Effects of dual-task resistance exercise on cognition, mood, depression, functional fitness, and activities of daily living in older adults with cognitive impairment: a single-blinded, randomized controlled trial.

BACKGROUND: Regular exercise is emphasized for the improvement of functional capacity and independence of older adults. This study aimed to compare the effects of a dual-task resistance exercise program and resistance exercise on cognition, mood, depression, physical function, and activities of daily living (ADL) in older adults with cognitive impairment. METHODS: A total of 44 older adults participated in the study. Participants were randomly allocated to an experimental group (n = 22) performing a dual-task resistance exercise program for cognitive function improvement and a control group (n = 22) performing a resistance exercise program. Both groups performed the exercise for 40 min per session, three times a week, for 6 weeks (18 sessions). Cognition, mood, depression, functional fitness, and ADL were quantified before and after the intervention using the Mini-Mental State Examination (MMSE), profile of mood states (POMS), geriatric depression scale (GDS), senior fitness test (SFT), and Korean version of ADL, respectively. RESULTS: There was a significant time and group interaction on the MMSE (p = 0.044). There were no significant time and group interactions in the POMS, GDS, SFT, or ADL. Cognitive function (p < 0.001), mood (p < 0.001), depression (p < 0.001), functional fitness (p < 0.001), and ADL (p < 0.001) significantly improved after dual-task resistance exercise, and cognitive function (p < 0.001), mood (p < 0.001), depression (p < 0.001), functional fitness (p < 0.001), and ADL (p < 0.001) significantly improved after resistance exercise. CONCLUSIONS: Dual-task resistance exercise is more effective than resistance exercise in improving cognitive function in older adults with cognitive impairment. Both dual-task resistance exercise and resistance exercise improves mood, depression, functional fitness, and ADL after the intervention. We propose using dual-task resistance exercises for cognitive and physical health management in the older adults with cognitive impairment. TRIAL REGISTRATION: This study was registered with the Clinical Research Information Service (WHO International Clinical Trials Registry Platform) (Registration ID, KCT0005389; Registration date, 09/09/2020).

3D Global Localization in the Underground Mine Environment Using Mobile LiDAR Mapping and Point Cloud Registration.

This study proposes a 3D global localization method that implements mobile LiDAR mapping and point cloud registration to recognize the locations of objects in an underground mine. An initial global point cloud map was built for an entire underground mine area using mobile LiDAR; a local LiDAR scan (local point cloud) was generated at the point where underground positioning was required. We calculated fast point feature histogram (FPFH) descriptors for the global and local point clouds to extract point features. The match areas between the global and the local point clouds were searched and aligned using random sample consensus (RANSAC) and iterative closest point (ICP) registration. The object's location on the global coordinate system was measured using the LiDAR sensor trajectory. Field experiments were performed at the Gwan-in underground mine using three mobile LiDAR systems. The local point cloud dataset formed for the six areas of the underground mine precisely matched the global point cloud, with a low average error of approximately 0.13 m, regardless of the type of mobile LiDAR system used. In addition, the LiDAR senor trajectory was aligned on the global coordinate system to confirm the change in the dynamic object's position over time.

Development and validation of dual-cardiotoxicity evaluation method based on analysis of field potential and contractile force of human iPSC-derived cardiomyocytes / multielectrode assay platform.

A recent in vitro cardiovascular safety pharmacology test uses cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs) to overcome the limitations of the classical test systems, such as species differences and local channel analysis. The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a new proarrhythmia screening paradigm proposed by a CiPA steering expert group, which essentially requires iPSCs derived cardiomyocyte-based electrophysiological evaluation technology. Moreover, the measurement of the contractile force is also emerging as an important parameter to recapitulate non-proarrhythmic cardiotoxicity. Therefore, we constructed an multielectrode assay (MEA) evaluation method that can measure the electrophysiological changes with 6 reference drugs in hiPSC-derived cardiomyocytes. Subsequently, it was confirmed that the electrophysiological were changed in accordance with the mechanism of action of the drugs. Furthermore, based on the multi-probe impedance, we confirmed the decrease in contractile force due to treatment with drugs, and developed a platform to evaluate cardiotoxicity according to drugs along with field potential changes. Our excitation-contraction coupling cardiotoxicity assessment is considered to be more supportive in cardiac safety studies on pharmacologic sensitivity by complementing each assessment parameter.

SLIT3 regulates endochondral ossification by ß-catenin suppression in chondrocytes.

Previously, we noted that SLIT3, slit guidance ligand 3, had an osteoprotective role with bone formation stimulation and bone resorption suppression. Additionally, we found that global Slit3 KO mice had smaller long bone. Skeletal staining showed short mineralized length in the newborn KO mice and wide hypertrophic chondrocyte area in the embryo KO mice, suggesting delayed chondrocyte maturation. The recombinant SLIT3 did not cause any change in proliferation of ATDC5 cells, but stimulated expressions of chondrocyte differentiation markers, such as COL2A1, SOX9, COL10A1, VEGF, and MMP13 in the cells. SLIT3 suppressed ß-catenin activity in the cells, and activation of Wnt/ß-catenin signaling by lithium chloride attenuated the SLIT3-stimulated differentiation markers. ATDC5 cells expressed only ROBO2 among their 4 isotypes, and the Robo2 knock-down with its siRNA reversed the SLIT3-stimulated differentiated markers in chondrocytes. Taken together, these indicate that SLIT3/ROBO2 promotes chondrocyte maturation via the inhibition of ß-catenin signaling.

Skeletal analysis and differential gene expression in Runx2/Osterix double heterozygous embryos.

The transcription factors, Runx2 and Osterix (Osx), act downstream in the BMP2 pathway, and they are essential for osteoblast differentiation and bone formation. While Runx2 expression is normal in Osx-null mice, Osx is not expressed in Runx2-null mice, indicating that Osx acts downstream of Runx2 during bone formation. Runx2 and Osx are also independently regulated during bone formation. To define the unknown correlation between Runx2 and Osx in the regulation of bone formation, we analyzed the bone of Runx2/Osx double heterozygotes generated by mating heterozygous Runx2 and Osx mice and elucidated the differential gene expressions due to the lack of Runx2 and Osx in bone. Compared to the Runx2 and Osx heterozygous embryos, Runx2/Osx double heterozygous embryos showed reduced bone length in the humerus and femur as well as hypoplastic or complete absence of the maxillary and palatine shelf, presphenoid bone, zygomatic bone, and tympanic ring. Severe inward bending was observed in the ribs and humerus. Histological analysis showed an expanded region of hypertrophic chondrocytes and a reduced area of mineralized bones in the Runx2/Osx double heterozygous embryos. DNA microarray analysis of the calvaria of embryos allowed gene classification based on similarities in the upregulated and downregulated expression patterns. Clusters 1 and 2 include 68 downregulated genes and 18 upregulated genes, respectively, in the Runx2/Osx double heterozygous embryos. Finally, the skeletal analysis and gene expression profiles obtained by clustering may facilitate the understanding of the correlation between Runx2 and Osx in skeletal development.

TNF-α mediates the stimulation of sclerostin expression in an estrogen-deficient condition.

Although recent clinical studies have suggested a possible role for sclerostin, a secreted Wnt antagonist, in the pathogenesis of postmenopausal osteoporosis, the detailed mechanisms how estrogen deficiency regulates sclerostin expression have not been well-elucidated. Bilateral ovariectomy or a sham operation in female C57BL/6 mice and BALB/c nude mice was performed when they were seven weeks of age. The C57BL/6 mice were intraperitoneally injected with phosphate-buffered serum (PBS), 5 µg/kg ß-estradiol five times per week for three weeks, or 10 mg/kg TNF-α blocker three times per week for three weeks. Bony sclerostin expression was assessed by immunohistochemistry staining in their femurs. The activity and expression of myocyte enhancer factors 2 (MEF2), which is essential for the transcriptional activation of sclerostin, in rat UMR-106 osteosarcoma cells were determined by luciferase reporter assay and western blot analysis, respectively. Bony sclerostin expression was stimulated by estrogen deficiency and it was reversed by estradiol supplementation. When the UMR-106 cells were treated with well-known, estrogen-regulated cytokines, only TNF-α, but not IL-1 and IL-6, increased the MEF2 activity. Consistently, TNF-α also increased the nuclear MEF2 expression. Furthermore, the TNF-α blocker prevented the stimulation of bony sclerostin expression by ovariectomy. We also found that there was no difference in sclerostin expression between ovariectomized nude mice and sham-operated nude mice. In conclusion, these results suggest that TNF-α originating from T cells may be at least in part responsible for stimulating the sclerostin expression observed in an estrogen-deficient condition.

Effects of Forest Healing Anti-Aging Program on Psychological, Physiological, and Physical Health of Older People with Mild Cognitive Impairment.

This study aimed to determine the effect of a forest healing anti-aging program on psychological, physiological, and physical health in older people with mild cognitive impairment (MCI). Twenty-two older people with MCI living in the city participated in a forest healing anti-aging program. Psychological indicators included the mini-mental state examination (MMSE), Beck depression inventory (BDI), profile of mood states (POMS), World Health Organization Quality of Life instrument (WHOQOL), and the Pittsburgh sleep quality index (PSQI). Physiological indicators included vital signs, body composition, and blood analysis. Physical indicators included the senior fitness test (SFT), muscle strength, spatiotemporal parameter of gait, static balance, and dynamic balance. Psychological, physiological, and physical indicators were evaluated at first and second pre-measurement, post-measurement, and one-month follow-up. MMSE, BDI, POMS, WHOQOL, body composition, blood analysis, SFT, muscle strength, spatiotemporal parameter of gait, and dynamic balance were significantly different between pre- and post-measurement. Beck depression inventory, POMS, WHOQOL, PSQI, SFT, muscle strength (elbow flexor muscle, knee extensor muscle), spatiotemporal parameter of gait significantly improved continually until the one-month follow-up. In conclusion, the forest healing program had a positive effect on the psychological, physiological, and physical health of older people with MCI.

Immunomodulation of Pluripotent Stem Cell-Derived Mesenchymal Stem Cells in Rotator Cuff Tears Model.

BACKGROUND: Rotator cuff tears (RCTs) induce chronic muscle weakness and shoulder pain. Treatment of RCT using surgery or drugs causes lipid infiltration and fibrosis, which hampers tissue regeneration and complete recovery. The pluripotent stem cell-derived multipotent mesenchymal stem cells (M-MSCs) represent potential candidate next-generation therapies for RCT. METHODS: The difference between M-MSCs and adult-MSCs was compared and analyzed using next-generation sequencing (NGS). In addition, using a rat model of RCT, the muscle recovery ability of M-MSCs and adult-MSCs was evaluated by conducting a histological analysis and monitoring the cytokine expression level. RESULTS: Using NGS, it was confirmed that M-MSC was suitable for transplantation because of its excellent ability to regulate inflammation that promotes tissue repair and reduced apoptosis and rejection during transplantation. In addition, while M-MSCs persisted for up to 8 weeks in vivo, they significantly reduced inflammation and adipogenesis-related cytokine levels in rat muscle. Significant differences were also confirmed in histopathological remission. CONCLUSIONS: M-MSCs remain in the body longer to modulate immune responses in RCTs and have a greater potential to improve muscle recovery by alleviating acute inflammatory responses. This indicates that M-MSCs could be used in potential next-generation RCT therapies.

Establishment of Neurotoxicity Assessment Using Microelectrode Array (MEA) with hiPSC-Derived Neurons and Evaluation of New Psychoactive Substances (NPS).

Background and Objectives: Currently, safety pharmacological tests for the central nervous system depend on animal behavioral analysis. However, due to the subjectivity of behavioral analysis and differences between species, there is a limit to appropriate nervous system toxicity assessment, therefore a new neurotoxicity assessment that can simulate the human central nervous system is required. Methods and Results: In our study, we developed an in vitro neurotoxicity assessment focusing on neuronal function. To minimize the differences between species and fast screening, hiPSC-derived neurons and a microelectrode array (MEA) that could simultaneously measure the action potentials of the neuronal networks were used. After analyzing the molecular and electrophysiological characters of our neuronal network, we conducted a neurotoxicity assessment on neurotransmitters, neurotoxicants, illicit drugs, and new psychoactive substances (NPS). We found that most substances used in our experiments responded more sensitively to our MEA-based neurotoxicity assessment than to the conventional neurotoxicity assessment. Also, this is the first paper that evaluates various illicit drugs and NPS using MEA-based neurotoxicity assessment using hiPSC-derived neurons. Conclusions: Our study expanded the scope of application of neurotoxicity assessment using hiPSC-derived neurons to NPS, and accumulated evaluation data of various toxic substances for hiPSC-derived neurons.

Generation of human iPSCs derived heart organoids structurally and functionally similar to heart.

Currently, due to the increasing demand for 3D culture, various organoids that mimic organs are being actively studied. Despite active reports, information on heart organoids (HOs), which are the first functional organs, is still insufficient. Parameters for reproducing hearts are: chamber formation, organization with cardiac cells, vascularization, and simulation of electrophysiological signals. In particular, since the heart reflects complex factors, it is necessary to develop HOs that can be simulated in depth. In this study, we have created self-organized HOs using human iPSCs, and validated mimicry of cardiac structures such as chamber and epicardium/myocardium and atrium/ventricle-similar areas. Furthermore, mechanical/electrophysiological features were verified through multiple analyzes after inhibition of ion channels. More importantly, the HOs function, due to the cardiovascular characteristics of HOs, was maintained through vascularization after in vivo transplantation. In conclusion, this study has the advantage of being able to easily and closely recapitulate morphological/functional aspects of the heart.

BAPTA, a calcium chelator, neuroprotects injured neurons in vitro and promotes motor recovery after spinal cord transection in vivo.

AIM: Despite animal evidence of a role of calcium in the pathogenesis of spinal cord injury, several studies conducted in the past found calcium blockade ineffective. However, those studies involved oral or parenteral administration of Ca++ antagonists. We hypothesized that Ca++ blockade might be effective with local/immediate application (LIA) at the time of neural injury. METHODS: In this study, we assessed the effects of LIA of BAPTA (1,2-bis (o-aminophenoxy) ethane-N, N, N', N'-tetraacetic acid), a cell-permeable highly selective Ca++ chelator, after spinal cord transection (SCT) in mice over 4 weeks. Effects of BAPTA were assessed behaviorally and with immunohistochemistry. Concurrently, BAPTA was submitted for the first time to multimodality assessment in an in vitro model of neural damage as a possible spinal neuroprotectant. RESULTS: We demonstrate that BAPTA alleviates neuronal apoptosis caused by physical damage by inhibition of neuronal apoptosis and reactive oxygen species (ROS) generation. This translates to enhanced preservation of electrophysiological function and superior behavioral recovery. CONCLUSION: This study shows for the first time that local/immediate application of Ca++ chelator BAPTA is strongly neuroprotective after severe spinal cord injury.

Smart Glasses-Based Personnel Proximity Warning System for Improving Pedestrian Safety in Construction and Mining Sites.

A smart glasses-based wearable personnel proximity warning system (PWS) was developed for pedestrian safety in construction and mining sites. The smart glasses receive signals transmitted by Bluetooth beacons attached to heavy equipment or vehicles, with the proximity determined by the signal strength. A visual alert is displayed to the wearer when in close proximity. The media access control address of the Bluetooth beacon provides information on the approaching equipment or vehicle, which is displayed to the wearer so that they can respond appropriately. There was a detection distance of at least 10 m regardless of the direction the pedestrian was looking and the alert was successful in all 40 trials at ≥10 meters. The subjective workload was evaluated using the NASA task load index on ten subjects, either without a personal PWS, with a smartphone-based PWS, or with the smart glasses-based PWS. The mental, temporal, and physical stresses were lowest when using the smart glasses-based PWS. Smart glasses-based PWSs can improve work efficiency by freeing both hands of the pedestrians, and various functions can be supported through application development. Therefore, they are particularly useful for pedestrian safety in construction and mining sites.

Anti-Inflammatory Effects of M-MSCs in DNCB-Induced Atopic Dermatitis Mice.

Atopic dermatitis (AD) is an inflammatory skin disease caused by an imbalance between Th1 and Th2 cells. AD patients suffer from pruritus, excessive dryness, red or inflamed skin, and complications such as sleep disturbances and depression. Although there are currently many AD treatments available there are insufficient data on their long-term stability and comparative effects. Moreover, they have limitations due to various side effects. Multipotent mesenchymal stem cells (M-MSCs) might have potential for next-generation AD therapies. MSCs are capable of immune function regulation and local inflammatory response inhibition. M-MSCs, derived from human embryonic stem cells (hESC), additionally have a stable supply. In L507 antibody array, M-MSCs generally showed similar tendencies to bone marrow-derived mesenchymal stem cells (BM-MSCs), although the immunoregulatory function of M-MSCs seemed to be superior to BM-MSCs. Based on the characteristics of M-MSCs on immunoregulatory functions, we tested a M-MSC conditioned media concentrate (MCMC) in mice with AD lesions on their dorsal skin. MCMC significantly decreased RNA expression levels of inflammatory cytokines in the mouse dorsal skin. It also suppressed serum IgE levels. In addition, significant histopathologic alleviation was identified. In conclusion, secretions of M-MSCs have the potential to effectively improve AD-related inflammatory lesions. M-MSCs showed potential for use in next-generation AD treatment.

Free Fatty Acid Receptor 4 (GPR120) Stimulates Bone Formation and Suppresses Bone Resorption in the Presence of Elevated n-3 Fatty Acid Levels.

Free fatty acid receptor 4 (FFA4) has been reported to be a receptor for n-3 fatty acids (FAs). Although n-3 FAs are beneficial for bone health, a role of FFA4 in bone metabolism has been rarely investigated. We noted that FFA4 was more abundantly expressed in both mature osteoclasts and osteoblasts than their respective precursors and that it was activated by docosahexaenoic acid. FFA4 knockout (Ffar4(-/-)) and wild-type mice exhibited similar bone masses when fed a normal diet. Because fat-1 transgenic (fat-1(Tg+)) mice endogenously converting n-6 to n-3 FAs contain high n-3 FA levels, we crossed Ffar4(-/-) and fat-1(Tg+) mice over two generations to generate four genotypes of mice littermates: Ffar4(+/+);fat-1(Tg-), Ffar4(+/+);fat-1(Tg+), Ffar4(-/-);fat-1(Tg-), and Ffar4(-/-);fat-1(Tg+). Female and male littermates were included in ovariectomy- and high-fat diet-induced bone loss models, respectively. Female fat-1(Tg+) mice decreased bone loss after ovariectomy both by promoting osteoblastic bone formation and inhibiting osteoclastic bone resorption than their wild-type littermates, only when they had the Ffar4(+/+) background, but not the Ffar4(-/-) background. In a high-fat diet-fed model, male fat-1(Tg+) mice had higher bone mass resulting from stimulated bone formation and reduced bone resorption than their wild-type littermates, only when they had the Ffar4(+/+) background, but not the Ffar4(-/-) background. In vitro studies supported the role of FFA4 as n-3 FA receptor in bone metabolism. In conclusion, FFA4 is a dual-acting factor that increases osteoblastic bone formation and decreases osteoclastic bone resorption, suggesting that it may be an ideal target for modulating metabolic bone diseases.