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Fall detection and physical activity (PA) classification are important health maintenance issues for the elderly and people with mobility dysfunctions. The literature review showed that most studies concerning fall detection and PA classification addressed these issues individually, and many were based on inertial sensing from the trunk and upper extremities. While shoes are common footwear in daily off-bed activities, most of the aforementioned studies did not focus much on shoe-based measurements. In this paper, we propose a novel footwear approach to detect falls and classify various types of PAs based on a convolutional neural network and recurrent neural network hybrid. The footwear-based detections using deep-learning technology were demonstrated to be efficient based on the data collected from 32 participants, each performing simulated falls and various types of PAs: fall detection with inertial measures had a higher F1-score than detection using foot pressures; the detections of dynamic PAs (jump, jog, walks) had higher F1-scores while using inertial measures, whereas the detections of static PAs (sit, stand) had higher F1-scores while using foot pressures; the combination of foot pressures and inertial measures was most efficient in detecting fall, static, and dynamic PAs. [ABSTRACT FROM AUTHOR]

Background: Combining robotic therapy (RT) with task-oriented therapy is an emerging strategy to facilitate motor relearning in stroke rehabilitation. This study protocol will compare novel rehabilitation regimens that use bilateral RT as a priming technique to augment two task-oriented therapies: mirror therapy (MT) and bilateral arm training (BAT) with a control intervention: RT combined with impairment-oriented training (IOT).Methods: This single-blind, randomized, comparative efficacy study will involve 96 participants with chronic stroke. Participants will be randomized into bilateral RT+MT, bilateral RT+BAT, and bilateral RT+IOT groups and receive 18 intervention sessions (90 min/day, 3 d/week for 6 weeks). The outcomes will include the Fugl-Meyer Assessment, Stroke Impact Scale version 3.0, Medical Research Council scale, Revised Nottingham Sensory Assessment, ABILHAND Questionnaire, and accelerometer and will be assessed at baseline, after treatment, and at the 3-month follow-up. Analysis of covariance and the chi-square automatic interaction detector method will be used to examine the comparative efficacy and predictors of outcome, respectively, after bilateral RT+MT, bilateral RT+BAT, and bilateral RT+IOT.Discussion: The findings are expected to contribute to the research and development of robotic devices, to update the evidence-based protocols in postacute stroke care programs, and to investigate the use of accelerometers for monitoring activity level in real-life situations, which may in turn promote home-based practice by the patients and their caregivers. Directions for further studies and empirical implications for clinical practice will be further discussed in upper-extremity rehabilitation after stroke.Trial Registration: This trial was registered December 12, 2018, at www.Clinicaltrials: gov ( NCT03773653 ). [ABSTRACT FROM AUTHOR]

In this work, we propose a novel design for optical neural network system based on reservoir computing. The optical neurons in the system consist of directional couplers, optical fibers, and optical amplifiers. The nonlinear activation function of optical neuron can be obtained by the optical amplifiers. Mach–Zehnder phase modulators and the directional couplers are used to build the readout matrix in the output layer. The performance of the system is studied by a commercial software of optical fiber telecommunication system. The results show that the randomly connected optical neuron networks of the reservoir computing can provide a better performance. [ABSTRACT FROM AUTHOR]

Introduction: The purpose was to investigate the age effects on central versus peripheral sources of strength, fatigue, and central neural excitabilities.Methods: 42 healthy subjects were recruited as young group (23.73 ± 2.15 years; n = 26) and middle-aged group (57.25 ± 4.57 years; n = 16). Maximum voluntary contraction force (MVC), voluntary activation level (VA), and twitch force of quadriceps were evaluated to represent general, central, and peripheral strengths. Central and peripheral fatigue indexes were evaluated using femoral nerve electrical stimulation. Cortical excitabilities were evaluated using transcranial magnetic stimulation (TMS).Results: The middle-aged group had lower MVC and twitch force of quadriceps, but not VA, than young group. No between group differences were found in fatigue indexes. The cortical excitability in middle-aged group was different from young group in paired TMS with inter-stimulus interval of 7 ms.Conclusion: The age-related strength loss at early stage was primarily caused by peripheral muscular strength. The deviation of central neural excitability can be detected but the activation level was not impaired in middle-age adults. [ABSTRACT FROM AUTHOR]

The neuromodulation of motor excitability has been shown to improve functional movement in people with central nervous system damage. This study aimed to investigate the mechanism of peripheral neuromuscular electrical stimulation (NMES) in motor excitability and its effects in people with spinocerebellar ataxia (SCA). This single-blind case-control study was conducted on young control ( n = 9), age-matched control ( n = 9), and SCA participants ( n = 9; 7 SCAIII and 2 sporadic). All participants received an accumulated 30 min of NMES (25 Hz, 800 ms on/800 ms off) of the median nerve. The central motor excitability, measured by motor evoked potential (MEP) and silent period, and the peripheral motor excitability, measured by the H-reflex and M-wave, were recorded in flexor carpi radialis (FCR) muscle before, during, and after the NMES was applied. The results showed that NMES significantly enhanced the MEP in all 3 groups. The silent period, H-reflex and maximum M-wave were not changed by NMES. We conclude that NMES enhances low motor excitability in patients with SCA and that the mechanism of the neuromodulation was supra-segmental. These findings are potentially relevant to the utilization of NMES for preparation of motor excitability. The protocol was registered at Clinicaltrials.gov (NCT02103075). [ABSTRACT FROM AUTHOR]

This study used a repeated measures design to assess the effect of an eight-week repetitive passive movement (RPM) intervention on lower extremity muscle tone and function in children with cerebral palsy (CP). Eighteen children (aged 9.5±2.1 years) with spastic CP were randomly assigned to a knee RPM intervention condition of 3 times a week for 8 weeks or a control condition. The 8 weeks were followed by 4 weeks of washout period, after which the participants were crossed over to the other group. In the RPM condition, each subject''s knees were intervened with continuous passive motion device (at a velocity of 15°/s) for 20min. The subjects were evaluated via variables measuring range-of-motion, muscle tone, and ambulatory function before, after, 1 day after, and 3 days after each intervention. Repeated-measures statistical analyses found significant differences between condition variable on active range-of-motion of the knee (AROM, increased), relaxation index (RI, increased), Modified Ashworth Scale (MAS, decreased), timed up-and-go (TUG, decreased), 6-min walk test (6MWT, increased); and significant differences among time variable including RI, MAS, and 6MWT. No difference was found in passive range-of-motion measurements. Repetitive passive movement reduced lower extremity spastic hypertonia in children with cerebral palsy, and it also improved ambulatory function in terms of walking speed. Effects of this treatment protocol on ambulation lasted up to 3 days post intervention. Findings of this study provide clinicians and patients an alternative, effective and efficient strategy for spastic control and ambulatory improvement. [Copyright &y& Elsevier]

Abstract: Background: Proprioception can be affected by many factors including exercise. Most exercises involve certain degrees of repeated passive movements, and different velocities of these movements might affect proprioception differently. The purpose of this study was to evaluate the influences of different angular velocities of repeated passive movement on knee proprioception via active repositioning and kinesthesia measurement. Methods: A quasi-experimental design with repeated measure on movement velocity (0°/s, 2°/s, 90°/s, and 150°/s). Sixteen healthy young adults participated in the study. All of them received 30 times repeated passive knee movement intervention in four different knee angular velocities – 0°/s, 2°/s, 90°/s, and 150°/s – with counter-balanced sequence in four successive days. Knee active repositioning and kinesthesia were measured with error scores before and after the intervention. Findings: The results revealed a decrease in error scores in both active repositioning and kinesthesia measurement with the velocities of 90°/s and 150°/s (p<0.05); however no significant change was seen with the static condition (0°/s ) or with the velocity of 2°/s. Interpretation: We concluded that repeated passive movement with rapid angular velocities was capable of improving knee proprioception, specifically in active repositioning and kinesthesia measurements. These results would provide information on the effects of different movement velocities onto knee proprioception. Along with further investigations, the findings could potentially enhance our knowledge on knee injury prevention, treatment, and rehabilitation. [Copyright &y& Elsevier]

Freezing of gait (FOG) is a disabling clinical phenomenon often found in patients with advanced Parkinson's disease (PD). FOG impairs motor function, causes falls and leads to loss of independence. Whereas dual tasking that distracts patients' attention precipitates FOG, auditory or visual cues ameliorate this phenomenon. The pathophysiology of FOG remains unclear. Previous studies suggest that the basal ganglia are involved in the generation of FOG. Investigation of the modulation of neuronal activities within basal ganglia structures during walking is warranted. To this end, we recorded local field potentials (LFP) from the subthalamic nucleus (STN) while PD patients performed single-task gait (ST) or walked while dual-tasking (DT). An index of FOG (iFOG) derived from trunk accelerometry was used as an objective measure to differentiate FOG-vulnerable gait from normal gait. Two spectral activities recorded from the STN region were associated with vulnerability to freezing. Greater LFP power in the low beta (15–21 Hz) and theta (5–8 Hz) bands were noted during periods of vulnerable gait in both ST and DT states. Whereas the elevation of low beta activities was distributed across STN, the increase in theta activity was focal and found in ventral STN and/or substantia nigra (SNr) in ST. The results demonstrate that low beta and theta band oscillations within the STN area occur during gait susceptible to freezing in PD. They also add to the evidence that narrow band ~18 Hz activity may be linked to FOG. • Narrow band beta ~18 Hz oscillations in subthalamic nucleus were found while FOG was more likely. • Two spectral activities in STN region (15–21 Hz and 5–8 Hz) were associated with FOG. • These results may inform the development of can be used for the adaptive DBS for FOG. [ABSTRACT FROM AUTHOR]

Objective . Start hesitation is a key issue for individuals with Parkinson's disease (PD) during gait initiation. Visual cues have proven effective in enhancing gait initiation. When applied to laser-light shoes, swing-limb detection efficiently activates the laser on the side of the stance limb, prompting the opposite swing limb to initiate stepping. Approach . This paper presents the development of two models for this purpose: a convolutional neural network that predicts the swing limb's side using center of pressure data, and a swing onset detection model based on sequential hypothesis test using foot pressure data. Main results . Our findings demonstrate an accuracy rate of 85.4% in predicting the swing limb's side, with 82.4% of swing onsets correctly detected within 0.05 s. Significance . This study demonstrates the efficiency of swing-limb detection based on foot pressures. Future research aims to comprehensively assess the impact of this method on improving gait initiation in individuals with PD., (© 2024 Institute of Physics and Engineering in Medicine. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Background: Stroke is a leading cause of long-term disability among stroke survivors. Despite the availability of numerous stroke rehabilitative therapies, such as mirror therapy, bilateral arm training, and robot-assisted therapy, the recovery of motor function after stroke remains incomplete. Bilateral arm function is a key component in stroke patients to perform activities of daily living and to reflect their functional autonomy., Objective: This clinimetric study investigated and compared the construct validity and responsiveness of 2 bimanual activity outcome measures, the Chedoke Arm and Hand Activity Inventory (CAHAI) and the ABILHAND Questionnaire, in individuals receiving stroke rehabilitation., Methods: The present study is a secondary analysis following the framework of the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). Individuals with chronic stroke ( N = 113) were recruited from outpatient rehabilitation settings. Participants received 18 to 20 sessions of robot-assisted therapy, mirror therapy, combined therapy, or conventional rehabilitation for 4 to 6 weeks. The CAHAI, ABILHAND Questionnaire, and a comparison instrument, the Motor Activity Log (MAL), were administered twice at a 4- to 6-week interval to all participants. ABILHAND scores, in logits, were converted from raw ordinal scores into a linear measure., Results: There was medium to large correlation of the CAHAI and the MAL ( ρ = 0.60-0.62, p < 0.01) as well as the ABILHAND Questionnaire and the MAL ( ρ = 0.44-0.51, p < 0.01). Change scores from the initial measurement to the post-intervention measurement demonstrated small to medium correlation of the CAHAI and the MAL ( ρ = 0.27-0.31, p < 0.01) and medium to large correlation of the ABILHAND Questionnaire and the MAL ( ρ = 0.37-0.41, p < 0.01). Overall, 7 of 8 hypotheses were supported. The hypothesis testing regarding the construct validity and responsiveness of the CAHAI and ABILHAND Questionnaire was confirmed., Conclusion: The CAHAI and ABILHAND Questionnaire are both responsive and suitable to detect changes in bilateral arm functional daily activities in individuals with chronic stroke. Patient-reported outcome measures are recommended to use along with therapist-rated outcome measures for upper limb capacity evaluation in stroke rehabilitation. Further study with a prospective study design to capture specific clinical features of participants and the use of body-worn sensors, such as the arm accelerometer, is suggested., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Tsai, Lau, Lin, Li, Lin, Yao, Lee, Chen, Chen, Chang and Horng.)

Background: Parkinson's disease (PD) is a neurogenerative disorder implicated in dysfunctions of motor functions, particularly gait and balance. Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation offered as a potential adjuvant therapy for PD. This systematic review and meta-analysis were conducted to identify whether tDCS alone and combined with additional rehabilitation therapies improve gait and balance among individuals with PD., Methods: We searched PubMed, Embase, Web of Science, and relevant databases for eligible studies from inception to December 2022. Studies with a comparative design investigating the effects of tDCS on motor functions, including gait and balance among individuals with PD, were included. A meta-analysis was performed for each outcome using a random effects model for subgroup analysis and pooling of overall effect sizes., Results: A total of 23 studies were included in the meta-analysis. The pooled results revealed that tDCS has moderate overall effects on gait, measured by gait speed (standardized mean deviation [SMD] = 0.238; 95% confidence interval [CI]  - 0.026 to 0.502); stride length (SMD = 0.318; 95% CI - 0.015 to 0.652); cadence (SMD =  - 0.632; 95% CI - 0.932 to - 0.333); freezing of gait questionnaire scores (SMD =  - 0.360; 95% CI - 0.692 to - 0.027); step length (SMD = 0.459; 95% CI - 0.031 to 0.949); walking time (SMD =  - 0.253; 95% CI - 0.758 to 0.252); stride time (SMD =  - 0.785; 95% CI: - 1.680 to 0.111); double support time (SMD = 1.139; 95% CI - 0.244 to 0.523); and balance, measured by timed up and go (TUG) test (SMD =  - 0.294; 95% CI - 0.516 to - 0.073), Berg balance scale (BBS) scores (SMD = 0.406; 95% CI - 0.059 to 0.87), and dynamic gait index (SMD = 0.275; 95% CI - 0.349 to 0.898). For the subgroup analysis, gait and balance demonstrated moderate effect sizes. However, only cadence, stride time, and TUG indicated a significant difference between real and sham tDCS (P = 0.027, P = 0.002, and P = 0.023, respectively), whereas cadence and BBS (P < 0.01 and P = 0.045, respectively) significantly differed after real tDCS plus other therapies rather than after sham tDCS plus other therapies., Conclusions: Our results indicated that tDCS is significantly associated with gait and balance improvements among individuals with PD. The findings of this study provide more proof supporting the effectiveness of tDCS, encouraging tDCS to be utilized alone or in combination with other therapies in clinical practice for PD rehabilitation., (© 2024. The Author(s).)

Gait disorders are a fundamental challenge in Parkinson's disease (PD). The use of laser-light visual cues emitted from shoes has demonstrated effective in improving freezing of gait within less restrictive environments. However, the effectiveness of shoes-based laser-light cueing may vary among individuals with PD who have different types of impairments. We introduced an innovative laser-light visual shoes system capable of producing alternating visual cues for the left and right feet through one-side cueing at a time, while simultaneously recording foot inertial data and foot pressures. The effects of this visual cueing system on gait patterns were assessed in individuals with PD, both those with well-gait and those with worse-gait. Our device successfully quantified gait characteristics, including the asymmetry in the center of pressure trajectory, in individuals with PD. Furthermore, visual cueing prolonged stride times and increased the percentage of stance phase, while concurrently reducing stride length in PD individuals with well-gait. Conversely, in PD individuals with worse-gait, visual cueing resulted in a decreased freeze index and a reduction in the proportion of intervals prone to freezing episodes. The effects of visual cueing varied between PD individuals with well-gait and those with worse-gait. Visual cueing slowed down gait in the well-gait group while it appeared to mitigate freezing episodes in worse-gait group. Future researches, including enhancements to extend the projection distance of visual cues and clinical assessments conducted in real-world settings, will help establish the clinical utility of our proposed visual cueing system., 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 © 2024 Chan, Chen, Kuo, Chen, Liaw, Liao, Lin, Chien and Chang.)

Background: Various neurocognitive tests have shown that cycling enhances cognitive performance compared to resting. Event-related potentials (ERPs) elicited by an oddball or flanker task have clarified the impact of dual-task cycling on perception and attention. In this study, we investigate the effect of cycling on cognitive recruitment during tasks that involve not only stimulus identification but also semantic processing and memory retention., Methods: We recruited 24 healthy young adults (12 males, 12 females; mean age = 22.71, SD = 1.97 years) to perform three neurocognitive tasks (namely color-word matching, arithmetic calculation, and spatial working memory) at rest and while cycling, employing a within-subject design with rest/cycling counterbalancing., Results: The reaction time on the spatial working memory task was faster while cycling than at rest at a level approaching statistical significance. The commission error percentage on the color-word matching task was significantly lower at rest than while cycling. Dual-task cycling while responding to neurocognitive tests elicited the following results: (a) a greater ERP P1 amplitude, delayed P3a latency, less negative N4, and less positivity in the late slow wave (LSW) during color-word matching; (b) a greater P1 amplitude during memory encoding and smaller posterior negativity during memory retention on the spatial working memory task; and (c) a smaller P3 amplitude, followed by a more negative N4 and less LSW positivity during arithmetic calculation., Conclusion: The encoding of color-word and spatial information while cycling may have resulted in compensatory visual processing and attention allocation to cope with the additional cycling task load. The dual-task cycling and cognitive performance reduced the demands of semantic processing for color-word matching and the cognitive load associated with temporarily suspending spatial information. While dual-tasking may have required enhanced semantic processing to initiate mental arithmetic, a compensatory decrement was noted during arithmetic calculation. These significant neurocognitive findings demonstrate the effect of cycling on semantic-demand and memory retention-demand tasks., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Gait disorder is a core problem in individuals with Parkinson's disease (PD), including bradykinesia, shuffling steps, festinating gait, and freeze of gait (FOG). Laser-light visual cueing has been demonstrated to be efficient in the mediation of gaits and the reduction in number of FOG episodes. However, previous approaches commonly adopted independent controls of visual cueing on left and right sides which was prone to produce two cues while individual was not in normal walking. In this study, we developed laser-light visual shoes which produced interlaced visual cues for left and right feet in a manner of one-side cueing at a time, solving the aforementioned problem. With parallel measurement of foot inertial data and foot pressures in each shoe, our results showed that the proposed visual cueing made PD individuals in the on-medication condition walk with a longer stance and swing times, that is, they walked more carefully and stable. The proposed approach can also be used to study kinematic and kinetic characteristics of gaits in the off-medication condition to clarify the mediation of visual cueing on motor control of PD individuals.Clinical Relevance- This demonstrates the effect of laser-light visual cueing on gaits in individuals with Parkinson's disease.

Genome-wide association studies (GWAS) have identified genetic risk loci for age-related macular degeneration (AMD) on the chromosome 10q26 (Chr10) locus and are tightly linked: the A69S (G>T) rs10490924 single-nucleotide variant (SNV) and the AATAA-rich insertion-deletion (indel, del443/ins54), which are found in the age-related maculopathy susceptibility 2 ( ARMS2 ) gene, and the G512A (G>A) rs11200638 SNV, which is found in the high-temperature requirement A serine peptidase 1 ( HTRA1 ) promoter. The fourth variant is Y402H complement factor H ( CFH ), which directs CFH  signaling. CRISPR manipulation of retinal pigment epithelium (RPE) cells may allow one to isolate the effects of the individual SNV and thus identify SNV-specific effects on cell phenotype. Clustered regularly interspaced short palindromic repeats (CRISPR) editing demonstrates that rs10490924 raised oxidative stress in induced pluripotent stem cell (iPSC)-derived retinal cells from patients with AMD. Sodium phenylbutyrate preferentially reverses the cell death caused by ARMS2 rs10490924 but not HTRA1 rs11200638. This study serves as a proof of concept for the use of patient-specific iPSCs for functional annotation of tightly linked GWAS to study the etiology of a late-onset disease phenotype. More importantly, we demonstrate that antioxidant administration may be useful for reducing reactive oxidative stress in AMD, a prevalent late-onset neurodegenerative disorder.

To safely walk in a community environment requires dual cognitive-walking ambulation ability for people with Parkinson's disease (PD). A past study showed inconsistent results on cognitive-walking performance for PD patients, possibly due to the various cognitive tasks used and task priority assignment. This study designed cognitive-walking tests that used executive-related cognitive tasks to evaluate patients with early-stage Parkinson's disease who did not have obvious cognitive deficits. The effect of assigning task prioritization was also evaluated. Sixteen individuals with PD (PD group) and 16 individuals without PD (control group) underwent single cognitive tests, single walking tests, dual walking tests, and prioritizing task tests. Three types of cognitive, spatial memory, Stroops, and calculation tasks were employed. The cognitive performance was evaluated by response time, accuracy, and speed-accuracy trade off composite score. The walking performance was evaluated by the temporal spatial gait characteristics and variation in gait. The results showed that the walking performance of the PD group was significantly worse than the control group in both single and dual walking conditions. The group difference in cognitive performance was shown in composite score under the dual calculation walking task but not under the single task. While assigning priority to walking, no group difference in walking was observed but the response accuracy rate of PD groups declined. This study concluded that the dual task walking test could sharpen the cognitive deficits for early-stage PD patients. The task priority assignment might not be recommended while testing gait deficits since it decreased the ability to discriminate group differences.

Iron accumulation causes cell death and disrupts tissue functions, which necessitates chelation therapy to reduce iron overload. However, clinical utilization of deferoxamine (DFO), an iron chelator, has been documented to give rise to systemic adverse effects, including ocular toxicity. This study provided the pathogenic and molecular basis for DFO-related retinopathy and identified retinal pigment epithelium (RPE) as the target tissue in DFO-related retinopathy. Our modeling demonstrated the susceptibility of RPE to DFO compared with the neuroretina. Intriguingly, we established upregulation of hypoxia inducible factor (HIF) 2α and mitochondrial deficit as the most prominent pathogenesis underlying the RPE atrophy. Moreover, suppressing hyperactivity of HIF2α and preserving mitochondrial dysfunction by α-ketoglutarate (AKG) protects the RPE against lesions both in vitro and in vivo. This supported our observation that AKG supplementation alleviates visual impairment in a patient undergoing DFO-chelation therapy. Overall, our study established a significant role of iron deficiency in initiating DFO-related RPE atrophy. Inhibiting HIF2α and rescuing mitochondrial function by AKG protect RPE cells and can potentially ameliorate patients' visual function., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

The application of metabolomics in ophthalmology helps to identify new biomarkers and elucidate disease mechanisms in different eye diseases, as well as aiding in the development of potential treatment options. Extracting metabolites successfully is essential for potential further analysis using mass spectrometry. In this chapter, we describe how to extract metabolites from a variety of sources including (1) cells on a dish, (2) cell culture medium, and (3) tissues in vivo with and without stable isotope tracers. Samples prepared using this protocol are suitable for a range of downstream mass spectrometry analyses and are stable in solvent for weeks at -80 °C., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Insights into genome engineering in cells have allowed researchers to cultivate and modify cells as organoids that display structural and phenotypic features of human diseases or normal health status. The generation of targeted mutants is a crucial step toward studying the biomedical effect of genes of interest. Modified organoids derived from patients' tissue cells are used as models to study diseases and test novel drugs. CRISPR-Cas9 technology has contributed to an explosion of advances that have the ability to edit genomes for the study of monogenic diseases and cancers. The generation of such mutants in human induced pluripotent stem cells (iPSCs) is of utmost importance as these cells carry the potential to be differentiated into any cell lineage. We describe recent developments that are broadening our understanding and extend DNA specificity, product selectivity, and fundamental capabilities. Furthermore, fundamental capabilities and remarkable advancements in basic research, biotechnology, and therapeutics development in cell engineering are detailed within this chapter. Using the CRISPR/Cas9 nuclease system for induction of targeted double-strand breaks, gene editing of target loci in iPSCs can be achieved with high efficiency. This chapter includes detailed protocols for the preparation of reagents to target loci of interest and transfection to genotype single cell-derived iPSC clones. Furthermore, we provide a protocol for the convenient generation of ribonucleoprotein (RNP) delivered directly to cells., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

A specific targeting nuclease is a powerful tool for mediating genome alternative expression with high precision. The RNA sequence-guided Cas9 nuclease from the microbial clustered regularly interspaced short palindromic repeats (CRISPR) adaptive immune system can be used to facilitate genome engineering in cells by using a 20-nt targeting sequence. In this chapter, we describe a set of tools for Cas9-mediated genome editing via non-homologous end joining (NHEJ) or homology-directed repair (HDR) in the generation of modified cell lines for downstream functional studies. This protocol provides experimentally derived guidelines for the selection of target sites, evaluation of cleavage efficiency, and analysis of off-target activity. Beginning with target design, we will cover gene modifications and modified clonal cell lines., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Continuous passive motion device (CPM) provides repetitive movement over extended periods of time for those who have low functional ability. The purpose of this research was to evaluate the effects of a four-week program of continuous passive motion of the ankle joint on the changes in soleus hypertonia in individuals with cerebral palsy who suffered from life-long hypertonia., Methods: A single group, repeated-measures study was conducted. Eight individuals (7 males and 1 female with a mean age of 21.8 ± 8.5 years) with spastic cerebral palsy underwent bilateral ankle CPM for 1 h a day, 5 days a week, for 4 weeks. The outcome measures included the Modified Ashworth Scale (MAS) score, passive range of motion (PROM) of the ankle, the ratio of maximum H reflex to maximum soleus M-response (H/M ratio), and post-activation depression (PAD). All outcomes were measured before and after the intervention. A paired t-test was used to examine treatment effects pre-versus post-intervention., Results: Paired t-tests showed that the CPM program significantly decreased the MAS score (p = 0.006), decreased the maximum H/M ratio (p=0.001), improved PAD (p = 0.003, p = 0.040, and p = 0.032 at 0.2 Hz, 1 Hz, and 2 Hz, respectively), and increased the passive ankle range of motion (p = 0.049)., Conclusion: Ankle CPM not only reduced soleus hypertonia but also improved the PROM in individuals with cerebral palsy. The results of this study show ankle CPM to be an effective intervention for individuals with cerebral palsy., Competing Interests: Conflicts of interest The authors declare that they have no competing interests., (Copyright © 2021 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

The strength of lower extremity is important for individuals to maintain balance and ambulation functions. The previous studies showed that individuals with Parkinson's disease suffered from fatigue and strength loss of central origin. The purpose of this study was to investigate the effect of lower extremities' cycling training on different components of force and fatigue in individuals with Parkinson's disease. Twenty-four individuals (13 males, 11 females, mean age: 60.58 ± 8.21 years) diagnosed with idiopathic Parkinson's disease were randomized into training and control groups. The maximum voluntary contraction (MVC) force, voluntary activation level (VA), and twitch force of knee extensors were measured using a custom-made system with surface electrical stimulation. The general, central, and peripheral fatigue indexes (GFI, CFI, and PFI) were calculated after a fatiguing cycling protocol. Subjects received 8 weeks of low resistance cycling training (training group) or self-stretching (control group) programs. Results showed that MVC, VA, and twitch force improved ( p < 0.05) only in the training group. Compared to the baseline, central fatigue significantly improved in the training group, whereas peripheral fatigue showed no significant difference in two groups. The cycling training was beneficial for individuals with Parkinson's disease not only in muscle strengthening but also in central fatigue alleviation. Further in-depth investigation is required to confirm the effect of training and its mechanism on central fatigue., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lin, Chen, Chen, Liu, Chan and Chang.)

Background: To investigate the effect and dose-response of functional electrical stimulation cycling (FES-cycling) training on spasticity in the individuals with spinal cord injury (SCI). Method: Five electronic databases [PubMed, Scopus, Medline (Proquest), Embase, and Cochrane Central Register of Controlled Trials (CENTRAL)] were searched before September 2021. The human trials and studies of English language were only included. Two authors independently reviewed and extracted the searched studies. The primary outcome measure was spasticity assessed by Modified Ashworth Scale or Ashworth Scale for lower limbs. The secondary outcome measures were walking abilities, such as 6 Min Walk Test (6MWT), Timed Up and Go (TUG), and lower limbs muscle strength (LEMS). A subgroup analysis was performed to investigate the efficacious threshold number of training sessions. A meta-regression analysis was used to examine the linear relationship between the training sessions and the effect on spasticity. Results: A total of 764 studies were identified. After screening, 12 selected studies were used for the qualitative synthesis, in which eight of them were quantitatively analyzed. Eight studies included ninety-nine subjects in total with SCI (male: female = 83:16). The time since injury was from less than 4 weeks to 17 years. The age ranged from 20 to 67 years. American Spinal Injury Association (ASIA) impairment level of the number of participants was 59 for ASIA A, 11 for ASIA B, 18 for ASIA C, and 11 for ASIA D. There were 43 subjects with tetraplegia and 56 subjects with paraplegia. Spasticity decreased significantly (95% CI = - 1.538 to - 0.182, p = 0.013) in favor of FES-cycling training. The walking ability and LEMS also improved significantly in favor of FES-cycling training. The subgroup analysis showed that spasticity decreased significantly only in more than 20 training sessions (95% CI = - 1.749 to - 0.149, p = 0.020). The meta-regression analysis showed training sessions and spasticity were not significantly associated (coefficient = - 0.0025, SE = 0.0129, p = 0.849, R 2 analog = 0.37). Conclusion: Functional electrical stimulation-cycling training can improve spasticity, walking ability, and the strength of the lower limbs in the individuals with SCI. The number of training sessions is not linearly related to the decrease of spasticity. Twenty sessions of FES-cycling training are required to obtain the efficacy to decrease spasticity., 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 © 2021 Fang, Lien, Tsai, Yang, Chan, Chen and Chang.)

Background: Stroke survivors can remain impaired in body functions, activity, and participation. A novel rehabilitation regimen is required to obtain scientific evidence and to help clinicians determine effective interventions for stroke. Mirror therapy (MT) and bilateral upper limb training (BULT) are based on the tenet of bilateral movement practice; however, the additional effect of bilateral robotic priming combined with these two therapies is unclear. Objectives: This study examined the effects of two hybrid therapies, robotic priming combined with MT and robotic priming combined with BULT, in stroke survivors. Methodology: The study randomized 31 participants to groups that received robotic priming combined with MT ( n = 15) or robotic priming combined with BULT ( n = 16). Outcome measures included the Fugl-Meyer Assessment (FMA), the revised Nottingham Sensory Assessment (rNSA), the Chedoke Arm and Hand Activity Inventory (CAHAI), and accelerometer data. Results: Both groups showed statistically significant within-group improvements in most outcome measures. Significant between-group differences and medium-to-large effect sizes were found in favor of the group that received robotic priming combined with MT based on the FMA distal part subscale scores, FMA total scores, and accelerometer data. Conclusion: Robotic priming combined with MT may have beneficial effects for patients in the improvements of overall and distal arm motor impairment as well as affected arm use in real life. Additional follow-up, a larger sample size, and consideration of the effect of lesion location or different levels of cognitive impairment are warranted to validate our findings in future studies. Clinical trial registration: www.ClinicalTrials.gov, identifier NCT03773653., 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 © 2021 Li, Lin, Chen, Yao, Chang, Lee and Liu.)

Time spent sitting is positively correlated with endothelial dysfunction and cardiovascular disease risk. The underlying molecular mechanisms are unknown. MicroRNAs contained in extracellular vesicles (EVs) reflect cell/tissue status and mediate intercellular communication. We explored the association between sitting patterns and microRNAs isolated from endothelial cell (EC)-derived EVs. Using extant actigraphy based sitting behavior data on a cohort of 518 postmenopausal overweight/obese women, we grouped the woman as Interrupted Sitters (IS; N = 18) or Super Sitters (SS; N = 53) if they were in the shortest or longest sitting pattern quartile, respectively. The cargo microRNA in EC-EVs from the IS and SS women were compared. MicroRNA data were weighted by age, physical functioning, MVPA, device wear days, device wear time, waist circumference, and body mass index. Screening of CVD-related microRNAs demonstrated that miR-199a-5p, let-7d-5p, miR-140-5p, miR-142-3p, miR-133b level were significantly elevated in SS compared to IS groups. Group differences in let-7d-5p, miR-133b, and miR-142-3p were validated in expanded groups. Pathway enrichment analyses show that mucin-type O-glycan biosynthesis and cardiomyocyte adrenergic signaling (P < 0.001) are downstream of the three validated microRNAs. This proof-of-concept study supports the possibility that CVD-related microRNAs in EC-EVs may be molecular transducers of sitting pattern-associated CVD risk in overweight postmenopausal women.

Background: EEGs are frequently employed to measure cerebral activations during physical exercise or in response to specific physical tasks. However, few studies have attempted to understand how exercise-state brain activity is modulated by exercise intensity., Methods: Ten healthy subjects were recruited for sustained cycle ergometer exercises at low and high resistance, performed on two separate days a week apart. Exercise-state EEG spectral power and phase-locking values (PLV) are analyzed to assess brain activity modulated by exercise intensity., Results: The high-resistance exercise produced significant changes in beta-band PLV from early to late pedal stages for electrode pairs F3-Cz, P3-Pz, and P3-P4, and in alpha-band PLV for P3-P4, as well as the significant change rate in alpha-band power for electrodes C3 and P3. On the contrary, the evidence for changes in brain activity during the low-resistance exercise was not found., Conclusion: These results show that the cortical activation and cortico-cortical coupling are enhanced to take on more workload, maintaining high-resistance pedaling at the required speed, during the late stage of the exercise period.

Background & Aims: Liver CRIg + (complement receptor of the immunoglobulin superfamily) macrophages play a critical role in filtering bacteria and their products from circulation. Translocation of microbiota-derived products from an impaired gut barrier contributes to the development of obesity-associated tissue inflammation and insulin resistance. However, the critical role of CRIg + macrophages in clearing microbiota-derived products from the bloodstream in the context of obesity is largely unknown., Methods: We performed studies with CRIg -/- , C3 -/- , cGAS -/- , and their wild-type littermate mice. The CRIg + macrophage population and bacterial DNA abundance were examined in both mouse and human liver by either flow cytometric or immunohistochemistry analysis. Gut microbial DNA-containing extracellular vesicles (mEVs) were adoptively transferred into CRIg -/- , C3 -/- , or wild-type mice, and tissue inflammation and insulin sensitivity were measured in these mice. After coculture with gut mEVs, cellular insulin responses and cGAS/STING-mediated inflammatory responses were evaluated., Results: Gut mEVs can reach metabolic tissues in obesity. Liver CRIg + macrophages efficiently clear mEVs from the bloodstream through a C3-dependent opsonization mechanism, whereas obesity elicits a marked reduction in the CRIg + macrophage population. Depletion of CRIg + cells results in the spread of mEVs into distant metabolic tissues, subsequently exacerbating tissue inflammation and metabolic disorders. Additionally, in vitro treatment of obese mEVs directly triggers inflammation and insulin resistance of insulin target cells. Depletion of microbial DNA blunts the pathogenic effects of intestinal EVs. Furthermore, the cGAS/STING pathway is crucial for microbial DNA-mediated inflammatory responses., Conclusions: Deficiency of CRIg + macrophages and leakage of intestinal EVs containing microbial DNA contribute to the development of obesity-associated tissue inflammation and metabolic diseases., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Extracellular signaling molecules, such as growth factors, cytokines, and hormones, regulate cell behaviors and fate through endocrine, paracrine, and autocrine actions and play essential roles in maintaining tissue homeostasis. MicroRNAs, an important class of posttranscriptional modulators, could stably present in extracellular space and body fluids and participate in intercellular communication in health and diseases. Indeed, recent studies demonstrated that microRNAs could be secreted through vesicular and non-vesicular routes, transported in body fluids, and then transmitted to recipient cells to regulate target gene expression and signaling events. Over the past decade, a great deal of effort has been made to investigate the functional roles of extracellular vesicles and extracellular microRNAs in pathological conditions. Emerging evidence suggests that altered levels of extracellular vesicles and extracellular microRNAs in body fluids, as part of the cellular responses to atherogenic factors, are associated with the development of atherosclerosis. This review article provides a brief overview of extracellular vesicles and perspectives of their applications as therapeutic tools for cardiovascular pathologies. In addition, we highlight the role of extracellular microRNAs in atherogenesis and offer a summary of circulating microRNAs in liquid biopsies associated with atherosclerosis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background Sedentary behavior is pervasive, especially in older adults, and is associated with cardiometabolic disease and mortality. Relationships between cardiometabolic biomarkers and sitting time are unexplored in older women, as are possible ethnic differences. Methods and Results Ethnic differences in sitting behavior and associations with cardiometabolic risk were explored in overweight/obese postmenopausal women (n=518; mean±SD age 63±6 years; mean body mass index 31.4±4.8 kg/m 2 ). Accelerometer data were processed using validated machine-learned algorithms to measure total daily sitting time and mean sitting bout duration (an indicator of sitting behavior pattern). Multivariable linear regression was used to compare sitting among Hispanic women (n=102) and non-Hispanic women (n=416) and tested associations with cardiometabolic risk biomarkers. Hispanic women sat, on average, 50.3 minutes less/day than non-Hispanic women ( P <0.001) and had shorter (3.6 minutes less, P =0.02) mean sitting bout duration. Among all women, longer total sitting time was deleteriously associated with fasting insulin and triglyceride concentrations, insulin resistance, body mass index and waist circumference; longer mean sitting bout duration was deleteriously associated with fasting glucose and insulin concentrations, insulin resistance, body mass index and waist circumference. Exploratory interaction analysis showed that the association between mean sitting bout duration and fasting glucose concentration was significantly stronger among Hispanic women than non-Hispanic women ( P -interaction=0.03). Conclusions Ethnic differences in 2 objectively measured parameters of sitting behavior, as well as detrimental associations between parameters and cardiometabolic biomarkers were observed in overweight/obese older women. The detrimental association between mean sitting bout duration and fasting glucose may be greater in Hispanic women than in non-Hispanic women. Corroboration in larger studies is warranted.

Background: This study used novel human neurophysiologic models to investigate whether the mechanism of rate-sensitive H-reflex depression lies in the pre-synaptic or post-synaptic locus in humans. We hypothesized that pre-synaptic inhibition would suppress Ia afferents and H-reflexes without suppressing alpha motor neurons or motor evoked potentials (MEPs). In contrast, post-synaptic inhibition would suppress alpha motor neurons, thereby reducing H-reflexes and MEPs., Methods: We recruited 23 healthy adults with typical rate-sensitive H-reflex depression, 2 participants with acute sensory-impaired spinal cord injury (SCI) (to rule out influence of sensory stimulation on supra-spinal excitability), and an atypical cohort of 5 healthy adults without rate-sensitive depression. After a single electrical stimulation to the tibial nerve, we administered either a testing H-reflex or a testing MEP at 50-5000 ms intervals., Results: Testing MEPs were not diminished in healthy subjects with or without typical rate-sensitive H-reflex depression, or in subjects with sensory-impaired SCI. MEP responses were similar in healthy subjects with versus without rate-sensitive H-reflex depression., Conclusions: Results from these novel in vivo human models support a pre-synaptic locus of rate-sensitive H-reflex depression for the first time in humans. Spinal reflex excitability can be modulated separately from descending corticospinal influence. Each represents a potential target for neuromodulatory intervention., (Copyright © 2019 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

Objective: Understanding message delivery among vascular cells is essential for deciphering the intercellular communications in cardiovascular diseases. MicroRNA (miR)-92a is enriched in endothelial cells (ECs) and circulation under atheroprone conditions. Macrophages are the primary immune cells in atherosclerotic lesions that modulate lesion development. Therefore, we hypothesize that, in response to atheroprone stimuli, ECs export miR-92a to macrophages to regulate their functions and enhance atherosclerotic progression. Approach and Results: We investigated the macrophage functions that are regulated by EC miR-92a under atheroprone microenvironments. We first determined the distributions of functional extracellular miR-92a by fractionating the intravesicular and extravesicular compartments from endothelial conditioned media and mice serum. The results indicate that extracellular vesicles are the primary vehicles for EC miR-92a transportation. Overexpression of miR-92a in ECs enhanced the proinflammatory responses and low-density lipoprotein uptake, while impaired the migration, of cocultured macrophage. Opposite effects were found in macrophages cocultured with ECs with miR-92a knockdown. Further analyses demonstrated that intravesicular miR-92a suppressed the expression of target gene KLF4 (Krüppel-like factor 4) in macrophages, suggesting a mechanism by which intravesicular miR-92a regulates recipient cell functions. Indeed, the overexpression of KLF4 rescued the EC miR-92a-induced macrophage atheroprone phenotypes. Furthermore, an inverse correlation of intravesicular miR-92a in blood serum and KLF4 expression in lesions was observed in atherosclerotic animals, indicating the potential function of extracellular miR-92a in regulating vascular diseases., Conclusions: EC miR-92a can be transported to macrophages through extracellular vesicles to regulate KLF4 levels, thus leading to the atheroprone phenotypes of macrophage and, hence, atherosclerotic lesion formation.

Objective: To investigate the effects of unilateral hybrid therapy (UHT) and bilateral hybrid therapy (BHT) compared with robot-assisted therapy (RT) alone in patients with chronic stroke., Design: A single-blind, randomized controlled trial., Setting: Four hospitals., Participants: Outpatients with chronic stroke and mild to moderate motor impairment (N=44)., Intervention: UHT combined unilateral RT (URT) and modified constraint-induced therapy. BHT combined bilateral RT (BRT) and bilateral arm training. The RT group received URT and BRT. The intervention frequency for the 3 groups was 90 min/d 3 d/wk for 6 weeks., Main Outcome Measures: Fugl-Meyer Assessment (FMA, divided into the proximal and distal subscale) and Stroke Impact Scale (SIS) version 3.0 scores before, immediately after, and 3 months after treatment and Wolf Motor Function Test (WMFT) and Nottingham Extended Activities of Daily Living (NEADL) scale scores before and immediately after treatment., Results: The results favored BHT over UHT on the FMA total score and distal score at the posttest (P=.03 and .04) and follow-up (P=.01 and .047) assessment and BHT over RT on the follow-up FMA distal scores (P=.03). At the posttest assessment, the WMFT and SIS scores of the 3 groups improved significantly without between-group differences, and the RT group showed significantly greater improvement in the mobility domain of NEADL compared with the BHT group (P<.01)., Conclusions: BHT was more effective for improving upper extremity motor function, particularly distal motor function at follow-up, and individuals in the RT group demonstrated improved functional ambulation post intervention., (Copyright © 2019 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Induced pluripotent stem cells (iPSCs) have demonstrated tremendous potential in numerous disease modeling and regenerative medicine-based therapies. The development of innovative gene transduction and editing technologies has further augmented the potential of iPSCs. Cas9-cytidine deaminases, for example, have developed as an alternative strategy to integrate single-base mutations (C → T or G → A transitions) at specific genomic loci. In this chapter, we specifically describe CRISPR (clustered regularly interspaced short palindromic repeats) base editing in iPSCs for editing precise locations in the genome. This state-of-the-art approach enables highly efficient and accurate modifications in genes. Thus, this technique not only has the potential to have biotechnology and therapeutic applications but also the ability to reveal underlying mechanisms regarding pathologies caused by specific mutations.

Gait disturbances in Parkinson's disease are commonly refractory to current treatment options and majorly impair patient's quality of life. Auditory cues facilitate gait and prevent motor blocks. We investigated how neural dynamics in the human subthalamic nucleus of Parkinsons's disease patients (14 male, 2 female) vary during stepping and whether rhythmic auditory cues enhance the observed modulation. Oscillations in the beta band were suppressed after ipsilateral heel strikes, when the contralateral foot had to be raised, and reappeared after contralateral heel strikes, when the contralateral foot rested on the floor. The timing of this 20-30 Hz beta modulation was clearly distinct between the left and right subthalamic nucleus, and was alternating within each stepping cycle. This modulation was similar, whether stepping movements were made while sitting, standing, or during gait, confirming the utility of the stepping in place paradigm. During stepping in place, beta modulation increased with auditory cues that assisted patients in timing their steps more regularly. Our results suggest a link between the degree of power modulation within high beta frequency bands and stepping performance. These findings raise the possibility that alternating deep brain stimulation patterns may be superior to constant stimulation for improving parkinsonian gait. SIGNIFICANCE STATEMENT Gait disturbances in Parkinson's disease majorly reduce patients' quality of life and are often refractory to current treatment options. We investigated how neural activity in the subthalamic nucleus of patients who received deep brain stimulation surgery covaries with the stepping cycle. 20-30 Hz beta activity was modulated relative to each step, alternating between the left and right STN. The stepping performance of patients improved when auditory cues were provided, which went along with enhanced beta modulation. This raises the possibility that alternating stimulation patterns may also enhance beta modulation and may be more beneficial for gait control than continuous stimulation, which needs to be tested in future studies., Competing Interests: Conflict of interest: B.C. has received travel support and unrestricted educational Grants for organizing CPD events from Medtronic, St. Jude Medical, and Boston Scientific (manufacturers of DBS electrodes); T.Z.A. has performed consultancy for and received speaking fees from Medtronic; S.L. has been a participant in a DBS teaching course funded by Medtronic; T.F., P.L., and L.Z. have received speaking fees and travel support from Medtronic and St. Jude Medical; M.S. has received travel support from Medtronic and St. Jude Medical, received speaker fees from St. Jude Medical and performed consultancy for St. Jude Medical; and P.B. has received fees and nonfinancial support from Medtronic and personal fees from Boston Scientific. The remaining authors declare no competing financial interests., (Copyright © 2018 Fischer et al.)

While cell-based immunotherapy, especially chimeric antigen receptor (CAR)-expressing T cells, is becoming a paradigm-shifting therapeutic approach for cancer treatment, there is a lack of general methods to remotely and noninvasively regulate genetics in live mammalian cells and animals for cancer immunotherapy within confined local tissue space. To address this limitation, we have identified a mechanically sensitive Piezo1 ion channel (mechanosensor) that is activatable by ultrasound stimulation and integrated it with engineered genetic circuits (genetic transducer) in live HEK293T cells to convert the ultrasound-activated Piezo1 into transcriptional activities. We have further engineered the Jurkat T-cell line and primary T cells (peripheral blood mononuclear cells) to remotely sense the ultrasound wave and transduce it into transcriptional activation for the CAR expression to recognize and eradicate target tumor cells. This approach is modular and can be extended for remote-controlled activation of different cell types with high spatiotemporal precision for therapeutic applications., Competing Interests: The authors declare no conflict of interest.

In this study, we aimed to seek for different ways of measuring cardiac stress in terms of heart rate variability (HRV) and heart rate (HR) dynamics, and to develop a novel index that can effectively summarize the information reflected by these measures to continuously and quantitatively characterize the cardiac stress status during physical exercise. Standard deviation, spectral measure of HRV as well as a nonlinear detrended fluctuation analysis (DFA) based fractal-like behavior measure of HR dynamics were all evaluated on the RR time series derived from windowed electrocardiogram (ECG) data for the subjects undergoing cycling exercise. We recruited eleven young healthy subjects in our tests. Each subject was asked to maintain a fixed speed under a constant load during the pedaling test. We obtained the running estimates of the standard deviation of the normal-to-normal interval (SDNN), the high-fidelity power spectral density (PSD) of HRV, and the DFA scaling exponent α, respectively. A trend analysis and a multivariate linear regression analysis of these measures were then performed. Numerical experimental results produced by our analyses showed that a decrease in both SDNN and α was seen during the cycling exercise, while there was no significant correlation between the standard lower frequency to higher frequency (LF-to-HF) spectral power ratio of HRV and the exercise intensity. In addition, while the SDNN and α were both negatively correlated with the Borg rating of perceived exertion (RPE) scale value, it seemed that the LF-to-HF power ratio might not have substantial impact on the Borg value, suggesting that the SDNN and α may be further used as features to detect the cardiac stress status during the physical exercise. We further approached this detection problem by applying a linear discriminant analysis (LDA) to both feature candidates for the task of cardiac stress stratification. As a result, a time-varying parameter, referred to as the cardiac stress measure (CSM), is developed for quantitatively on-line measuring and stratifying cardiac stress status., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objectives: To compare the reciprocal control of agonist and antagonist muscles in individuals with and without spinocerebellar ataxia (SCA) and to evaluate the effect of a 4-week leg cycling regimen on functional coordination and reciprocal control of agonist and antagonist muscles in patients with SCA., Design: Randomized controlled trial with repeated measures., Setting: Research laboratory in a general hospital., Participants: Individuals with SCA (n=20) and without SCA (n=20)., Interventions: A single 15-minute session of leg cycling and a 4-week cycling regimen., Main Outcome Measures: Individuals with SCA (n=20) and without SCA (n=20) underwent disynaptic reciprocal inhibition and D1 inhibition tests of the soleus muscles before and after a single 15-minute cycling session. Individuals with SCA were randomly assigned to either participate in 4 weeks of cycling training (n=10) or to receive no training (n=10). The disynaptic reciprocal inhibition and D1 inhibition and International Cooperative Ataxia Rating Scale (ICARS) scores were evaluated in both groups after 4 weeks., Results: Individuals with SCA showed abnormally strong resting values of disynaptic reciprocal inhibition and D1 inhibition (P<.001) and impaired inhibition modulation capacity after a single 15-minute session of cycling (P<.001). The inhibition modulation capacity was restored (P<.001), and the ICARS scores improved significantly (pre: 13.5±9.81, post: 11.3±8.74; P=.046) after 4 weeks of cycling training., Conclusions: A 4-week cycling regimen can normalize the modulation of reciprocal inhibition and functional performance in individuals with SCA. These findings are applicable to the coordination training of patients., (Copyright © 2015 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

A combination of various therapeutic approaches has emerged as a promising strategy for cancer treatment. A safe and competent nano-delivery system is thus in urgent demand to facilitate the simultaneous transport of various therapeutic agents to cancer cells and a tumor region to achieve synergistic effect. Gold nanoparticles (GNPs) and mesoporous silica nanoparticle (MSNs) were fabricated herein as potential candidates for drug delivery. Serving as gatekeepers, GNPs (5 nm in diameter) were attached onto the amino-functionalized MSNs (denoted as NMSNs) via a relatively weak gold-nitrogen bonding. The resulting nanohybrids (denoted as GCMSNs) were uptaken by cells, and the detachment of GNPs and subsequent intracellular drug release from NMSNs were achieved by competitive binding of intracellular glutathione to GNPs. In addition to the function of gatekeeping, GNPs also play another role as the oxidative stress elicitor. Our in vitro studies revealed that GCMSNs induced higher oxidative stress in lung cancer cells (A549) than in normal cells (3T3-L1). This growth inhibitory effect found in the cancer cells was likely induced by mitochondria dysfunction originated from the GCMSN-induced, oxidative stress-triggered mitochondria-mediated autophagy. The redox-responsive nanohybrids were further loaded with camptothecin and the intensified synergistic therapeutic effects were observed associated with combined chemotherapy and oxidative stress strategy. The results clearly demonstrate that such unique nanohybrids hold great promise for selective and effective cancer treatments., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A simple indole-based receptor 1 was prepared by a simple Schiff-base reaction of 1H-indole-3-carbaldehyde with ethane 1,2-diamine and its fluoroionophoric properties toward anions were investigated. Indole-based receptor 1 acts as a selective turn-on fluorescent sensor for HSO4(-) in methanol among a series of tested anions. Fluorescence spectroscopy, ultraviolet and nuclear magnetic resonance imaging support that the HSO4(-) indeed interacted with imine nitrogen and the proton of nitrogen in indole ring., (Copyright © 2013 John Wiley & Sons, Ltd.)

Suboptimal repair occurs in a peripheral nerve gap, which can be partially restored by bridging the gap with various biosynthetic conduits or cell-based therapy. In this study, we developed a combination of chitosan coating approach to induce neurosphere cells from human adipose-derived stem cells (ASCs) on chitosan-coated plate and then applied these cells to the interior of a chitosan-coated silicone tube to bridge a 10-mm gap in a rat sciatic nerve. Myelin sheath degeneration and glial scar formation were discovered in the nerve bridged by the silicone conduit. By using a single treatment of chitosan-coated conduit or neurosphere cell therapy, the nerve gap was partially recovered after 6 weeks of surgery. Substantial improvements in nerve regeneration were achieved by combining neurosphere cells and chitosan-coated conduit based on the increase of myelinated axons density and myelin thickness, gastrocnemius muscle weight and muscle fiber diameter, and step and stride lengths from gait analysis. High expressions of interleukin-1β and leukotriene B4 receptor 1 in the intra-neural scarring caused by using silicone conduits revealed that the inflammatory mechanism can be inhibited when the conduit is coated with chitosan. This study demonstrated that the chitosan-coated surface performs multiple functions that can be used to induce neurosphere cells from ASCs and to facilitate nerve regeneration in combination with a cells-assisted coated conduit., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

This paper describes the fabrication of a highly efficient, non-cytotoxic drug delivery platform designed for photodynamic therapy (PDT): phospholipid-capped, protoporphyrin IX-loaded and FITC-sensitized mesoporous silica nanocarriers (Lipo-FMSNs/PpIX). After derivatization with folate on the phospholipid-capped FMSNs (denoted fa-Lipo-FMSNs/PpIX, the so-called nanoPDT system), we confirmed the nanoPDT systems' selective targeting of and entry into the folic acid receptor-overexpressed HeLa cells by means of cell viability assessment and confocal microscopic analysis. The decrease in the unfavorable dark toxicity of fa-Lipo-FMSNs/PpIX enabled the delivery of high concentrations of PpIX into cells. Moreover, the cellular uptake of the nanoPDT systems was greater than that of free PpIX. Upon irradiation with visible light, the nanoPDT system generated singlet oxygen efficaciously in aqueous environments-a decisive factor affecting its therapeutic applicability in PDT, demonstrating enhanced in vitro photocytotoxicity. Furthermore, an in vivo study of subcutaneous melanoma in nude mice inoculated with B16F10 cells revealed the capability for the nanoPDT system to mitigate nearly 65% of tumor growth., (Copyright © 2013 Elsevier Ltd. All rights reserved.)