The influence of sound waves and musical experiences on movement coordination with beats.

Synchronizing movement with external stimuli is important in musicians and athletes. This study investigated the effects of sound characteristics, including sound with harmonics (square wave) and without harmonics (sine wave) and levels of expertise in sports and music on rhythmic ability. Thirty-two university students participated in the study. The participants were divided into sixteen music education (ME) and sixteen physical education (PE) majors. They were asked to perform finger tapping tasks with 1,2 and 3 Hz beat rates, tapping in time with the sine and square wave beat produced by a metronome. The relative phase angle of finger tapping and the onset time of metronome sound were calculated using circular statistics. The results showed that type of wave and music experience affected the rhythmic ability of participants. Our study highlights the importance of types of waves on rhythmic ability, especially for participants with no background in music. The square wave is recommended for athletes to learn to synchronize their movement with beats.

Cell cycle-dependent gene networks for cell proliferation activated by nuclear CK2α complexes.

Nuclear expression of protein kinase CK2α is reportedly elevated in human carcinomas, but mechanisms underlying its variable localization in cells are poorly understood. This study demonstrates a functional connection between nuclear CK2 and gene expression in relation to cell proliferation. Growth stimulation of quiescent human normal fibroblasts and phospho-proteomic analysis identified a pool of CK2α that is highly phosphorylated at serine 7. Phosphorylated CK2α translocates into the nucleus, and this phosphorylation appears essential for nuclear localization and catalytic activity. Protein signatures associated with nuclear CK2 complexes reveal enrichment of apparently unique transcription factors and chromatin remodelers during progression through the G1 phase of the cell cycle. Chromatin immunoprecipitation-sequencing profiling demonstrated recruitment of CK2α to active gene loci, more abundantly in late G1 phase than in early G1, notably at transcriptional start sites of core histone genes, growth stimulus-associated genes, and ribosomal RNAs. Our findings reveal that nuclear CK2α complexes may be essential to facilitate progression of the cell cycle, by activating histone genes and triggering ribosomal biogenesis, specified in association with nuclear and nucleolar transcriptional regulators.

How do elite artistic swimmers generate fluid forces by hand during sculling motions?

The purpose of this study was to clarify how elite artistic (synchronised) swimmers generate fluid forces with their hands during two kinds of sculling motions: flat sculling in the back-layout position and support sculling in the vertical position. We used the pressure-distribution measuring method to estimate unsteady fluid forces acting on the hand during sculling motions performed by seven elite artistic swimmers. In addition, we simultaneously analysed sculling motions using three dimensional-direct linear transformation methods. We found that sculling motions continuously generated fluid forces that are large during the stroke phase and small during the transition phase. Lift force was efficiently generated, and a large upward propulsive force was obtained during the stroke phase in both flat and support sculling. During the outside transition from out- to in-sculling, the net vertical load (= gravitational force-buoyant force) was supported by the drag force. In both flat and support sculling, artistic swimmers generated an even fluid force in the upward direction during the in-sculling and out-sculling phases to maintain a stable position.

Kinetics of four limb joints during kick-start motion in competitive swimming.

The kick-start technique in competitive swimming generates a force acting on the starting platform owing to gravity, muscle contraction and resulting joint torque. To understand optimal body movement on the starting platform for maximising take-off velocity, it is necessary to investigate the joint torque in relation to the joint's rotation effects. Joint torques were calculated by inverse dynamics using kinetic and kinematic data. A one-way ANOVA showed significantly greater extensional torque for shoulders than for elbows or wrists, and for hips than for knees or ankles. The results indicated that the force of the hands was mainly influenced by extension torque at the shoulder joint. Hip joint extension torque on the front side lower limb (FSLL) was mainly used for supporting the body weight until hands off. After hands off, the front-foot force originated mainly by increases in ankle joint plantar flexion and knee joint extension torque on the FSLL. Rear side lower limb torque increases in the hip, knee and ankle joints provided the rear-foot force. This investigation clarified the magnitudes and functions of each joint torque acting on the extremities during the kick-start, providing practical information for improving starting performance.

Differences in limb coordination in polyrhythmic production among water polo players, artistic swimmers and drummers.

This study compares polyrhythmic production ability between water polo players (WPs), artistic swimmers (ASs) and drummers (Ds), to assess how their differing experiences in coordinating complex inter-limb activity with music affected this ability. Eight ASs, eight WPs and eight Ds participated. They were asked to perform finger and foot taps in a single-rhythm task (every 750 ms) and two polyrhythmic tasks (finger and foot taps at 750 and 500 ms, respectively, and vice versa). The percentage of correct response cycles (PCRC), subjective difficulty scores were collected and analysed using a two-way mixed analysis of variance (ANOVA) and coefficients of variation of the inter-tap interval (CVITI) were collected and analysed using a three-way mixed analysis of variance (ANOVA). The three groups showed no statistically significant differences in the single-rhythm task. However, on polyrhythmic tasks, the WPs were significantly outperformed by the other two groups in PCRC and CVITI. These results suggest that the experience of coordinating limbs with music has positive impacts on polyrhythmic production ability. They also imply that ASs and Ds have similar polyrhythmic production ability despite the apparent differences in task complexity in their daily training and performances.

Intracellular localization of CK2α as a prognostic factor in invasive breast carcinomas.

Overexpression of the ubiquitous protein kinase, CK2α, has been reported in various human cancers. Here, we demonstrate that nuclear and nucleolar CK2α localization in invasive ductal carcinomas of the breast is a reliable predictor of poor prognosis. Cellular localization of CK2α in nuclei and nucleoli was analyzed immunohistochemically using surgical tissue blocks from 112 patients, who had undergone surgery without neoadjuvant chemotherapy. Clinical data collection and median follow-up period were for more than 5 y. In total, 93.8% of patients demonstrated elevated CK2α expression in nuclei and 36.6% of them displayed elevated expression predominantly in nucleoli. Clinicopathological malignancy was strongly correlated with elevated nuclear and nucleolar CK2α expression. Recurrence-free survival was significantly worse (P = .0002) in patients with positive nucleolar CK2α staining. The 5-y survival rate decreased to a roughly 50% in nucleolar CK2α-positive patients of triple-negative (P = .0069) and p Stage 3 (P = .0073) groups. In contrast, no patients relapsed or died in the triple-negative group who exhibited a lack of nucleolar CK2α staining. Evaluation of nucleolar CK2α staining showed a high secondary index with a hazard ratio of 6.629 (P = .001), following lymph node metastasis with a hazard ratio of 14.30 (P = .0008). Multivariate analysis demonstrated that nucleolar CK2α is an independent factor for recurrence-free survival. Therefore, we propose that histochemical evaluation of nucleolar CK2α-positive staining may be a new and robust prognostic indicator for patients who need further treatment. Functional consequences of nucleolar CK2 dysfunction may be a starting point to facilitate development of novel treatments for invasive breast carcinoma.

Effects of exceeding stroke frequency of maximal effort on hand kinematics and hand propulsive force in front crawl.

This study aimed to assess kinematic and kinetic changes in front crawl with various stroke frequency (SF) conditions to investigate why swimming velocity (SV) does not increase above a certain SF (SFmax). Eight male swimmers performed 20 m front crawl four times. The first trial involved maximal effort, whereas SF was controlled during the next three trials. The instructed SFs were 100 (T100%), 110 (T110%), and 120% (T120%) of the SFmax. Through pressure measurement and underwater motion analysis, hand propulsive force (calculated by the difference between the palm and dorsal pressure value and the hand area) and the angle of attack of the hand were quantified, and differences between trials were assessed by a repeated-measures ANOVA. There was no difference in SV between the conditions, while the angle of attack during the latter half of the underwater stroke at T120% was smaller by 25.7% compared with T100% (p = 0.007). The lower angle of attack induced a lower pressure value on the palm that consequently caused a smaller hand propulsive force at T120% than T100% (p = 0.026). Therefore, the decrease in the angle of attack must be minimised to maintain the hand propulsive force.

The effect of experience in movement coordination with music on polyrhythmic production: Comparison between artistic swimmers and water polo players during eggbeater kick performance.

The aim of this study was to compare artistic swimmers (ASs) and water polo players (WPs) in their polyrhythmic production ability and entrainment between arm and leg motion frequency. Nine ASs and nine WPs participated in the study. First, we assessed the natural eggbeater kick frequency of each participant without any additional motion for 20 s. We then required the participants to perform a circular arm movement in synchronization with two sequences of metronome rhythms (either 100%, 80% and 120% or100%, 120% and 80% of their natural eggbeater kick frequency) while maintaining their natural eggbeater kick frequency. All tasks were repeated three times. The participants' performances were recorded by a motion capture system synchronized with the metronome. A two-way mixed-design ANOVA was performed on the coefficient of variation of natural eggbeater kick frequency obtained from the first task to confirm the consistency of participants' kicking motion. In the second task, a three-way mixed-design ANOVA was performed on the average frequency of the arm and leg motions to assess the entrainment between the two. In the first task, there were no significant main effects and interaction between group and trial in the coefficient of variation of eggbeater kick frequency, suggesting that both WPs and ASs maintained their natural eggbeater kick frequency equally consistently. In the second task, however, WPs were not able to maintain their natural eggbeater kick frequency when they were required to do circular arm movements at 120% tempo (p < .01). On the other hand, ASs successfully maintained their natural eggbeater kick frequency with all metronome rhythms, suggesting that they have a better polyrhythmic production ability than WPs.

Prenylated quinolinecarboxylic acid derivative prevents neuronal cell death through inhibition of MKK4.

The development of neuroprotective agents is necessary for the treatment of neurodegenerative diseases. Here, we report PQA-11, a prenylated quinolinecarboxylic acid (PQA) derivative, as a potent neuroprotectant. PQA-11 inhibits glutamate-induced cell death and caspase-3 activation in hippocampal cultures, as well as inhibits N-Methyl-4-phenylpyridinium iodide- and amyloid ß1-42-induced cell death in SH-SY5Y cells. PQA-11 also suppresses mitogen-activated protein kinase kinase 4 (MKK4) and c-jun N-terminal kinase (JNK) signaling activated by these neurotoxins. Quartz crystal microbalance analysis and in vitro kinase assay reveal that PQA-11 interacts with MKK4, and inhibits its sphingosine-induced activation. The administration of PQA-11 by intraperitoneal injection alleviates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced degeneration of nigrostriatal dopaminergic neurons in mice. These results suggest that PQA-11 is a unique MKK4 inhibitor with potent neuroprotective effects in vitro and in vivo. PQA-11 may be a valuable lead for the development of novel neuroprotectants.

Physiological responses during the practice of synchronized swimming: a systematic review.

This study is aimed at analysing the scientific literature related to physiological responses in synchronized swimmers, produced from 2006 to 2016. A systematic review was conducted using electronic databases (Google Scholar, PubMed, SportDiscus, Web Science, Scielo and Scopus) in national and international journals. The articles were selected using the following inclusion criteria: composed samples of synchronized swimmers of both sexes, articles in English, Spanish and Portuguese, published from 2006 to 2016. Ten studies were included. The concentration of the articles and their publication was as follows: Europe (77%) and North America (23%). The protocols used analyse physiological responses in synchronized swimmers athletes during competitions or laboratory tests, lactate measurements, heart rate, rates of perceived exertion, VO2 and lung volume. The subjects of 100% of the studies included in this review were athletes of junior and senior categories who volunteered. Only 03 of the 10 studies have compared the physiological responses in volunteers who were not synchronized swimmers to synchronized swimmer athletes. The studies were conducted using different methodologies, which makes it difficult to compare them, so the standardization of instruments and definitions is essential for the scientific advancement in this field. In addition, it would be interesting to expand the research of these physiological responses in synchronized swimmers using base level or beginners as sample.

Mitochondrial reactive oxygen species suppress humoral immune response through reduction of CD19 expression in B cells in mice.

Reactive oxygen species (ROS) are implicated in the modulation of diverse processes including immune responses. To evaluate the effects of metabolic ROS produced by mitochondria on B-cell function and development, we created transgenic (Tg) mice expressing a phosphorylation-defective mutant of succinate dehydrogenase A in B cells (bSDHAY215F ). Splenic B cells in male, but not female, bSDHAY215F mice produced three times more ROS than those in the control mice, and had decreased production of IgM, IgG1 , and IgG3 , and affinity maturation of IgG1 against T-cell-dependent antigens. Following immunization, the male bSDHAY215F mice further displayed suppressed germinal center (GC) formation, and proliferation of GC B cells. Signaling analysis revealed defects in the intrinsic BCR responses, such as activation of Lyn, Btk, and PLCγ2, thus resulting in reduced intracellular Ca2+ mobilization. Notably, the expression levels of B-cell co-receptor CD19 and its interaction with Lyn after BCR ligation were significantly reduced in B cells from male bSDHAY215F mice. These results suggest that mitochondrial ROS suppress humoral immune responses through reduction of CD19 expression and resultant BCR signaling in B cells. Therefore, B-cell immunity may be more labile to oxidative stress in male mice than in female mice.

Enhanced cAMP-stimulated protein kinase A activity in human fibrolamellar hepatocellular carcinoma.

BACKGROUND: Fibrolamellar hepatocellular carcinoma (FL-HCC) affects children without underlying liver disease. A consistent mutation in FL-HCCs leads to fusion of the genes encoding a heat shock protein (DNAJB1) and the catalytic subunit of protein kinase A (PRKACA). We sought to characterize the resultant chimeric protein and its effects in FL-HCC. METHODS: The expression pattern and subcellular localization of protein kinase A (PKA) subunits in FL-HCCs were compared to paired normal livers by quantitative polymerase chain reaction (qPCR), immunoblotting, and immunofluorescence. PKA activity was measured by radioactive kinase assay, and we determined whether the FL-HCC mutation is present in other primary liver tumors. RESULTS: The fusion transcript and chimeric protein were detected exclusively in FL-HCCs. DNAJB1-PRKACA was expressed 10-fold higher than the wild-type PRKACA transcript, resulting in overexpression of the mutant protein in tumors. Consequently, FL-HCCs possess elevated cAMP-stimulated PKA activity compared to normal livers, despite similar Kms between the mutant and wild-type kinases. CONCLUSION: FL-HCCs in children and young adults uniquely overexpress DNAJB1-PRKACA, which results in elevated cAMP-dependent PKA activity. These data suggest that aberrant PKA signaling contributes to liver tumorigenesis.

Prenylated quinolinecarboxylic acid derivative suppresses immune response through inhibition of PAK2.

Development of new immunosuppressing agents is necessary in organ transplantation or immune diseases. Because Ppc-1 exhibits a suppressing effect on interleukin-2 (IL2) production in Jurkat cells, we synthesized and screened Ppc-1 derivatives that preserve prenylated quinolinecarboxylic acid (PQA) structure, and identified compound 18 (PQA-18) as a novel molecule with immunosuppressing effect. PQA-18 suppressed not only IL2 but also IL4, IL6, and tumor necrosis factor-α production in human peripheral lymphocytes without affecting cell viability. Two-dimensional gel electrophoresis analysis and in vitro kinase assay revealed that PQA-18 inhibits kinase activity of p21-activated kinase 2 (PAK2). Administration of PQA-18 by intraperitoneal injection suppressed the population of a subset of regulatory T cells and the immunoglobulin (Ig) production against T cell-dependent antigens in mice. Treatment with the PQA-18 ointment on Nc/Nga mice, a model of human atopic dermatitis, improved skin lesions and serum IgE levels. These results suggest that PQA-18 is a unique PAK2 inhibitor with potent immunosuppressing effects in vitro and in vivo. PQA-18 may be a valuable lead for the development of novel immunosuppressants.

Weight loss by Ppc-1, a novel small molecule mitochondrial uncoupler derived from slime mold.

Mitochondria play a key role in diverse processes including ATP synthesis and apoptosis. Mitochondrial function can be studied using inhibitors of respiration, and new agents are valuable for discovering novel mechanisms involved in mitochondrial regulation. Here, we screened small molecules derived from slime molds and other microorganisms for their effects on mitochondrial oxygen consumption. We identified Ppc-1 as a novel molecule which stimulates oxygen consumption without adverse effects on ATP production. The kinetic behavior of Ppc-1 suggests its function as a mitochondrial uncoupler. Serial administration of Ppc-1 into mice suppressed weight gain with no abnormal effects on liver or kidney tissues, and no evidence of tumor formation. Serum fatty acid levels were significantly elevated in mice treated with Ppc-1, while body fat content remained low. After a single administration, Ppc-1 distributes into various tissues of individual animals at low levels. Ppc-1 stimulates adipocytes in culture to release fatty acids, which might explain the elevated serum fatty acids in Ppc-1-treated mice. The results suggest that Ppc-1 is a unique mitochondrial regulator which will be a valuable tool for mitochondrial research as well as the development of new drugs to treat obesity.

Synthesis of prenylated quinolinecarboxylic acid derivatives and their anti-obesity activities.

Mitochondrial uncoupling is one of the therapeutic strategies used to control energy metabolism in various metabolic diseases and in obesity. Ppc-1 (1), a prenylated quinolinecarboxylic acid isolated from cellular slime molds, shows uncoupling activity in vitro and anti-obesity activity in vivo. In this study, we synthesized Ppc-1 (1) and its derivatives, and revealed the structure-activity relationship of uncoupling activities. The triprenylated compound 18 showed mitochondrial uncoupling activity that was more potent than that of Ppc-1 (1). Compound 18 also suppressed weight gain in mice without undesired effects such as lesions on tissues. These results indicate that compound 18 could be used as a seed compound for new anti-obesity drugs.

Phosphorylation of flotillin-1 by mitochondrial c-Src is required to prevent the production of reactive oxygen species.

We have shown that mitochondrial c-Src regulates reactive oxygen species (ROS) production by phosphorylating the succinate dehydrogenase A of respiratory complex II (CxII). To elucidate the molecular mechanisms underlying ROS production regulated by c-Src in the CxII, we investigated the CxII protein complex derived from cells treated with Src family kinase inhibitor PP2. We identified flotillin-1 as a c-Src target that prevents ROS production from CxII. Phosphorylation-site analysis suggests Tyr56 and Tyr149 on flotillin-1 as sites for phosphorylation by c-Src. A comparison of cells expressing flotillin-1 and its phosphorylation defective mutants confirms the requirement for flotillin-1 phosphorylation for its interaction with CxII and subsequent reduction in ROS production. Our findings suggest a critical role of flotillin-1 in ROS production mediated by c-Src.

Maximizing the potential of scientists in Japan: promoting equal participation for women scientists through leadership development.

In order to examine the current status of gender equality in academic societies in Japan, we inquired about the number of women involved in leadership activities at society conferences and annual meetings, as these activities are critical in shaping scientific careers. Our findings show a clear bias against female scientists, and a need to raise consciousness and awareness in order to move closer to equality for future generations.

Mitochondrial c-Src regulates cell survival through phosphorylation of respiratory chain components.

Mitochondrial protein tyrosine phosphorylation is an important mechanism for the modulation of mitochondrial functions. In the present study, we have identified novel substrates of c-Src in mitochondria and investigated their function in the regulation of oxidative phosphorylation. The Src family kinase inhibitor PP2 {amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo [3,4d] pyrimidine} exhibits significant reduction of respiration. Similar results were obtained from cells expressing kinase-dead c-Src, which harbours a mitochondrial-targeting sequence. Phosphorylation-site analysis selects c-Src targets, including NDUFV2 (NADH dehydrogenase [ubiquinone] flavoprotein 2) at Tyr(193) of respiratory complex I and SDHA (succinate dehydrogenase A) at Tyr(215) of complex II. The phosphorylation of these sites by c-Src is supported by an in vivo assay using cells expressing their phosphorylation-defective mutants. Comparison of cells expressing wild-type proteins and their mutants reveals that NDUFV2 phosphorylation is required for NADH dehydrogenase activity, affecting respiration activity and cellular ATP content. SDHA phosphorylation shows no effect on enzyme activity, but perturbed electron transfer, which induces reactive oxygen species. Loss of viability is observed in T98G cells and the primary neurons expressing these mutants. These results suggest that mitochondrial c-Src regulates the oxidative phosphorylation system by phosphorylating respiratory components and that c-Src activity is essential for cell viability.

Dysregulation of very long chain acyl-CoA dehydrogenase coupled with lipid peroxidation.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease of unknown etiology. We previously revealed increased oxidative stress and high expression of antioxidant proteins in culture cell lines established from lesional lung tissues with IPF (Kabuyama Y, Oshima K, Kitamura T, Homma M, Yamaki J, Munakata M, Homma Y. Genes Cells 12: 1235-1244, 2007). In this study, we show that IPF cells contain high levels of free cholesterol and its peroxidized form as compared with normal TIG7 lung fibroblasts, suggesting that radical oxygen species (ROS) are generated within specific organelles. To understand the molecular basis underlying the generation of ROS in IPF cells, we performed proteomic analysis of mitochondrial proteins from TIG and IPF cells. This analysis shows that the phosphorylation of Ser586 of very long chain acyl-CoA dehydrogenase (VLCAD) is significantly reduced in IPF cells. Similar results are obtained from immunoblotting with anti-pS586 antibody. Kinase activity toward a peptide containing Ser586 from IPF cells is significantly lower than that from TIG cells. Furthermore, a phosphorylation-negative mutant (S586A) VLCAD shows reduced electron transfer activity and a strong dominant-negative effect on fatty acid beta-oxidation. The ectopic expression of the S586A mutant induced human embryonic kidney (HEK) 293 cells to produce significantly high amounts of oxidized lipids and hydrogen peroxide. HEK293 cells expressing the S586A mutant exhibit a reduction in cell growth and an enhancement in apoptosis. These results suggest a novel regulatory mechanism for homeostatic VLCAD activity, whose dysregulation might be involved in the production of oxidative stress and in the pathogenesis of IPF.