Effect of dual-task interaction combining postural and visual perturbations on cortical activity and postural control ability.

Previous studies have suggested cortical involvement in postural control in humans by measuring cortical activities and conducting dual-task paradigms. In dual-task paradigms, task performance deteriorates and can be facilitated in specific dual-task settings. Theoretical frameworks explaining these dual-task interactions have been proposed and debated for decades. Therefore, we investigated postural control performance under different visual conditions using a virtual reality system, simultaneously measuring cortical activities with a functional near-infrared spectroscopy system. Twenty-four healthy participants were included in this study. Postural stability and cortical activities after perturbations were measured under several conditions consisting of postural and visual perturbations. The results showed that concurrent visual and postural perturbations could facilitate cortical activities in the supplementary motor area and superior parietal lobe. Additionally, visual distractors deteriorated postural control ability and cortical activation of the supplementary motor area. These findings supported the theoretical framework of the "Cross talk model", in which concurrent tasks using similar neural domains can facilitate these task performances. Furthermore, it indicated that the cortical resource capacity and domains activated for information processing should be considered in experiments involving dual-task paradigms and training.

Modulation of corticospinal excitability related to the forearm muscle during robot-assisted stepping in humans.

In recent years, the neural control mechanisms of the arms and legs during human bipedal walking have been clarified. Rhythmic leg stepping leads to suppression of monosynaptic reflex excitability in forearm muscles. However, it is unknown whether and how corticospinal excitability of the forearm muscle is modulated during leg stepping. The purpose of the present study was to investigate the excitability of the corticospinal tract in the forearm muscle during passive and voluntary stepping. To compare the neural effects on corticospinal excitability to those on monosynaptic reflex excitability, the present study also assessed the excitability of the H-reflex in the forearm muscle during both types of stepping. A robotic gait orthosis was used to produce leg stepping movements similar to those of normal walking. Motor evoked potentials (MEPs) and H-reflexes were evoked in the flexor carpi radialis (FCR) muscle during passive and voluntary stepping. The results showed that FCR MEP amplitudes were significantly enhanced during the mid-stance and terminal-swing phases of voluntary stepping, while there was no significant difference between the phases during passive stepping. Conversely, the FCR H-reflex was suppressed during both voluntary and passive stepping, compared to the standing condition. The present results demonstrated that voluntary commands to leg muscles, combined with somatosensory inputs, may facilitate corticospinal excitability in the forearm muscle, and that somatosensory inputs during walking play a major role in monosynaptic reflex suppression in forearm muscle.

Risk factors for hamstring strain injury in male college American football players -a preliminary prospective cohort study.

BACKGROUND: Given the frequency of hamstring strain injuries (HSI) among male college American football players, several studies have attempted to determine whether certain risk factors can predict their occurrence. However, no consensus on modifiable risk factors for HSIs in male college American football players has yet been reached to prevent these injuries. This study aimed to clarify risk factors for HSI prospectively in college male American football players. METHODS: A total of 78 male college American football players, whose positions were limited to skill positions, were medically assessed for potential risk factors of HSI. The preseason medical assessment included anthropometric measurements, joint laxity and flexibility, muscle flexibility, muscle strength, and balance ability. RESULTS: HSI occurred in a total of 25 thighs from 25 players (32.1%). Injured players had significantly lower hamstring flexibility (p = 0.02) and hamstring to quadriceps strength ratio (H/Q) (p = 0.047) compared to uninjured players. Additionally, injured players had significantly lower general joint laxity scores, especially for the total (p = 0.04), hip (p = 0.007), and elbow (p = 0.04) scores, compared to uninjured players. CONCLUSIONS: Lower hamstring flexibility, lower hamstring to quadriceps strength ratio, and lower general joint laxity score were identified as risk factors for HSI in male college American football players placed in skill positions. The muscle flexibility and H/Q ratio could be useful in preventing HSI in such players.

Feasibility and applicability of locomotive syndrome risk test in elderly patients who underwent total knee arthroplasty.

OBJECTIVES: The concept of locomotive syndrome (LS) and its evaluation method, the LS risk test, have been applied in an integrated manner to capture the decline in mobility resulting from musculoskeletal disorders. The purpose of this study was to evaluate the impact of total knee arthroplasty (TKA) in the elderly with knee osteoarthritis, a common disorder found in LS. METHODS: A total of 111 patients were registered prior to TKA and postoperatively followed up for 1 year. Three components of the LS risk test (the two-step test, stand-up test, and Geriatric Locomotive Function Scale-25) were assessed pre- and postoperatively. RESULTS: After surgery, all three components of the test showed significant improvements from the baseline. The ratio of Stage 3 LS patients (progressed stage of decrease in mobility) reduced from 82.3% to 33.9% postoperatively. There was no significant difference in the degree of change in the scores between the younger (60-74 years) and older (≥75 years) age groups. CONCLUSIONS: We found that TKA has a major impact in preventing the progression of LS in patients with knee osteoarthritis. The LS risk test is a feasible tool for the longitudinal evaluation of patients with musculoskeletal diseases of varying severity and with multiple symptoms.

An Advanced Internet of Things System for Heatstroke Prevention with a Noninvasive Dual-Heat-Flux Thermometer.

Heatstroke is a concern during sudden heat waves. We designed and prototyped an Internet of Things system for heatstroke prevention, which integrates physiological information, including deep body temperature (DBT), based on the dual-heat-flux method. A dual-heat-flux thermometer developed to monitor DBT in real-time was also evaluated. Real-time readings from the thermometer are stored on a cloud platform and processed by a decision rule, which can alert the user to heatstroke. Although the validation of the system is ongoing, its feasibility is demonstrated in a preliminary experiment.

Therapeutic Strategies for Oligodendrocyte-Mediated Remyelination.

Given recent progress in our understanding of oligodendrocyte biology, significant attention has been directed toward cell therapy for myelin repair and remyelination. This trend has been reinforced by findings about the importance of white matter lesions in a variety of central nervous system (CNS) diseases, including demyelinating diseases as well as brain or spinal cord trauma and degenerative disorders such as Alzheimer's disease. Remyelination strategies include the implementation of myelin forming cells and the surrounding conditions and pathological disease context. Successful remyelination requires proper number of cells at the required location and subsequent maturation. Those processes involve variety of molecules, related to oligodendrocyte development or inflammation in the lesion. Understanding and manipulation of the functions of those molecules may improve the outcome of the cell therapies toward remyelination. Furthermore, the development of monitoring method for myelination is also anticipated to evaluate the effects of therapeutic interventions.

Chd7 Collaborates with Sox2 to Regulate Activation of Oligodendrocyte Precursor Cells after Spinal Cord Injury.

Oligodendrocyte precursor cells (OPCs) act as a reservoir of new oligodendrocytes (OLs) in homeostatic and pathological conditions. OPCs are activated in response to injury to generate myelinating OLs, but the underlying mechanisms remain poorly understood. Here, we show that chromodomain helicase DNA binding protein 7 (Chd7) regulates OPC activation after spinal cord injury (SCI). Chd7 is expressed in OPCs in the adult spinal cord and its expression is upregulated with a concomitant increase in Sox2 expression after SCI. OPC-specific ablation of Chd7 in injured mice leads to reduced OPC proliferation, the loss of OPC identity, and impaired OPC differentiation. Ablation of Chd7 or Sox2 in cultured OPCs shows similar phenotypes to those observed in Chd7 knock-out mice. Chd7 and Sox2 form a complex in OPCs and bind to the promoters or enhancers of the regulator of cell cycle (Rgcc) and protein kinase Cθ (PKCθ) genes, thereby inducing their expression. The expression of Rgcc and PKCθ is reduced in the OPCs of the injured Chd7 knock-out mice. In cultured OPCs, overexpression and knock-down of Rgcc or PKCθ promote and suppress OPC proliferation, respectively. Furthermore, overexpression of both Rgcc and PKCθ rescues the Chd7 deletion phenotypes. Chd7 is thus a key regulator of OPC activation, in which it cooperates with Sox2 and acts via direct induction of Rgcc and PKCθ expression.SIGNIFICANCE STATEMENT Spinal cord injury (SCI) leads to oligodendrocyte (OL) loss and demyelination, along with neuronal death, resulting in impairment of motor or sensory functions. Oligodendrocyte precursor cells (OPCs) activated in response to injury are potential sources of OL replacement and are thought to contribute to remyelination and functional recovery after SCI. However, the molecular mechanisms underlying OPC activation, especially its epigenetic regulation, remain largely unclear. We demonstrate here that the chromatin remodeler chromodomain helicase DNA binding protein 7 (Chd7) regulates the proliferation and identity of OPCs after SCI. We have further identified regulator of cell cycle (Rgcc) and protein kinase Cθ (PKCθ) as novel targets of Chd7 for OPC activation.

Local cyclical compression modulates macrophage function in situ and alleviates immobilization-induced muscle atrophy.

Physical inactivity gives rise to numerous diseases and organismal dysfunctions, particularly those related to aging. Musculoskeletal disorders including muscle atrophy, which can result from a sedentary lifestyle, aggravate locomotive malfunction and evoke a vicious circle leading to severe functional disruptions of vital organs such as the brain and cardiovascular system. Although the significance of physical activity is evident, molecular mechanisms behind its beneficial effects are poorly understood. Here, we show that massage-like mechanical interventions modulate immobilization-induced pro-inflammatory responses of macrophages in situ and alleviate muscle atrophy. Local cyclical compression (LCC) on mouse calves, which generates intramuscular pressure waves with amplitude of 50 mmHg, partially restores the myofiber thickness and contracting forces of calf muscles that are decreased by hindlimb immobilization. LCC tempers the increase in the number of cells expressing pro-inflammatory proteins, tumor necrosis factor-α and monocyte chemoattractant protein-1 (MCP-1), including macrophages in situ The reversing effect of LCC on immobilization-induced thinning of myofibers is almost completely nullified when macrophages recruited from circulating blood are depleted by administration of clodronate liposomes. Furthermore, application of pulsatile fluid shear stress, but not hydrostatic pressure, reduces the expression of MCP-1 in macrophages in vitro Together with the LCC-induced movement of intramuscular interstitial fluid detected by µCT analysis, these results suggest that mechanical modulation of macrophage function is involved in physical inactivity-induced muscle atrophy and inflammation. Our findings uncover the implication of mechanosensory function of macrophages in disuse muscle atrophy, thereby opening a new path to develop a novel therapeutic strategy utilizing mechanical interventions.

Association between the gait pattern characteristics of older people and their two-step test scores.

BACKGROUND: The Two-Step test is one of three official tests authorized by the Japanese Orthopedic Association to evaluate the risk of locomotive syndrome (a condition of reduced mobility caused by an impairment of the locomotive organs). It has been reported that the Two-Step test score has a good correlation with one's walking ability; however, its association with the gait pattern of older people during normal walking is still unknown. Therefore, this study aims to clarify the associations between the gait patterns of older people observed during normal walking and their Two-Step test scores. METHODS: We analyzed the whole waveforms obtained from the lower-extremity joint angles and joint moments of 26 older people in various stages of locomotive syndrome using principal component analysis (PCA). The PCA was conducted using a 260 × 2424 input matrix constructed from the participants' time-normalized pelvic and right-lower-limb-joint angles along three axes (ten trials of 26 participants, 101 time points, 4 angles, 3 axes, and 2 variable types per trial). RESULTS: The Pearson product-moment correlation coefficient between the scores of the principal component vectors (PCVs) and the scores of the Two-Step test revealed that only one PCV (PCV 2) among the 61 obtained relevant PCVs is significantly related to the score of the Two-Step test. CONCLUSIONS: We therefore concluded that the joint angles and joint moments related to PCV 2-ankle plantar-flexion, ankle plantar-flexor moments during the late stance phase, ranges of motion and moments on the hip, knee, and ankle joints in the sagittal plane during the entire stance phase-are the motions associated with the Two-Step test.

Age independency of mobility decrease assessed using the Locomotive Syndrome Risk Test in elderly with disability: a cross-sectional study.

BACKGROUND: Mobility decrease is reportedly age-dependent in community dwelling elderly, and a major factor of disability in the geriatric population. The purpose of this study is to examine whether mobility decrease, as assessed using a set of tests, is similarly age-dependent in elderly adults who already have disability. METHODS: One hundred thirty-five community-dwelling elderly (54 men, 81 women) with disability and 1469 independent community dwellers (1009 men, 460 women) were analyzed. Disability was defined having a certified need for care under the long-term care insurance system in Japan. Lower extremity mobility decrease was quantified using the Locomotive Syndrome Risk Test, which comprises the two-step test, stand-up test, and 25-Question Geriatric Locomotive Function Scale (GLFS-25). RESULTS: Multivariable regression analyses indicated no age-related decrease in the three test scores among elderly with disability, whereas these scores all decreased with age among independent community dwellers. All the test scores decreased as care level increased. CONCLUSIONS: Mobility decrease among elderly adults with disability is unrelated to age. However, the severity of care level is associated with mobility decrease.

Oligodendrocyte Progenitor Cells Directly Utilize Lactate for Promoting Cell Cycling and Differentiation.

Oligodendrocyte progenitor cells (OPCs) undergo marked morphological changes to become mature oligodendrocytes, but the metabolic resources for this process have not been fully elucidated. Although lactate, a metabolic derivative of glycogen, has been reported to be consumed in oligodendrocytes as a metabolite, and to ameliorate hypomyelination induced by low glucose conditions, it is not clear about the direct contribution of lactate to cell cycling and differentiation of OPCs, and the source of lactate for remyelination. Therefore, we evaluated the effect of 1,4-dideoxy-1,4-imino-d-arabinitol (DAB), an inhibitor of the glycogen catabolic enzyme glycogen phosphorylase, in a mouse cuprizone model. Cuprizone induced demyelination in the corpus callosum and remyelination occurred after cuprizone treatment ceased. This remyelination was inhibited by the administration of DAB. To further examine whether lactate affects proliferation or differentiation of OPCs, we cultured mouse primary OPC-rich cells and analyzed the effect of lactate. Lactate rescued the slowed cell cycling induced by 0.4 mM glucose, as assessed by the BrdU-positive cell ratio. Lactate also promoted OPC differentiation detected by monitoring the mature oligodendrocyte marker myelin basic protein, in the presence of both 36.6 mM and 0.4 mM glucose. Furthermore, these lactate-mediated effects were suppressed by the reported monocarboxylate transporter inhibitor, α-cyano-4-hydroxy-cinnamate. These results suggest that lactate directly promotes the cell cycling rate and differentiation of OPCs, and that glycogen, one of the sources of lactate, contributes to remyelination in vivo. J. Cell. Physiol. 232: 986-995, 2017. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.

Neuregulin-1 type III knockout mice exhibit delayed migration of Schwann cell precursors.

In an embryonic developmental stage of the peripheral nervous system (PNS), Schwann cell precursors migrate along neuronal axons to their final destinations. After birth, they eventually wrap around individual axons to form myelin sheaths, which insulate axons to increase the nerve conduction velocity. Some growth factors and adhesion molecules are known to control these developmental stages from in the fish to in the mammal. Neuregulin-1 (NRG1), which is composed of many alternative splicing variants, is such a growth factor. Among these variants, the type III isoform of NRG1, interacting with ErbB2 and ErbB3 receptors on Schwann cells, plays an essential role in myelination in the fish and the mammal. NRG1 type III is also known to promote migration of fish Schwann cell precursors; however, it still remains to be clarified whether mammalian type III isoform does it. We have therefore generated type III isoform-specific knockout mice in inbred strain. The mice result in delayed migration of the precursors from the dorsal to ventral root via a peripheral ganglion, comparing littermate controls. Similar results are observed in an in vitro migration assay using reaggregated Schwann cell precursors. Furthermore, the knockout mice exhibit reduced myelin thickness, consistent with the established role of NRG1 type III in myelination. These results indicate that in mice, NRG1 type III plays a key role not only in myelination but also in migration.

Relationship between physician-judged functioning level and self-reported disabilities in elderly people with locomotive disorders.

PURPOSE: Locomotive disorders due to musculoskeletal involvement are one of the main causes requiring long-term care services in aging Japan. "Locomotive syndrome (LoS)" is a concept referring to the condition under which people require assistance from others or at risk in future. The object of this study is to examine the relationship between self-reported measure and physician-judged degrees on ADL disability in elder people with locomotive disorders. METHODS: In a cross-sectional study, 711 patients who were aged 65 years old or more were recruited from 49 outpatient clinics and hospitals. We investigated ADL disabilities by self-reported questionnaire (Geriatric Locomotive Function Scale-25: GLFS-25) and physician-judged grading (Locomotive Dysfunction Grade: LDG) and examined the relationship between these two. RESULTS: We classified the severity of locomotive disability by clinical phenotype into six grades: LDG Grade 1 (N = 77), Grade 2 (213), Grade 3 (139), Grade 4 (162), Grade 5 (78), and Grade 6 (42). The mean of GLFS-25 was 25.9. The mean of GLFS-25 was 5.68 for Grade 1, 14.33 for Grade 2, 22.34 for Grade 3, 35.40 for Grade 4, 43.25 for Grade 5, and 60.24 for Grade 6. Significant differences of GLFS-25 scores were found between adjacent LDGs. CONCLUSIONS: Physician-judged grade of locomotive dysfunction was significantly related to self-reported assessment scale on ADL disability. Physician-judged dysfunction grade is readily administered scale and useful to assess the severity of locomotive dysfunction. Self-reported scale provides precise information on ADL disabilities due to locomotive organ dysfunction and is useful to develop intervention programs.

Characteristics of disability in activity of daily living in elderly people associated with locomotive disorders.

BACKGROUND: Ageing is associated with a decline of motor function and ability to perform daily activities. Locomotive disorders are one of the major disorders resulting in adverse health condition in elderly people. Concept of Locomotive syndrome (LoS) was proposed to tackle the problems and prolong healthy life expectancy of people with locomotive disorders. To develop intervention strategy for LoS it is mandatory to investigate impairments, functional disabilities which people with locomotive disorder experience and to examine relationships among these parameters. For this purpose we have developed Geriatric Locomotive Function Scale-25 (GLFS-25). Though several physical performance tests were reported for identification or monitoring the severity of LoS, there are few studies reported on characteristics of disability which people with locomotive disorders experience. The aim of this study was to report the characteristics of ADL disabilities in elderly people with locomotive disorders in terms of numbers and degree of activity limitations. METHODS: We organized a cohort study and recruited 314 participants aged 65 years and over from five orthopedic clinics or nursing care facilities. This was a cross-sectional study to use the baseline data of such cohort. ADL disabilities were assessed using GLFS-25 scale arranging the GLFS-25 scores in ordinal levels using "R language" program. Numbers and degrees of activity limitations were determined and compared among the levels. Frequency of limitation in activities regarding social activity, housework, locomotion, mobility and self-care was compared among across the disability level. RESULTS: The GLFS-25 score was mathematically categorized into 7 levels. The number of activity limitations and the degrees of each activity limitation were significantly greater in high GLFS-25 levels than in low levels. Difficulties in mobility appeared in less severe level, difficulties in domestic and social life appeared in moderately severe level, and difficulties in self-care appeared in advanced level. CONCLUSIONS: High GLFS-25 score represented high degree of disability on ADLs. Concordant increase of numbers of activity limitation and severity progression in activity limitation may contribute to progression of disability. Activity limitation may occur in the following order: sports activity, walking, transferring, and self-care.

The crucial role of Erk2 in demyelinating inflammation in the central nervous system.

BACKGROUND: Brain inflammation is a crucial component of demyelinating diseases such as multiple sclerosis. Although the initiation of inflammatory processes by the production of cytokines and chemokines by immune cells is well characterized, the processes of inflammatory aggravation of demyelinating diseases remain obscure. Here, we examined the contribution of Erk2, one of the isoforms of the extracellular signal-regulated kinase, to demyelinating inflammation. METHODS: We used the cuprizone-induced demyelinating mouse model. To examine the role of Erk2, we used Nestin-cre-driven Erk2-deficient mice. We also established primary culture of microglia or astrocytes in order to reveal the crosstalk between two cell types and to determine the downstream cascades of Erk2 in astrocytes. RESULTS: First, we found that Erk is especially activated in astrocytes within the corpus callosum before the peak of demyelination (at 4 weeks after the start of cuprizone feeding). Then, we found that in our model, genetic ablation of Erk2 from neural cells markedly preserved myelin structure and motor function as measured by the rota-rod test. While the initial activation of microglia was not altered in Erk2-deficient mice, these mice showed reduced expression of inflammatory mediators at 3-4 model weeks. Furthermore, the subsequent inflammatory glial responses, characterized by accumulation of microglia and reactive astrocytes, were significantly attenuated in Erk2-deficient mice. These data indicate that Erk2 in astrocytes is involved in augmentation of inflammation and gliosis. We also found that activated, cultured microglia could induce Erk2 activation in cultured astrocytes and subsequent production of inflammatory mediators such as Ccl-2. CONCLUSIONS: Our results suggest that Erk2 activation in astrocytes plays a crucial role in aggravating demyelinating inflammation by inducing inflammatory mediators and gliosis. Thus, therapies targeting Erk2 function in glial cells may be a promising approach to the treatment of distinct demyelinating diseases.

Locomotive Syndrome: Definition and Management.

Locomotive syndrome is a condition of reduced mobility due to impairment of locomotive organs. Since upright bipedal walking involves minutely controlled movement patterns, impairment of any aspect of the locomotive organs has the potential to adversely affect it. In addition to trauma, chronic diseases of the locomotive organs, which progress with repeated bouts of acute exacerbations, are common causes of the locomotive syndrome. In Japan's super-aging society, many people are likely to experience locomotive syndrome in the later part of their lives. Exercise intervention is effective in improving motor function, but because the subjects are elderly people with significant degenerative diseases of the locomotor organs, caution should be taken in choosing the type and intensity of exercise. The present review discusses the definition, current burden, diagnosis and interventions pertaining to the locomotive syndrome. The concept and measures are spreading throughout Japan as one of the national health policy targets.

The effect of an external hip joint stabiliser on gait function after surgery for tumours located around the circumference of the pelvis: analysis of seven cases of internal hemipelvectomy or proximal femur resection.

PURPOSE: Limb-sparing resection of malignant pelvic tumours provides the opportunity for patients to obtain better post-operative mobility. However, because few studies have examined in detail the gait function of patients following pelvic tumour resection, the factors affecting gait performance remain to be clarified. Here, with the laboratory-based computer-assisted gait analysis, we evaluated these patients' gait objectively and the impact of a hip-stabilising supporter on gait improvement was simultaneously examined. METHODS: Three-dimensional gait analysis was performed to obtain cross-sectional data for seven post-operative patients (mean age, 42.7 years; range, 20-61 years) who underwent various types of resection, including P1/4 internal hemipelvectomy (IH), P1/2/3 IH, and proximal femur resection with prosthetic reconstruction. To assess the immediate effects of a hip joint stabiliser, we instructed subjects to walk at their self-selected preferred speed and compared gait parameters with and without use of the hip stabiliser. RESULTS: At baseline, the average walking speed was 0.75 m/s (95% CI 0.53-0.97). As shown by the intra-subject comparison, the hip stabiliser increased walking speed in all but one subject, increasing both temporal and spatial parameters. Ground reaction force of operated limbs increased for some subjects, while step length increased on at least one side in all subjects. CONCLUSIONS: Improvement in the gait parameters is indicative of better control provided by the external hip stabiliser over the affected limb. Moreover, our findings show the potential of a biomechanical approach to improve gait function following pelvic tumour resection.

Nicotinic acetylcholine receptors mediate donepezil-induced oligodendrocyte differentiation.

Oligodendrocytes are the myelin-forming cells of the central nervous system (CNS). Failure of myelin development and oligodendrocyte loss results in serious human disorders, including multiple sclerosis. Here, we show that donepezil, an acetlycholinesterase inhibitor developed for the treatment of Alzheimer's disease, can stimulate oligodendrocyte differentiation and maturation of neural stem cell-derived oligodendrocyte progenitor cells without affecting proliferation or cell viability. Transcripts for essential myelin-associated genes, such as PLP, MAG, MBP, CNPase, and MOG, in addition to transcription factors that regulate oligodendrocyte differentiation and myelination, were rapidly increased after treatment with donepezil. Furthermore, luciferase assays confirmed that both MAG and MBP promoters display increased activity upon donepezil-induced oligodendrocytes differentiation, suggesting that donepezil increases myelin gene expression mainly through enhanced transcription. We also found that the increase in the number of oligodendrocytes observed following donepezil treatment was significantly inhibited by the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine, but not by the muscarinic acetylcholine receptor antagonist scopolamine. Moreover, donepezil-induced myelin-related gene expression was suppressed by mecamylamine at both the mRNA and protein level. These results suggest that donepezil stimulates oligodendrocyte differentiation and myelin-related gene expression via nAChRs in neural stem cell-derived oligodendrocyte progenitor cells. We show that donepezil, a drug for the treatment of Alzheimer disease, can stimulate oligodendrocyte differentiation and maturation of oligodendrocyte progenitor cells. Transcripts for essential myelin-associated genes, such as PLP, MAG, MBP, CNPase and MOG in addition to transcripton factors that regulate oligodendrocyte differentiation and myelination were rapidly increased after treatment with donepezil. These effects were partly dependent on nicotinic acetylcholine receptor (nAChR).

High mobility group nucleosome-binding family proteins promote astrocyte differentiation of neural precursor cells.

Astrocytes are the most abundant cell type in the mammalian brain and are important for the functions of the central nervous system. Although previous studies have shown that the STAT signaling pathway or its regulators promote the generation of astrocytes from multipotent neural precursor cells (NPCs) in the developing mammalian brain, the molecular mechanisms that regulate the astrocytic fate decision have still remained largely unclear. Here, we show that the high mobility group nucleosome-binding (HMGN) family proteins, HMGN1, 2, and 3, promote astrocyte differentiation of NPCs during brain development. HMGN proteins were expressed in NPCs, Sox9(+) glial progenitors, and GFAP(+) astrocytes in perinatal and adult brains. Forced expression of either HMGN1, 2, or 3 in NPCs in cultures or in the late embryonic neocortex increased the generation of astrocytes at the expense of neurons. Conversely, knockdown of either HMGN1, 2, or 3 in NPCs suppressed astrocyte differentiation and promoted neuronal differentiation. Importantly, overexpression of HMGN proteins did not induce the phosphorylation of STAT3 or activate STAT reporter genes. In addition, HMGN family proteins did not enhance DNA demethylation and acetylation of histone H3 around the STAT-binding site of the gfap promoter. Moreover, knockdown of HMGN family proteins significantly reduced astrocyte differentiation induced by gliogenic signal ciliary neurotrophic factor, which activates the JAK-STAT pathway. Therefore, we propose that HMGN family proteins are novel chromatin regulatory factors that control astrocyte fate decision/differentiation in parallel with or downstream of the JAK-STAT pathway through modulation of the responsiveness to gliogenic signals.

Association between new indices in the locomotive syndrome risk test and decline in mobility: third survey of the ROAD study.

BACKGROUND: We aimed to clarify the association between new indices in a locomotive syndrome risk test and decline in mobility. METHODS: In the third survey of the Research on Osteoarthritis/osteoporosis Against Disability (ROAD) study, data on the indices were obtained from 1575 subjects (513 men, 1062 women) of the 1721 participants in mountainous and coastal areas. As outcome measures for decline in mobility, we used the five-times-sit-to-stand test (FTSST) and walking speed with cutoff values of 12 s and 0.8 m/s, respectively. RESULTS: We first estimated the prevalence of the indices in locomotive syndrome risk test stage 1, including two-step test score <1.3, difficulty with one-leg standing from a 40-cm-high seat in the stand-up test, and 25-question GLFS score ≥7, which were found to be 57.4, 40.6, and 22.6 %, respectively. Next, we investigated the prevalence of the indices in locomotive syndrome risk test stage 2, including two-step test score <1.1, difficulty with standing from a 20-cm-high seat using both legs in the stand-up test, and 25-question GLFS score ≥16, which were found to be 21.1, 7.9, and 10.6 %, respectively. Logistic regression analysis using slow FTSST time or slow walking speed as the objective factor, and presence or absence of indices as the independent factor, after adjusting for confounders, showed all three indices in both stages 1 and 2 were significantly and independently associated with immobility. Finally, we clarified the risk of immobility according to an increasing number of indices in both stages 1 and 2 and found that the odds ratio for both slow FTSST time and slow walking speed increased exponentially. CONCLUSION: We found that the three indices independently predicted immobility and that accumulation of indices increased the risk of immobility exponentially.