and Unpleasant). During the task, the COP, electromyogram (EMG) of the tibialis anterior and soleus muscles, and electrocardiogram (ECG) were recorded. The heart rate calculated from the ECG was significantly affected by valence; the value was lower in Unpleasant than that in Neutral and Pleasant. The 95% confidence ellipse area and standard deviation of COP in the anterior-posterior direction were lower, and the mean power frequency of COP in the anterior-posterior direction was higher in Unpleasant than in Pleasant. Although the mean velocity of the COP in the medio-lateral direction was significantly lower in Unpleasant than in Pleasant, the effect was observed only when arousal was low. Although the EMG variables were not significantly affected by emotional conditions, some EMG variables were significantly correlated with the COP variables that were affected by emotional conditions. Therefore, ankle muscle activity may be partially associated with postural changes triggered by emotional intervention. In conclusion, both valence and arousal affect the COP variables, and ankle muscle activity may be partially associated with these COP changes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Takahashi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Non-thermal atmospheric-pressure plasma (NTAPP) is attracting widespread interest for use in medical applications. The tissue repair capacity of NTAPP has been reported in various fields; however, little is known about its effect on fracture healing. Non-union or delayed union after a fracture is a clinical challenge. In this study, we aimed to investigate how NTAPP irradiation promotes fracture healing in a non-union fracture model and its underlying mechanism, in vitro and in vivo. For the in vivo study, we created normal and non-union fracture models in LEW/SsNSlc rats to investigate the effects of NTAPP. To create a fracture, a transverse osteotomy was performed in the middle of the femoral shaft. To induce the non-union fracture model, the periosteum surrounding the fracture site was cauterized after a normal fracture model was created. The normal fracture model showed no significant difference in bone healing between the control and NTAPP-treated groups. The non-union fracture model demonstrated that the NTAPP-treated group showed consistent improvement in fracture healing. Histological and biomechanical assessments confirmed the fracture healing. The in vitro study using pre-osteoblastic MC3T3-E1 cells demonstrated that NTAPP irradiation under specific conditions did not reduce cell proliferation but did enhance osteoblastic differentiation. Overall, these results suggest that NTAPP is a novel approach to the treatment of bone fractures., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Saito et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

This study investigated the specific gaze control ability of expert players and low-skill players of League of Legends (LoL). Eleven expert and nine low-skill players were divided according to their official ranking. Then, the gaze movement of each participant when performing each task (e.g., easy task and moderate task) while competing against a computer artificial intelligence system was recorded. Experts were found to have a significantly wide horizontal gaze distribution. Additionally, experts had a consistently short gaze fixation duration during the moderate task. These results suggest that a wide horizontal gaze distribution allows experts to obtain information from a wider area. Additionally, the consistently short fixation duration of the experts indicated that they need only a short period to assess information, which is advantageous because large amounts of information need to be processed within a limited time while playing. This specific gaze control ability could be an important factor that contributes to the superior performance of expert LoL players., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Jeong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Previous evidence indicated that interventions with combined neuromuscular electrical stimulation (NMES) and voluntary muscle contractions could have superior effects on corticospinal excitability when the produced total force is larger than each single intervention. However, it is unclear whether the superior effects exist when the produced force is matched between the interventions. Ten able-bodied individuals performed three intervention sessions on separate days: (i) NMES-tibialis anterior (TA) stimulation; (ii) NMES+VOL-TA stimulation combined with voluntary ankle dorsiflexion; (iii) VOL-voluntary ankle dorsiflexion. Each intervention was exerted at the same total output of 20% of maximal force and applied intermittently (5 s ON / 19 s OFF) for 16 min. Motor evoked potentials (MEP) of the right TA and soleus muscles and maximum motor response (Mmax) of the common peroneal nerve were assessed: before, during, and for 30 min after each intervention. Additionally, the ankle dorsiflexion force-matching task was evaluated before and after each intervention. Consequently, the TA MEP/Mmax during NMES+VOL and VOL sessions were significantly facilitated immediately after the interventions started until the interventions were over. Compared to NMES, larger facilitation was observed during NMES+VOL and VOL sessions, but no difference was found between them. Motor control was not affected by any interventions. Although superior combined effects were not shown compared to voluntary contractions alone, low-level voluntary contractions combined with NMES resulted in facilitated corticospinal excitability compared to NMES alone. This suggests that the voluntary drive could improve the effects of NMES even during low-level contractions, even if motor control is not affected., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: MRP is a shareholder and director in company MyndTec Inc. The remaining authors have no conflicts of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Yamaguchi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Action observation (AO) and motor imagery (MI) are used for the rehabilitation of patients who face difficulty walking. Rehabilitation involving AO, MI, and AO combined with MI (AO+MI) facilitates gait recovery after neurological disorders. However, the mechanism by which it positively affects gait function is unclear. We previously examined the neural mechanisms underlying AO and MI of walking, focusing on AO+MI and corticospinal and spinal motor neuron excitability, which play important roles in gait function. Herein, we investigated the effects of a short intervention using AO+MI of walking on the corticospinal and spinal motor neuron excitability and MI ability of participants. Twelve healthy individuals participated in this study, which consisted of a 20 min intervention. Before the experiment, we measured MI ability using the Vividness of Movement Imagery Questionnaire-2 (VMIQ-2). We used motor evoked potential and F-wave measurements to evaluate the corticospinal and spinal motor neuron excitability at rest, pre-intervention, 0 min, and 15 min post-intervention. We also measured corticospinal excitability during MI of walking and the participant's ability to perform MI using a visual analog scale (VAS). There were no significant changes in corticospinal and spinal motor neuron excitability during and after the intervention using AO+MI (p>0.05). The intervention temporarily increased VAS scores, thus indicating clearer MI (p<0.05); however, it did not influence corticospinal excitability during MI of walking (p>0.05). Furthermore, there was no significant correlation between the VMIQ-2 and VAS scores and changes in corticospinal and spinal motor neuron excitability. Therefore, one short intervention using AO+MI increased MI ability in healthy individuals; however, it was insufficient to induce plastic changes at the cortical and spinal levels. Moreover, the effects of intervention using AO+MI were not associated with MI ability. Our findings provide information about intervention using AO+MI in healthy individuals and might be helpful in planning neurorehabilitation strategies., Competing Interests: The authors have declared that no competing interests exist.

Musicians tend to have better auditory and motor performance than non-musicians because of their extensive musical experience. In a previous study, we established that loudness discrimination acuity is enhanced when sound is produced by a precise force generation task. In this study, we compared the enhancement effect between experienced pianists and non-musicians. Without the force generation task, loudness discrimination acuity was better in pianists than non-musicians in the condition. However, the force generation task enhanced loudness discrimination acuity similarly in both pianists and non-musicians. The reaction time was also reduced with the force control task, but only in the non-musician group. The results suggest that the enhancement of loudness discrimination acuity with the precise force generation task is independent of musical experience and is, therefore, a fundamental function in auditory-motor interaction., Competing Interests: The authors have declared that no competing interests exist.

Clofarabine, an FDA approved purine analog, is used in the treatment of relapsed or refractory acute lymphoblastic leukemia. Clofarabine acts by inhibiting DNA synthesis. We demonstrated that clofarabine may have a novel function though inhibiting CD99, a transmembrane protein highly expressed on Ewing Sarcoma (ES) cells. CD99 is a validated target in ES whose inhibition may lead to a high therapeutic index for patients. Here we present additional data to support the hypothesis that clofarabine acts on CD99 and regulates key signaling pathways in ES. Cellular thermal shift assay indicated a direct interaction between clofarabine and CD99 in ES cell lysates. Clofarabine induced ES cell death does not require clofarabine's conversion to its active form by deoxycytidine kinase. A phosphokinase array screen with clofarabine and a CD99 blocking antibody identified alterations in signaling pathways. CD99 inhibition with clofarabine in ES cells caused rapid and sustained phosphorylation of ERK, MSK, and CREB. However, activation of this pathway did not correlate with clofarabine induced ES cell death. In summary, we demonstrated that clofarabine may activate ERK, MSK, and CREB phosphorylation through CD99 within minutes, however this paradoxical activation and subsequent ES cell death requires additional investigation., Competing Interests: The authors have declared that no competing interests exist.

Electrical stimulation involving visual areas of the brain produces artificial light percepts called phosphenes. These visual percepts have been extensively investigated in previous studies involving intracortical microsimulation (ICMS) and serve as the basis for developing a visual prosthesis for the blind. Although advances have been achieved, many challenges still remain with implementing a functional ICMS for visual rehabilitation purposes. Transcranial magnetic stimulation (TMS) over the primary occipital lobe offers an alternative method to produce phosphenes non-invasively. A main challenge facing blind individuals involves navigation. Within the scientific community, methods to evaluate the ability of a visual prosthesis to facilitate in navigation has been neglected. In this study, we investigate the effectiveness of evoking lateralized phosphenes to navigate a computer simulated virtual environment. More importantly, we demonstrate how virtual environments along with the development of a visual prosthesis share a mutual relationship benefiting both patients and researchers. Using two TMS devices, a pair of 40mm figure-of-eight coils were placed over each occipital hemisphere resulting in lateralized phosphene perception. Participants were tasked with making a series of left and right turns using peripheral devices depending on the visual hemifield in which a phosphene is present. If a participant was able to accurately perceive all ten phosphenes, the simulated target is able to advance and fully exit the virtual environment. Our findings demonstrate that participants can interpret lateralized phosphenes while highlighting the integration of computer based virtual environments to evaluate the capability of a visual prosthesis during navigation., Competing Interests: The authors have declared that no competing interests exist.

Background and Aim: Autophagy is an essential process involved in the pathogenesis of inflammatory bowel disease (IBD). Although there are many data showing the roles of autophagy in intestinal epithelial cells (IECs), the mechanisms involved remain to be fully elucidated. We investigated the influence of autophagy in IECs on gastrointestinal tract inflammation., Methods: Mice with conditional knockout of Atg5 in IECs (Atg5flox/flox/villin-Cre mice) were subjected to dextran sulfate sodium (DSS)-induced colitis and analyzed for colitis susceptibility. Additionally, we used Atg5-silenced rat IECs (IEC6shAtg5 cells) for in vitro assays., Results: Sensitivity to DSS markedly increased in Atg5flox/flox/villin-Cre mice compared to that in wild-type mice. In IEC6shAtg5 cells, apoptosis was enhanced, and cell viability significantly decreased compared to IEC-6 cells. The expression of proinflammatory cytokines increased upon suppression of autophagy. Furthermore, silencing of Atg5 was associated with inflammation of IECs, activation of the mitogen-activated protein kinase (MAPK) signaling pathway by the intracellular reactive oxygen species accumulation, and NF-κB p65 phosphorylation., Conclusions: Autophagy in IECs plays an essential role in the maintenance of intestinal homeostasis, and autophagy deficiency triggers inflammation. Development of methods targeting autophagy might be beneficial in the treatment of IBD., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To investigate the use of imaging methods for predicting carcinogenesis in lobular endocervical glandular hyperplasia (LEGH)., Methods: We retrospectively analyzed preoperative images on transvaginal sonography and magnetic resonance imaging (MRI) in 23 cases with histologically diagnosed LEGH., Results: Shape of cervical multicystic lesions on MR images could be divided into two types the flower-type with many small cysts surrounded by larger cysts, and the raspberry-type with many tiny, closely aggregated cysts. Six (46%) of 13 cases had raspberry-type lesions that were not detected on transvaginal sonography but were seen on MRI. Adenocarcinoma in situ (AIS) was identified in 4 postmenopausal women with raspberry-type lesions during the follow-up periods. In these cases, cytologic examination by targeted endocervical sampling using sonography enabled early detection of AIS., Conclusions: MRI and cytologic examination by targeted endocervical sampling may be very useful for predicting carcinogenesis in LEGH., Competing Interests: The authors have declared that no competing interests exist.

Transcutaneous electrical stimulation is a relatively new technique to evoke spinal reflexes in lower limb muscles. The advantage of this technique is that the spinal reflex responses can be obtained from multiple lower limb muscles simultaneously. However, repeatability of spinal reflexes evoked by transcutaneous spinal cord stimulation between days has not been evaluated. We aimed to examine repeatability of recruitment properties of the spinal reflexes evoked by transcutaneous spinal cord stimulation. Recruitment curves of the spinal reflexes evoked by transcutaneous spinal cord stimulation of 8 lower limb muscles (i.e., foot, lower leg, and thigh muscles) of 20 males were measured on two consecutive days. To confirm that responses were caused by activation of the sensory fiber, a double-pulse stimulation with 50 ms inter-pulse interval was delivered. Peak-to-peak amplitude of the first response was calculated for each muscle when no response was observed in the second response owing to post-activation depression. For comparison with the spinal reflexes evoked by transcutaneous spinal cord stimulation, the recruitment curves of the H-reflex amplitude of the soleus of 9 males were measured. Threshold intensity and maximal slope of the recruitment curves were calculated, and inter-day repeatability of the properties was quantified using intraclass correlation coefficients. For the spinal reflexes evoked by transcutaneous spinal cord stimulation, the intraclass correlation coefficient values of threshold intensity and maximal slope for each muscle ranged from 0.487 to 0.874 and from 0.471 to 0.964, respectively. Regarding the soleus H-reflex, the intraclass correlation coefficients of threshold intensity and maximal slope were 0.936 and 0.751, respectively. The present data showed that repeatability of the recruitment properties of the spinal reflexes evoked by transcutaneous spinal cord stimulation in the lower limb was moderate to high. Measurement of the spinal reflexes evoked by transcutaneous spinal cord stimulation would be useful for longitudinal neurophysiological studies., Competing Interests: The authors have declared that no competing interests exist.

Zirconia (3Y-TZP) dental prostheses are widely used in clinical dentistry. However, the effect of ultrasonic scaling performed as a part of professional tooth cleaning on 3Y-TZP dental prostheses, especially in conjunction with low-temperature degradation (LTD), has not been fully investigated. The present study aimed to evaluate the influence of ultrasonic scaling and LTD on the surface properties of 3Y-TZP in relation to bacterial adhesion on the treated surface. 3Y-TZP specimens (4 × 4 × 2 mm) were polished and then subjected to autoclaving at 134°C for 100 h to induce LTD, followed by 10 rounds of ultrasonic scaling using a steel scaler tip for 1 min each. Surface roughness, crystalline structure, wettability, and hardness were analyzed by optical interferometry, X-ray diffraction analysis, contact angle measurement, and nano-indentation technique, respectively. Subsequently, bacterial adhesion onto the treated 3Y-TZP surface was evaluated using Streptococcus mitis and S. oralis. The results demonstrated that the combination of ultrasonic scaling and LTD significantly increased the Sa value (surface roughness parameter) of the polished 3Y-TZP surface from 1.6 nm to 117 nm. LTD affected the crystalline structure, causing phase transformation from the tetragonal to the monoclinic phase, and decreased both the contact angle and surface hardness. However, bacterial adhesion was not influenced by these changes in surface properties. The present study suggests that ultrasonic scaling may be acceptable for debridement of 3Y-TZP dental prostheses because it did not facilitate bacterial adhesion even in the combination with LTD, although it did cause slight roughening of the surface., Competing Interests: The authors have declared that no competing interests exist.

An execution of cognitive processing interferes with postural sway during quiet standing. It reduces sway variability in young adults, but the mechanism is not clear. To elucidate the mechanisms, we focused on breathing in the present study. The purpose of this study was to clarify whether a decrease in postural sway amplitude during a postural-cognitive task is related to the change in breathing movement. The center of pressure (COP) was recorded via a force plate and the motion of leg joints (ankle, knee, and hip), and breathing movements were measured with a 3D motion capture system in quiet standing and standing with cognitive (mental arithmetic) task conditions. The change ratios of each variable from the quiet standing condition to the cognitive task were also calculated. It was shown that the MASt condition produced a significantly smaller RMS of COP displacement as compared to the QSt condition (p < 0.01). The results revealed that the breathing rate was faster and the amplitude of breathing movement smaller when subjects performed the cognitive task. A significant positive correlation (r = 0.75, p < 0.01) was found between the change ratio of breathing amplitude and the COP amplitude. The present results suggest that reduced standing postural sway during a cognitive task is related, at least in part, to a decrease in breathing amplitude., Competing Interests: The authors have declared that no competing interests exist.

The adaptability of human bipedal locomotion has been studied using split-belt treadmill walking. Most of previous studies utilized experimental protocol under remarkably different split ratios (e.g. 1:2, 1:3, or 1:4). While, there is limited research with regard to adaptive process under the small speed ratios. It is important to know the nature of adaptive process under ratio smaller than 1:2, because systematic evaluation of the gait adaptation under small to moderate split ratios would enable us to examine relative contribution of two forms of adaptation (reactive feedback and predictive feedforward control) on gait adaptation. We therefore examined a gait behavior due to on split-belt treadmill adaptation under five belt speed difference conditions (from 1:1.2 to 1:2). Gait parameters related to reactive control (stance time) showed quick adjustments immediately after imposing the split-belt walking in all five speed ratios. Meanwhile, parameters related to predictive control (step length and anterior force) showed a clear pattern of adaptation and subsequent aftereffects except for the 1:1.2 adaptation. Additionally, the 1:1.2 ratio was distinguished from other ratios by cluster analysis based on the relationship between the size of adaptation and the aftereffect. Our findings indicate that the reactive feedback control was involved in all the speed ratios tested and that the extent of reaction was proportionally dependent on the speed ratio of the split-belt. On the contrary, predictive feedforward control was necessary when the ratio of the split-belt was greater. These results enable us to consider how a given split-belt training condition would affect the relative contribution of the two strategies on gait adaptation, which must be considered when developing rehabilitation interventions for stroke patients.

While previous studies have shown that muscle stretching suppresses monosynaptic spinal reflex excitability in stretched muscles, its effects on non-stretched muscles is still largely unknown. The purpose of this study was to examine the effects of muscle stretching on monosynaptic spinal reflex in non-stretched muscles. Ten healthy male subjects participated in this study. Muscle stretching of the right triceps surae muscle was performed using a motor torque device for 1 minute. Three different dorsiflexion torques (at approximately 5, 10, and 15 Nm) were applied during muscle stretching. Spinal reflexes evoked by transcutaneous spinal cord stimulation were recorded in both the lower-limb muscles before, during, and at 0 and 5 min following muscle stretching. The amplitudes of the spinal reflexes in both the stretched and non-stretched muscles in the right (ipsilateral) leg were smaller during stretching compared to before, and at 0 and 5 min after stretching. Furthermore, the degree of reduction in the amplitude of the spinal reflexes in the right (ipsilateral) leg muscles increased significantly as the dorsiflexion torque (i.e., stretching of the right triceps surae muscles) increased. In contrast, reduction in the amplitude of the spinal reflexes with increasing dorsiflexion torque was not seen in the left (contralateral) leg muscles. Our results clearly indicate that muscle stretching has inhibitory effects on monosynaptic spinal reflexes, not only in stretched muscles, but also in non-stretched muscles of the ipsilateral leg.

The purpose of the present study was to investigate how stretch reflex (SR) responses in the ankle extensor (soleus: SOL) and flexor (tibialis anterior: TA) muscles would be modulated with temporal and/or spatial predictions of external perturbations and whether their effects are specific to the standing posture. SR responses in the SOL/TA were elicited by imposing quick ankle toes-up/toes-down rotations while standing upright and in the supine position. We designed four experimental conditions based on pre-information about perturbations: no information (No Cue), the timing of the perturbation onset (TIM), the direction of the perturbation (DIR), and both the timing and direction of the perturbation (TIM/DIR). Each condition was separated and its order was counterbalanced. In the SR of TA evoked by toes-down rotation, integrated electromyography activities of the late component were significantly reduced in the TIM and TIM/DIR conditions as compared with those in the No Cue and DIR conditions. The occurrence rate of late SR components that reflects how often the reflex response was observed was also lower in the TIM and TIM/DIR conditions as compared with that in the No Cue and DIR conditions. On the other hand, no significant changes were seen among the four conditions in the early SR component in the TA and both SR components in the SOL. The same results in the occurrence rate were found in the supine position. The present results suggest (1) only temporal predictions have a remarkable effect on the SR excitability of the TA, and (2) this effect is independent of posture.

The development of upright postural control has often been investigated using time series of center of foot pressure (COP), which is proportional to the ankle joint torque (i.e., the motor output of a single joint). However, the center of body mass acceleration (COMacc), which can reflect joint motions throughout the body as well as multi-joint coordination, is useful for the assessment of the postural control strategy at the whole-body level. The purpose of the present study was to investigate children's postural control during quiet standing by using the COMacc. Ten healthy children and 15 healthy young adults were instructed to stand upright quietly on a force platform with their eyes open or closed. The COMacc as well as the COP in the anterior-posterior direction was obtained from ground reaction force measurement. We found that both the COMacc and COP could clearly distinguish the difference between age groups and visual conditions. We also found that the sway frequency of COMacc in children was higher than that in adults, for which differences in biomechanical and/or neural factors between age groups may be responsible. Our results imply that the COMacc can be an alternative force platform measure for assessing developmental changes in upright postural control.

The aim of the present study was to elucidate the adaptive and de-adaptive nature of human running on a split-belt treadmill. The degree of adaptation and de-adaptation was compared with those in walking by calculating the antero-posterior component of the ground reaction force (GRF). Adaptation to walking and running on a split-belt resulted in a prominent asymmetry in the movement pattern upon return to the normal belt condition, while the two components of the GRF showed different behaviors depending on the gaits. The anterior braking component showed prominent adaptive and de-adaptive behaviors in both gaits. The posterior propulsive component, on the other hand, exhibited such behavior only in running, while that in walking showed only short-term aftereffect (lasting less than 10 seconds) accompanied by largely reactive responses. These results demonstrate a possible difference in motor strategies (that is, the use of reactive feedback and adaptive feedforward control) by the central nervous system (CNS) for split-belt locomotor adaptation between walking and running. The present results provide basic knowledge on neural control of human walking and running as well as possible strategies for gait training in athletic and rehabilitation scenes.

Background: Cardiomyocytes located at the ischemic border zone of infarcted ventricle are accompanied by redistribution of gap junctions, which mediate electrical transmission between cardiomyocytes. This ischemic border zone provides an arrhythmogenic substrate. It was also shown that sodium (Na+) channels are redistributed within myocytes located in the ischemic border zone. However, the roles of the subcellular redistribution of Na+ channels in the arrhythmogenicity under ischemia remain unclear., Methods: Computer simulations of excitation conduction were performed in a myofiber model incorporating both subcellular Na+ channel redistribution and the electric field mechanism, taking into account the intercellular cleft potentials., Results: We found in the myofiber model that the subcellular redistribution of the Na+ channels under myocardial ischemia, decreasing in Na+ channel expression of the lateral cell membrane of each myocyte, decreased the tissue excitability, resulting in conduction slowing even without any ischemia-related electrophysiological change. The conventional model (i.e., without the electric field mechanism) did not reproduce the conduction slowing caused by the subcellular Na+ channel redistribution. Furthermore, Na+ channel blockade with the coexistence of a non-ischemic zone with an ischemic border zone expanded the vulnerable period for reentrant tachyarrhythmias compared to the model without the ischemic border zone. Na+ channel blockade tended to cause unidirectional conduction block at sites near the ischemic border zone. Thus, such a unidirectional conduction block induced by a premature stimulus at sites near the ischemic border zone is associated with the initiation of reentrant tachyarrhythmias., Conclusions: Proarrhythmia of Na+ channel blockade in patients with old myocardial infarction might be partly attributable to the ischemia-related subcellular Na+ channel redistribution.

Niemann-Pick C1-Like 1 (NPC1L1) mediates cholesterol absorption, and ezetimibe is a potent NPC1L1 inhibitor applicable for medication of hypercholesterolemia. Epidemiological studies demonstrated that consumption of polyphenols correlates with a decreased risk for atherosclerosis due to their antioxidant effect. This activity can hardly be attributable to the antioxidant activity only, and we hypothesized that polyphenols inhibit intestinal transport of cholesterol. We elucidated the kinetic parameters of intestinal cholesterol absorption, screened several polyphenols for their ability to specifically inhibit intestinal cholesterol absorption, and determined the inhibitory effects of selected flavonoids in vitro and in vivo. The concentration-dependent uptake of cholesterol by Caco-2 cells obeyed a monophasic saturation process. This indicates the involvement of an active-passive transport, i.e., NPC1L1. Parameters of cholesterol uptake by Caco-2 cells were as follows: Jmax, Kt, and Kd were 6.89±2.96 19.03±11.58 µM, and 0.11±0.02 pmol/min/mg protein, respectively. Luteolin and quercetin inhibited cholesterol absorption by Caco-2 cells and human embryonic kidney 293T cells expressing NPC1L1. When preincubated Caco-2 cells with luteolin and quercetin before the assay, cholesterol uptake significantly decreased. The inhibitory effects of these flavonoids were maintained for up to 120 min. The level of inhibition and irreversible effects were similar to that of ezetimibe. Serum cholesterol levels significantly decreased more in rats fed both cholesterol and luteolin (or quercetin), than in those observed in the cholesterol feeding group. As quercetin induced a significant decrease in the levels of NPC1L1 mRNA in Caco-2 cells, the in vivo inhibitory effect may be due to the expression of NPC1L1. These results suggest that luteolin and quercetin reduce high blood cholesterol levels by specifically inhibiting intestinal cholesterol absorption mediated by NPC1L1.

The sinoatrial node (SAN) is heterogeneous in terms of cell size, ion channels, current densities, connexins and electrical coupling. For example, Nav1.5 (responsible for INa) and Cx43 (responsible for electrical coupling) are absent from the centre of the SAN (normally the leading pacemaker site), but present in the periphery (at SAN-atrial muscle junction). To test whether the heterogeneity is important for the functioning of the SAN, one- and two-dimensional models of the SAN and surrounding atrial muscle were created. Normal functioning of the SAN (in terms of cycle length, position of leading pacemaker site, conduction times, activation and repolarization sequences and space constants) was observed when, from the centre to the periphery, (i) cell characteristics (cell size and ionic current densities) were changed in a gradient fashion from a central-type (lacking INa) to a peripheral-type (possessing INa) and (ii) coupling conductance was increased in a gradient fashion. We conclude that the heterogeneous nature of the node is important for its normal functioning. The presence of Nav1.5 and Cx43 in the periphery may be essential for the node to be able to drive the atrial muscle: Nav1.5 provides the necessary depolarizing current and Cx43 delivers it to the atrial muscle.

Pharmacological and genetic studies support a role for NMDA receptor (NMDAR) hypofunction in the etiology of schizophrenia. We have previously demonstrated that NMDAR obligatory subunit 1 (GluN1) deletion in corticolimbic interneurons during early postnatal development is sufficient to confer schizophrenia-like phenotypes in mice. However, the consequence of NMDAR hypofunction in cortical excitatory neurons is not well delineated. Here, we characterize a conditional knockout mouse strain (CtxGluN1 KO mice), in which postnatal GluN1 deletion is largely confined to the excitatory neurons in layer II/III of the medial prefrontal cortex and sensory cortices, as evidenced by the lack of GluN1 mRNA expression in in situ hybridization immunocytochemistry as well as the lack of NMDA currents with in vitro recordings. Mutants were impaired in prepulse inhibition of the auditory startle reflex as well as object-based short-term memory. However, they did not exhibit impairments in additional hallmarks of schizophrenia-like phenotypes (e.g. spatial working memory, social behavior, saccharine preference, novelty and amphetamine-induced hyperlocomotion, and anxiety-related behavior). Furthermore, upon administration of the NMDA receptor antagonist, MK-801, there were no differences in locomotor activity versus controls. The mutant mice also showed negligible levels of reactive oxygen species production following chronic social isolation, and recording of miniature-EPSC/IPSCs from layer II/III excitatory neurons in medial prefrontal cortex suggested no alteration in GABAergic activity. All together, the mutant mice displayed cognitive deficits in the absence of additional behavioral or cellular phenotypes reflecting schizophrenia pathophysiology. Thus, NMDAR hypofunction in prefrontal and cortical excitatory neurons may recapitulate only a cognitive aspect of human schizophrenia symptoms.

Computer simulation techniques for cardiac beating motions potentially have many applications and a broad audience. However, most existing methods require enormous computational costs and often show unstable behavior for extreme parameter sets, which interrupts smooth simulation study and make it difficult to apply them to interactive applications. To address this issue, we present an efficient and robust framework for simulating the cardiac beating motion. The global cardiac motion is generated by the accumulation of local myocardial fiber contractions. We compute such local-to-global deformations using a kinematic approach; we divide a heart mesh model into overlapping local regions, contract them independently according to fiber orientation, and compute a global shape that satisfies contracted shapes of all local regions as much as possible. A comparison between our method and a physics-based method showed that our method can generate motion very close to that of a physics-based simulation. Our kinematic method has high controllability; the simulated ventricle-wall-contraction speed can be easily adjusted to that of a real heart by controlling local contraction timing. We demonstrate that our method achieves a highly realistic beating motion of a whole heart in real time on a consumer-level computer. Our method provides an important step to bridge a gap between cardiac simulations and interactive applications.

The two major modes of locomotion in humans, walking and running, may be regarded as a function of different speed (walking as slower and running as faster). Recent results using motor learning tasks in humans, as well as more direct evidence from animal models, advocate for independence in the neural control mechanisms underlying different locomotion tasks. In the current study, we investigated the possible independence of the neural mechanisms underlying human walking and running. Subjects were tested on a split-belt treadmill and adapted to walking or running on an asymmetrically driven treadmill surface. Despite the acquisition of asymmetrical movement patterns in the respective modes, the emergence of asymmetrical movement patterns in the subsequent trials was evident only within the same modes (walking after learning to walk and running after learning to run) and only partial in the opposite modes (walking after learning to run and running after learning to walk) (thus transferred only limitedly across the modes). Further, the storage of the acquired movement pattern in each mode was maintained independently of the opposite mode. Combined, these results provide indirect evidence for independence in the neural control mechanisms underlying the two locomotive modes.