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Volume 4 - 2023 | https://doi.org/10.3389/frvir.2023.1302720 This article is part of the Research TopicVirtual Agents in Virtual Reality: Design and Implications for VR UsersView all 5 articles Stress-inducing virtual reality (VR) systems have various applications in research ranging from training to therapy to the observation of biological stress responses Stress in VR can be evoked through environmental Although various VR tasks can induce an autonomic nervous system (ANS) stress response hypothalamic-pituitary-adrenal (HPA) axis stress responses have only been confirmed in VR for the virtual Trier social stress test (V-TSST) Understanding the impact of a wider variety of tasks on HPA-axis stress response could lead to the development of more effective stress relief measures and treatments This study aims to clarify whether a virtual communication simulation using a static procedure with a predetermined dialog Employing a virtual customer service system we varied the intensity of the presented stress by changing the tone and gestures of the virtual customer The findings confirm that HPA-axis stress responses can be elicited by such static virtual customer service training systems and the stress responses can be adjusted by altering the avatar’s attitude These findings suggest potential applications in research for observing human physiological responses to stress and development of stress reduction strategies thereby affirming the effectiveness of VR in communication training To evaluate whether VR stress tasks induce stress in users both subjective evaluations using questionnaires such as the State-trait anxiety inventory (STAI) and physiological stress biomarkers that include heart rate variability (HRV) These biomarkers reflect the significant responses from the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system (ANS) The ANS stress response is a rapid reaction that can occur within seconds to minutes of exposure to a stressor and is mediated primarily by the sympathetic nervous system resulting in physiological changes like increased heart rate and blood pressure The HPA axis stress response is slower than that of ANS which has widespread effects in the body including suppressing inflammation these responses have only been evidenced in a specific task called V-TSST If these VR training systems can be proven to induce HPA axis stress responses they could be used as an indicator of training effectiveness leading to the development of more effective social skill training systems this study also aims to elucidate how the simulated communication load alters the stress response Adjusting the intensity of stress load according to objectives and target individuals is crucial when inducing stress responses through a VR system In the context of training or mental therapy excessive stress could potentially cause severe damage to the trainee or patient when applying stress for research purposes the level of the stress applied to the participants of the experiment should be commensurate with the purpose To realize the research objectives, a specific VR experiment involving a CST was designed using the framework provided by Tanikawa et al. (2021) thereby adjusting it for the specific research needs participants are in the position of handling a complaint from a customer who is upset about a delayed flight due to airport mishaps The dialog between the participant and the virtual customer is predetermined making this a scripted dialog virtual communication We modified this training system by changing only the tone of voice and gestures of the virtual customer while keeping the dialog content the same to manipulate the intensity of the presented stress This experiment allowed us to examine how differences in the presented stress intensity affect the HPA-axis stress response specifically cortisol concentration in the saliva Three primary stressor elements have been identified by researchers to help distinguish the differences in stressor effects on individuals These include the elements of social evaluative threat defined as the fear of being negatively judged by others; uncontrollability defined as the inability to change or alter the course of events; and unpredictability of future events Stress responses can be broadly categorized into as originating from the ANS and HPA-axis responses (Thayer and Lane, 2000; Kudielka et al., 2009) The ANS stress response occurs within seconds to minutes of stressor exposure causing physiological changes such as an increase in heart rate The ANS stress response is primarily mediated by the sympathetic nervous system and its activation triggers the release of adrenaline and noradrenaline occurring within tens of minutes after exposure to stress The activation of the HPA axis begins with the hypothalamus releasing corticotropin-releasing hormone (CRH) promoting the release of adrenocorticotropic hormone (ACTH) ACTH reaches the adrenal cortex through the bloodstream where it stimulates the production and release of the stress hormone cortisol Cortisol has widespread effects throughout the body The response of the HPA axis provides a longer-term strategy for dealing with more persistent stress reports on stressors that cause an HPA-axis response are limited compared to those causing ANS stress responses Experimental methods that have been reported to elicit HPA axis stress responses include the socially evaluated cold pressor test referred to as SECPT and the Trier social stress test referred to as TSST The SECPT stressor involves immersing the hand of a participant in ice water for a certain period while capturing on film their suffering. In previous studies, cortisol levels in saliva have been shown to increase before and after SECPT (Schwabe et al., 2008) SECPT is feasible to implement and does not require specially trained experimenters Another advantage of SECPT is that the intensity of the stressor can be adjusted by modifying the temperature of the ice water or the duration of hand immersion the situation of this task differs greatly from the stressful situations experienced in real-life society Although TSST does not carry the risk of physical harm adjusting the intensity of the stressor is difficult because the timing of adjusting the intensity is restricted primarily to the period the participants receive instructions from the experimenters The interventions provided by the experimenters during TSST are limited to speech-related instructions and for highlighting mistakes during the calculation task if the participants finish before the allotted time there is still room for more research on stressors that trigger HPA-axis stress responses as the number of reported stressors is limited Virtual reality stress tasks have attracted attention as a new methodology for stress presentation because they can reproduce stressful environments that are impossible or difficult to realize in the real world VR stresses can be classified into those that cause anxiety or fear (high-altitude or tragedy) In this study, we selected CST as a stressor using VR for the reasons stated in the Introduction section and examined whether it would cause an HPA stress response through a between-subject experimental design. Specifically, we used a modified version of the customer-service VR system developed by Tanikawa et al. (2021). In this experimental system, the trainer interacted with the customer’s avatar at a virtual airport service counter (Figure 1) the conversation route can branch depending on the response of the trainer and the training difficulty can be adjusted based on the emotional state of the trainer To ensure that the participants perform the training task under the same conditions and experience the same conversation we omitted the conversation-branching function of Tanikawa’s system in this experiment The conversation involved customers complaining about missing their connecting flight because of a delay in scheduled departure resulting in a long wait at the airport for the next flight participants in the experiment wore a head mounted display (HMD) and were stranded at the airport within a virtual environment The flow of the conversation was predetermined; the participant read the words displayed on the screen and the timing of the customer avatar’s speech was controlled by the experimenter according to the participant’s speech A virtual customer stands in front of a virtual airport customer counter Participants listen to the customer and read the lines at the center to respond which involved the performance of a professional actor using a motion-capture system Figure 2 shows the experimental procedure. The stressor protocol was based on the guidelines of TSST, which has been commonly used in previous studies as a stressor to induce HPA-axis stress responses (Birkett, 2011) As salivary cortisol concentration has been reported to increase after a short period under stress we observed that salivary cortisol concentration changed immediately after the participants experienced VR training and within a short period compared to the state immediately before they experienced VR training As part of the pre-experiment instructions for participants they were instructed to avoid eating for 2 hours before the start of the experiment and to refrain from consuming caffeine or other stimulants They were also advised to avoid intense exercise during this period These instructions were provided to the participants at the time of recruitment and adherence to these instructions was confirmed through a questionnaire before the start of the experiment It was verified that all participants complied with these instructions prior to participation Of the two rooms prepared for the experiment one was for the VR CST and the other served as a relaxation room for waiting These two rooms were provided to separate the stress and relaxation states The participants were informed of the false experimental purpose and methodology similar to the TSST protocol This process is called “deception” in psychological experiments The participants were informed that the experiment was intended to evaluate customer service attitudes and that their customer service behaviors during the experiment would be recorded and evaluated later the aim was to increase participants’ perception of the seriousness of the VR CST and provide them with a level of tension equivalent to that of actual VR training we obtained their consent to participate and attached an electrocardiogram (ECG) to measure their biological information (PLUX biosignals) The data were recorded at 1,000 Hz the participants were guided to a relaxation room and instructed to wait for 45 min participants were informed that they could leave the relaxation room to use the restroom and read a magazine They were also instructed to avoid vigorous exercise and remain calm and relaxed while waiting the experimenter entered the relaxation room to collect saliva samples and measure cortisol levels before the VR CST Saliva was collected using swabs (SAL-5001.02-50; SAL) Participants were instructed to insert the swab into the back of their tongue for 1 minute after which the swab was collected in a storage tube (SAL-5001.05-50; SAL) The collected swabs were frozen at −80°C within 1 hour the participants’ electrocardiogram data were measured during this time as “Pre-stress” data Participant gazing at the cross point during the Calm period Participant waiting in the virtual environment preparing the lines the participants were again provided with an overview of the customer service content prior to initiating the customer service response VR experience The participants were informed that although the dialog was predetermined and body language would be evaluated as part of the assessment virtual customer with high-intensity stressor the virtual customer glares tightly at the participants the customer does not glare at the participants instead speaking softly with small gestures Comparison of voice and gesture characteristics between high-intensity and low-intensity groups saliva was collected immediately and labeled as “Post-stress.” The method of saliva collection was the same as that described above measurements were conducted at two time points immediately after the task The experimenters did not enter the relaxation room except during saliva collection the participants were informed that the experiment was over They were then asked whether they had experienced any stress during the experiment or noticed deception regarding the purpose of the experiment participants were informed that they would not be screened for customer service attitudes “Post-stress,” “Recovery1,” and “Recovery2” cortisol levels were normalized by “Pre-stress” levels for each participant Statistical analysis was conducted to examine saliva measurement timing and VR training intensity with saliva measurement timing as a within-participant factor and VR training intensity as a between-participant factor at a significance level of p = 0.05 the normality of the data was first confirmed using the Shapiro-Wilk test a mixed-design two-way ANOVA was conducted to analyze the data Dunnett’s test was used within each VR training intensity group to examine whether the “Post-stress,” “Recovery1,” and “Recovery2” salivary cortisol levels significantly differed from those at “Pre-stress.” Additionally, the effect sizes (d and ESsg) were calculated to compare the results of previous studies on TSST and V-TSST with ours. ESsg has been used in meta-analyses of multiple studies related to V-TSST (Helminen et al., 2019) Please refer to Supplemental Material for details on the ESsg calculation formula clarifying these aspects was not within the scope of this study A survey and ECG measurements were conducted to confirm that the experiment was conducted without any issues The study recruited participants who were between 20 and 30 years old without any prior knowledge of the experiment and capable of using Japanese at a conversational level or higher participants were subjected to restrictions regarding eating and exercising before the experiment and it was planned not to conduct the experiment with participants who did not meet these criteria The sample size estimation was conducted using the statsmodels package in Python The primary effect we wanted to confirm in this experiment was whether cortisol levels in the High intensity condition significantly increased at the Recover1 timing compared to the pre-stress period we recruited four participants for a preliminary validation and calculated an effect size of 0.96 with a significance level of 0.05 and a power of 0.7 the estimated sample size for a one-sided test was 11 we gathered 11 participants for each condition for the experiment we identified samples from which cortisol levels and biometric data were not obtained To ensure that there was no significant difference in communication skills between the high- and low-intensity groups participants were initially asked to rate their subjective communication abilities on a 7-point Likert scale (1: very poor participants were then assigned to one of the two condition groups so that the average scores of subjective communication abilities would be equivalent in both groups nine participants (eight males and one female) were placed in the high-intensity group while 10 participants (nine males and one female) were placed in the low-intensity group we considered that the magnitude of the stress response to the system may be dependent on the customer service experience Considering that a difference in the number of participants with customer service experience between the high and low intensity groups could affect the results recruitment was limited to include participants with no prior customer service experience The experimental plan was approved by the Research Ethics Committee of the University of Tokyo (No.22-72) and written informed consent was obtained from all participants the normalized values for each participant’s data are separately plotted for the high- and low-intensity groups for avatars with severe and relatively moderate attitudes participants who exhibited little to no HPA-axis stress response to the stressor were two out of nine in the high difficulty and six out of ten in the low difficulty group with the non-responders determined by the number of participants whose cortisol levels did not exceed 1.1 times their pre-stress levels Time course of normalized salivary cortisol levels for high- and low-intensity VR training groups Cortisol concentrations were normalized to pre-stress levels Error bars represent 95% confidence intervals the normality for each condition was checked using the Shapiro-Wilk test Because no significant difference from the normal distribution was detected a mixed-design two-way ANOVA was conducted The results demonstrated the main effects of saliva measurement timing (F3,51 = 3.72 p < 0.05) and VR training intensity (F1,17 = 5.03 p < 0.05) and found a significant interaction between saliva measurement timing and VR training intensity (F3,51 = 3.71 As a post hoc test, Dunnett’s test revealed that the “Post-stress” and “Recovery1” values in the high-intensity group were significantly higher than that of “Pre-stress,” with p < 0.05 (Table 2a) no significant difference was observed between “Recovery2” and “Pre-stress,” and in the low-intensity group no significant differences were found between any of the conditions (p > 0.05) Results of Dunnett’s test and unpaired t-test as post hoc tests indicated by p values and effect sizes (cohen’s d and ESsg) These values suggest that the results with significant differences in the simple main effect of saliva measurement timing have a large effect size and the results with significant differences in the simple main effect of VR training intensity have a moderate effect size The ANS stress response during the VR training task was analyzed to determine whether stress was induced. Figure 7 shows the LF/HF value during the stress task for each participant normalized by the LF/HF value of “Pre-stress.” Values larger than the baseline value of 1.0 (dashed line) indicate that the LF/HF increases during the task compared to the resting state before the task suggesting that a stronger ANS stress response is induced by the task statistical analyses were conducted to determine whether the normalized LF/HF value was greater than the baseline value The Shapiro-Wilk test was conducted to check the normality of the data and the results confirmed that the data did not follow a normal distribution revealing that the normalized LF/HF value in the high-intensity group was significantly higher than the baseline value of 1.0 (p < 0.01) no significant difference was found between the normalized LF/HF value and the baseline criterion in the low-intensity group (p = 0.39) Box plots of LF/HF values during the stress task normalized by the “Pre-stress” values for high- and low-intensity VR training groups The box represents the interquartile range (IQR) with the median indicated by the horizontal line inside the box The mean is represented by an ‘X’ marker A dashed line at 1.0 indicates the baseline level representing each participant’s normalized pre-stress value In the post-experiment questionnaire, participants rated the stress they felt on a scale of 1–5 (1: no stress, 5: high stress). The distribution of responses for each condition is shown in Figure 8 six out of nine participants reported feeling stressed (score of 4 or higher) during the task three out of 10 participants reported feeling stressed The Wilcoxon rank-sum test revealed a significant difference between the high- and low-intensity groups (p = 0.031) and a large effect size was observed (d = 0.91) Box plots of participants’ subjective stress level (5-point Likert scale) In the open-ended response section conducted at the end of the experiment the participants indicated the reasons for being stressed or not stressed by the task five people felt stressed because they felt scolded by the avatar’s actions and four people felt stressed by the tone of the avatar’s voice two people felt stressed by the avatar’s attitude and one person felt stressed by the tone of the voice Among the reasons for not feeling stressed three people indicated not receiving any complaints and one person in each condition mentioned the low realism of the VR as the reason for not feeling stressed This result suggests that VR communication simulations may elicit HPA-axis stress responses equivalent to or greater than those of V-TSST We believe the reason for the results obtained in this study lies in the differences between our experimental system and the interaction between avatars and participants in V-TSST avatars mostly react to participants’ speeches avatars actively complain to the participants incorporating exaggerated gestures such as raising their voices Responses from open-ended questions also indicated that the attitude and tone of the avatars were stressful This aspect likely enhanced the effectiveness of our system as a stressor This interpretation was supported by the open-ended responses after the experimental task indicating that both the tone and gestures of the avatar were stressful to the participants In addition to the comparison with V-TSST results, we also compared with the traditional TSST results. A recent meta-analysis evaluated 186 studies to determine the effectiveness of the traditional TSST and indicated that this stress task was effective in eliciting a cortisol response with a large effect size (d = 0.925 (Goodman et al., 2017)) existing meta-reviews suggest that although V-TSST is effective as a stressor it may not achieve the same effectiveness as traditional TSST in terms of eliciting cortisol responses the VR training task in the high-intensity group was effective in eliciting a cortisol response with a large effect size (d = 0.94 This suggests that the aggressive attitude of the interactive avatar in the communication simulation may potentially elicit stress-load effects equivalent to those of TSST Previous studies measuring HPA-axis stress responses in VR tasks that induce social stress have only been confirmed for the V-TSST task where participants generate their own responses in speech Such responses have not been confirmed in static communication simulations where the conversation content is predefined or scripted The results obtained in this study suggest new possibilities for designing HPA-axis stressors using VR Additionally, the difference in the results between the high- and low-intensity groups suggests that the degree of HPA-axis stress can be changed by the behavior of the avatar. Previous studies confirmed that the level of ANS stress, judging from heart rate information, changes depending on the dialog feedback response (positive or negative) between humans and virtual characters (Hartanto et al., 2014) this study suggests that the HPA-axis stress response can be elicited by VR communication simulation and that the response level varies depending on the tone and attitude of the conversational avatar in the communication training environment used in this study the LF/HF significantly increased in the high-intensity group compared to that in the pre-task resting state confirming the occurrence of ANS stress responses This trend was also evident in subjective stress evaluations with the high-intensity group indicating significantly higher stress assessment values on a 5-point Likert scale than the low-intensity group These results are consistent with previous findings and show that the avatar’s behavior can indeed modulate not only HPA-axis stress responses but also autonomic nervous system stress responses and subjective stress levels we confirmed that HPA-axis stress responses can be induced by the attitude of the avatar in a VR communication simulation with scripted dialog it is unclear which factors of the avatars’ behavior have a greater influence on the HPA-axis stress response The participants’ open-ended responses suggest that both tone of voice and gestures contribute to stress separating and clarifying the effects of each element as well as understanding the impact of other factors such as the expressions of avatars would be beneficial in constructing effective VR communication simulation systems for use as training systems and stressors Moreover, this experiment was conducted using a between-subjects design, with approximately 10 participants in each condition. This number is small compared to previous studies of V-TSST (Helminen et al., 2019) although the difference between the high- and low-intensity groups was significant in terms of effect size in terms of the generalizability of the results Additionally, there was an imbalance in the gender ratio of participants, with only one female in each group. This imbalance could have influenced the results. For example, it has been reported that women have quicker and stronger HPA-axis stress responses to stressors compared to men (Goel et al., 2011). However, no significant gender difference has been reported in the cortisol response induced by V-TSST (Santl et al., 2019) Future studies should address this imbalance in participants and examine the generalizability of HPA-axis stress responses in fixed dialog VR communication simulations the quality of the avatar could influence the intensity of stress in VR communication simulations which needs to be clarified in future experiments Identifying the factors that trigger HPA-axis stress responses in VR is important for VR utilization as a stressor in the research and development of VR communication training systems which should be addressed in future research The factors causing such stress are likely to differ based on individual user characteristics underscoring the need for future investigations into personalized VR communication simulations the extent to which the intensity of the load can be adjusted should be determined by changing the attitude of the avatar In the low-intensity training group of this study salivary cortisol levels did not significantly increase from pre-stress levels at any time point methods should be developed to adjust the attitude of the avatar for more precise load adjustment reduction in stress load may be avoided by changing the appearance or voice of the avatar even if the conversation scenario remains the same a user study was conducted to investigate whether a virtual communication simulation with scripted dialog can elicit HPA-axis stress response The experiment employed a virtual customer service system in which participants addressed a complaining customer in a scenario involving a flight delay due to airport mishandling By changing only the tone and gestures of the virtual customer while keeping the content of the conversation the same we examined how varying the intensity of the presented stress affects HPA-axis stress response specifically the cortisol levels in saliva The results of the experiment confirmed that HPA-axis stress responses can be elicited by a static virtual CST system and the stress responses can be adjusted by differences in the attitude of a virtual customer Because the only established VR social stress task that can generate HPA-axis stress is the V-TSST the results of this study have potential applications in observing human physiological responses to stress and formulating stress reduction strategies the finding that a VR-based communication simulation can elicit an HPA-axis stress response similar to actual verbal interactions provides evidence of the effectiveness of communication training using VR The raw data supporting the conclusions of this article will be made available by the authors The studies involving humans were approved by the Research Ethics Committee of the University of Tokyo The studies were conducted in accordance with the local legislation and institutional requirements The participants provided their written informed consent to participate in this study Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article The author(s) declare financial support was received for the research This research was partially supported by Council for Science “Cross-ministerial Strategic Innovation Promotion Program (SIP) Big-data and AI-enabled Cyberspace Technologies.” (funding agency: NEDO) 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 All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher The Supplementary Material for this article can be found online at: 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The use distribution or reproduction in other forums is permitted provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited in accordance with accepted academic practice distribution or reproduction is permitted which does not comply with these terms *Correspondence: Yuki Ban, YmFuQGVkdS5rLnUtdG9reW8uYWMuanA= Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher 94% of researchers rate our articles as excellent or goodLearn more about the work of our research integrity team to safeguard the quality of each article we publish Please view the main text area of the page by skipping the main menu. I volunteered as an English teacher at a nursery school in Inazawa The school educates around 170 children ages 0-6 I had many opportunities to experience various aspects of Japanese culture I learned about Buddhist practices at the temple next door to the school and visited other Buddhist and Shinto temples and shrines throughout Japan I also attended summer festivals like the 七夕祭り and 海の日 and visited many historical sites that I learned about in my Asian Studies courses at Bowdoin I communicated almost entirely in Japanese so my language skills significantly improved (my two years of Japanese at 8 a.m This summer was my first time living alone and in a foreign country I learned the importance of planning but also learned to embrace spontaneity I feel fortunate to have met so many amazing interesting people in Japan who will be life-long friends My experiences in Japan deepened my interest in a future career in education or working with children and I hope to have another opportunity to teach English internationally in the future.​ Internship funded by the Annual Fund For Career Readiness provided by Mark E The following is the latest list of selected news summaries by Kyodo News Trump unleashes 25% tariffs on all steel, aluminum imports WASHINGTON - President Donald Trump on Monday imposed 25 percent tariffs on steel and aluminum imports for most countries a move that could heighten tensions with U.S trading partners and set off a renewed bout of inflation at home It was Trump's first sector-based tariff order since returning to the White House on Jan The tariffs on steel and aluminum imports are set to take effect on March 12 eye defense chiefs' meeting in Japan in late March TOKYO - Japan and the United States are arranging a late March meeting in Japan between Defense Minister Gen Nakatani and U.S Defense Secretary Pete Hegseth to strengthen cooperation and discuss strategies for countering regional security challenges posed by China They are expected to 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Report When she heard about the Tokyo Olympic organizing committee chief’s sexist comments blaming women for causing lengthy meetings Yuko Inazawa thought he must be talking about her The recent scandal engulfing the sports world has sent Inazawa on a troubling trip down memory lane Inazawa became the first woman to sit on the board of the Japan Rugby Football Union (JRFU) in 2013 a former prime minister and the president of the Tokyo Organizing Committee of the Olympic and Paralympic Games Inazawa was not just the sole female board member but also the first person to take the job as an outsider without much experience or knowledge in competitive sports “Many of my comments and questions during board meetings back then must have seemed out of the blue to Mori and other board members,” said Inazawa now a professor of media theory at Showa Women’s University in Tokyo “I am afraid that I certainly contributed to prolonging meetings.” But she said she took on the role to raise questions and give opinions from a novice's perspective Inazawa said the JRFU’s move to offer her a position came at a difficult time for Japan’s sports world The International Olympic Committee at the time was considering dropping wrestling one of the events where Japanese athletes were strongly competitive Japan’s judo scene was jolted by a scandal where more than a dozen female judoka on the national team accused their coaches of power harassment “Sports associations did some serious soul-searching and recognized that a key factor behind their problems was that few women were represented on their boards,” she said Inazawa said she was tapped to become a JRFU board member due to her long history of writing about women’s issues and editing a website for women at the Yomiuri Shimbun she was unsure if she was the right person given that she had little knowledge of the sport so she questioned a senior director of the JRFU about the post “We need to turn people who have never watched rugby games into fans as the sport’s popularity has been floundering,” he replied shared that view and she never suspected that he was annoyed by her behavior His sexist comments came as a shock to her 3 extraordinary meeting of the Japanese Olympic Committee Council Concerning the committee’s policy to raise the number of female board members he gave his “personal opinion” that women prolong meetings because they feel compelled to speak out if one of their female colleagues does so “It is only natural for women to give their opinions at meetings,” she said they have a big role to play in those jobs She said seasoned athletes in competitive careers feel that they should not step out of line They find it extremely difficult to speak up even when they are at odds with some longstanding practices in the sports world “Bringing in more women and outside experts who previously had little to do with sports is meaningful in terms of stimulating discussions,” she said The media reported that board members laughed when Mori made the remark and none of them protested It was a bitter reminder of what she endured decades earlier entered the workforce before the Equal Employment Opportunity Law was enforced in 1986 landmark legislation that bans discrimination against women in the workplace In male-dominated Japanese business circles she often found herself the only woman in the room She admitted she joined men in laughing when someone made comments demeaning to women feeling that she had no other choice but to laugh “That is why Japan is still placed nearly at the bottom of the Gender Gap ranking I regret my past behavior and feel sorry for my students at the university.” The World Economic Forum’s Global Gender Gap Report 2020 ranked Japan 121st out of 153 countries in gender equality--the worst among developed countries “Japan should be transformed into a society where people speak out when they find something disagreeable,” she said The number of women on the JRFU’s board increased to five in 2019 and they don’t think the same way just because they are women,” she said “They give their opinions based on their varied viewpoints.” it is a reason for Japan’s national rugby team’s success with many players representing different countries Since the introduction of the Equal Employment Opportunity Law Japan has added more laws aiming to achieve gender equality such as a 2018 law that calls for political parties to field equal numbers of male and female candidates and a 2016 law that obliges businesses to draw up numerical targets to promote women into managerial positions Inazawa said these laws exemplify Japan’s endeavor toward advancing the status of women in society Mori’s remarks led to an outpouring of grievances not just among women “The controversy gave us an opportunity to ponder why we need to resolve the gender gap,” she said but I would like to thank Mori for giving us a chance to contemplate.” Apology does little to quell fury over Mori’s sexist remarks Olympic chief Mori apologizes but won’t resign for sexist remark Suga criticizes Mori but won’t takes sides on resignation calls Mori: Talkative women cause time-consuming meetings OLYMPICS/ IOC says Tokyo 2020 chief Mori comments ‘absolutely inappropriate’ Japanese women speak out to put ‘misogynist’ Mori in his place Information on the latest cherry blossom conditions Please right click to use your browser’s translation function.) A series based on diplomatic documents declassified by Japan’s Foreign Ministry Here is a collection of first-hand accounts by “hibakusha” atomic bomb survivors chefs and others involved in the field of food introduce their special recipes intertwined with their paths in life A series about Japanese-Americans and their memories of World War II In-house News and Messages No reproduction or republication without written permission Metrics details The epithelial-mesenchymal transition (EMT) contributes to various processes in cancer progression Since we have already established a cell-based reporter system for identifying EMT-suppressive microRNAs (miRNAs) in the pancreatic cancer cell line Panc1 we performed a function-based screening assay by combining this reporter system and a miRNA library composed of 1,090 miRNAs we identified miR-509-5p and miR-1243 as EMT-suppressive miRNAs although the mechanisms for EMT-suppression induced by these miRNAs have yet to be clarified we demonstrated that overexpression of miR-509-5p and miR-1243 increased the expression of E-cadherin through the suppression of EMT-related gene expression and that drug sensitivity increased with a combination of each of these miRNAs and gemcitabine miR-509-5p was associated with worse overall survival in patients with pancreatic cancer and was identified as an independently selected predictor of mortality Our findings suggest that miR-509-5p and miR-1243 might be novel chemotherapeutic targets and serve as biomarkers in pancreatic cancer a detailed understanding of the miRNA-based molecular mechanisms by which pancreatic cancer is so malignant might provide useful insights into the identification of biomarkers and development of novel therapeutic strategies for this virulent tumor inhibiting EMT is a potential therapeutic strategy for cancers We demonstrated that miR-509-5p induced an MET phenotype by directly regulating VIM and HMGA2 miR-1243 directly regulated SMAD2 and SMAD4 which regulate the TGF-β signaling pathway resulting in an induction of the MET phenotype we found that those miRNAs could increase the sensitivity of the pancreatic cancer cell line Panc1 to gemcitabine the expression of miR-509-5p was significantly associated with a worse overall survival in patients with pancreatic cancer and was indicated as an independently selected predictor for overall survival our findings suggest that a novel therapeutic strategy for pancreatic cancer might involve a combination of gemcitabine and miR-509-5p or miR-1243 and that miR-509-5p might be useful as a prognostic biomarker in pancreatic cancer The lower closed arrow indicates the 1090 miRNAs examined (c) Venn diagram showing the overlap of six miRNAs between PEcadZsG-Panc1 #1 and #2 (d) The expression of E-cadherin in PEcadZsG-Panc1 #1 and parental Panc1 cells transfected with each candidate miRNA that was selected in the screening Suppression of HMGA2 inhibits cell motility and invasion through an MET phenotype alteration whereas these abilities are not affected by suppression of SMADs SMAD2 plus SMAD4 (left) and HMGA2 (right) via specific siRNAs was confirmed by western blotting in Panc1 cells The protein expression of these endogenous genes was downregulated by each specific siRNA compared with control siRNA (b) The number of viable cells 24–72 hours after transfection of each siRNA was assessed by the WST-8 assay and is presented as the mean ± SD (bars) for triplicate experiments (c,d) Transwell migration and invasion assays were performed in 24-well modified Boyden chambers without and with Matrigel siRNA-transfected Panc1 cells (4 × 104 cells per well [migration and invasion assay]) were transferred into the upper chamber and the migrated or invaded cells on the lower surface of the filters were fixed stained and counted after 24 hours of incubation and each data point represents the mean (bars Student’s t-test was used for statistical analysis and asterisks represent P < 0.05 versus si-NC transfectants (e) Model for the miR-509-5p- and miR-1243-mediated pathway in EMT Cell indexes were normalized with the last time point before treatment with gemcitabine (c) Representative curves of the growth-suppressive effects at 120 hours following treatment with gemcitabine in cells transfected with miR-NC The expression of miR-509-5p is associated with overall survival in human PDAC (a,b) Representative results of the in situ hybridization for miR-509-5p (a) FFPE of Panc1 cells 24 hours after transfection with miR-NC (upper) and miR-509-5p (bottom) (b) Primary PDAC with negative staining (upper) and positive staining (bottom) (c) Kaplan-Meier curves for the overall survival rates of patients with primary PDAC A lack of miR-509-5p expression in tumor cells was significantly associated with a worse overall survival (P = 0.0175 only a few studies have focused on the correlation between EMT and miR-509-5p the function of miR-1243 has not yet been clarified almost PDAC shows low expression of miR-509-5p and miR-1243 we concluded that inhibition of these miRNAs could not induce the EMT phenotype The statistical difference between TCGA and ours may be due to TCGA database not including Japanese PDAC tumors or a difference in the guidelines for the management of patients with pancreatic cancer between Japan and other countries such as the US and Europe the expression of miR-1243 in our miRNA-ISH assay was not associated with the prognosis in pancreatic cancer in contrast to miR-509-5p Since there were only 50 PDAC samples in the present study we may need to examine the relationship between the prognosis and expression of miR-1243 in large scale with more number of cases combinatorial therapeutics with anti-cancer drugs and overexpression of miR-509-5p or miR-1243 might serve as a novel cancer therapy that can overcome chemoresistance overexpression of miR-509-5p and miR-1243 increased the sensitivity of pancreatic cancer cells to gemcitabine We hypothesize that gemcitabine-induced cytotoxicity was increased via the induction of the MET phenotype through the downregulation of HMGA2 which in turn was caused by the overexpression of miR-509-5p Because cell death could be induced by a single treatment of miR-1243 the combination of miR-1243 and gemcitabine may have produced a synergistic effect on cell growth the MET phenotype and other effects caused by miR-1243 might increase the sensitivity to gemcitabine these results suggest that such combinatorial therapeutics might be useful for chemoresistant cancer we have established a cell-based reporter system to monitor the promoter activity of CDH1 and identified miR-509-5p and miR-1243 as EMT-suppressive miRNAs using this system Overexpression of miR-509-5p and miR-1243 markedly induced the MET phenotype and inhibited cell motility and invasion in vitro through the regulation of the target genes of each miRNA miR-509-5p and miR-1243 enhanced the effect of gemcitabine on cell growth The expression level of miR-509-5p could predict prognosis in patients with pancreatic cancer Our findings implicate the EMT-suppressive miR-509-5p and miR-1243 as potential therapeutic targets for pancreatic cancer and suggest that miR-509-5p might be a prognostic biomarker which was used to identify EMT-related molecules can be utilized with other libraries of cDNA A total of 50 primary PDAC samples were obtained from patients with PDAC who underwent pancreatectomy at Kyoto Prefectural University of Medicine between 2000 and 2011 These samples were embedded in paraffin after 24 hours of formalin fixation None of these patients underwent preoperative chemotherapy or radiotherapy and none had metachronous multiple cancers in other organs All samples were obtained with the informed consent of each patient after approvals by the local ethics committees of the Medical Research Institute and Faculty of Medicine in Tokyo Medical and Dental University (approval number: 2015-001) and Kyoto Prefectural University of Medicine (approval number: ERB-C-67-2) The methods were carried out in accordance with the approved guidelines and regulations The dsRNA mimicking mature human miRNA for miR-200c (MC11714) miR-1243 (MC13161) and negative control miRNA (negative control #1) were purchased from Thermo Fisher Scientific and negative control siRNAs (D-001810-05) were purchased from GE Healthcare (Buckinghamshire The miRNA inhibitors for anti-miR-509-5p (MH13068) anti-miR-1243 (MH13161) and negative control anti-miRNA (negative control #1) were purchased from Thermo Fisher Scientific siRNAs and miRNA inhibitors were transfected individually into cells at the indicated concentrations using Lipofectamine RNAiMAX (Thermo Fisher Scientific) according to the manufacturer’s instructions After each miRNA transfectant was treated with TGF-β (5 ng/ml) the expression of E-cadherin was evaluated by western blot analysis Total RNA was extracted using TRIsure reagent (BIOLINE total RNA was reverse transcribed using Taqman Reverse Transcription Kit followed by qRT-PCR performed using Custom Taqman miRNA Assays kit (Applied Biosystems) The miRNA expression was normalized to endogenous control RNU6B Single-stranded cDNA generated from the total RNA was amplified with a gene-specific primer set Gene expression was normalized to the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) The qRT-PCR was performed using an ABI PRISM 7500 sequence detection System (Applied Biosystems USA) according to the manufacturer’s instructions The following primers were used for the Taqman assay (Thermo Fisher Scientific): human miR-509-5p (002235) VIM (Hs00958111_m1) and GAPDH (Hs02758991_g1) CFPAC1 and KMP3 cells (4 × 104 per well) in serum-free medium were transferred into the upper chamber the cells that migrate to the lower chamber which contained 10% FBS as a chemoattractant Luciferase reporter plasmids were made by inserting the 3′-UTR of Smad2 HMGA2 and ZEB1 downstream of the luciferase gene within a pmirGLO Dual-Luciferase miRNA Target Expression Vector (Promega All site-specific mutations used the GeneTailor site-directed mutagenesis system (Thermo Fisher Scientific) Luciferase reporter plasmid or control plasmid (pmirGLO) was transfected into Panc1 cells using Lipofectamine 2000 (Thermo Fisher Scientific) miR-509-5p or miR-1243) was also transfected 6 hours later Firefly and Renilla luciferase activities were measured using the Dual-Luciferase Reporter Assay System (Promega) and relative luciferase activity was calculated by normalizing the Firefly luciferase reading with its corresponding internal Renilla luciferase control Panc1 cells (5 × 103) were seeded in wells of the E-Plate 16 (ACEA Biosciences miR-509-5p or miR-1243) was transfected into Panc1 cells these transfectants were treated with gemcitabine (0.1 Cell-electrode impedance was monitored using the xCELLigence RTCA DP system (ACEA Biosciences) to produce time-dependent cell response dynamic curves Data were collected every 10 min after treatment with gemcitabine for the first four hours and then every 1 hour for an additional 4 days The ISH assay was performed on formalin-fixed and paraffin-embedded (FFPE) tissue sections according to the manufacturer’s instructions (miRCURY LNA microRNA ISH Optimization Kit; Exiqon Inc. the sections were deparaffinized in xylene rehydrated with graded ethanol and incubated with proteinase-K for 10 min at 37 °C the sections were hybridized with the miR-509-5p and miR-1243 double-digoxigenin (DIG)-labeled LNA probes for 1 hour at 55 °C and were washed stringently prior to incubation with blocking for 15 min and probing with specific anti-DIG antibody directly conjugated with alkaline phosphatase the sections were counterstained with nuclear red We classified samples stained even a little as each miRNA-positive groups and samples with no stain as each miRNA-negative groups To explore the generality of the miRNA expression and clinical features among pancreatic cancer, we examined the publicity dataset from TCGA (http://cancergenome.nih.gov) retrieved on 20th February 2017 We took the primary pancreatic cancer data (TCGA-PAAD) from the TCGA data set which included mRNA data on 178 samples and 1881 miRNAs and examined correlation of prognosis and expression of miR-509-5p and miR-1243 using 141 samples excluding Stage IV macroscopic residual tumors (R2) or unevaluable presence of tumors (RX) Expression of miR509-5p was taken as the sum of expression of miR-509-1 and miR-509-2 The association between clinicopathological characteristics and the status of miR-509-5p or miR-1243 expression in patients with PDAC was evaluated with the χ2 or Fisher’s exact test differences between subgroups were tested with the log-rank test Univariate and multivariate survival analyses were performed using the likelihood ratio test of the stratified Cox proportional hazards model Differences between subgroups were tested with the Student’s t-test and considered significant at P < 0.05 Wang, Y. C. et al. miR221 targets HMGA2 to inhibit bleomycininduced pulmonary fibrosis by regulating TGFbeta1/Smad3-induced EMT. International journal of molecular medicine, doi:10.3892/ijmm.2016.2705 (2016) Zhang, B. et al. Antimetastatic role of Smad4 signaling in colorectal cancer. Gastroenterology 138, 969–980 e961–963, doi:10.1053/j.gastro.2009.11.004 (2010) Muramatsu, T. et al. The hypusine cascade promotes cancer progression and metastasis through the regulation of RhoA in squamous cell carcinoma. Oncogene. doi:10.1038/onc.2016.71 (2016) Download references This study was supported by the Joint Usage/Research Program of Medical Research Institute Tokyo Medical and Dental University (TMDU) This work was supported by KAKENHI (15H05908 and partially supported by the Project for Development of Innovative Research on Cancer Therapeutics (P-DIRECT) and the Project for Cancer Research And Therapeutic Evolution (P-CREATE) from Japan Agency for Medical Research and development was involved in research design and wrote the manuscript The authors declare that they have no competing interests Download citation DOI: https://doi.org/10.1038/s41598-017-04191-w Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. Experimental Hematology & Oncology (2021) Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. As the performance concluded, nearly 750 guests were treated to an elegant gala dinner, masterfully curated by renowned chefs Grégory Marchand, Takao Inazawa, Nadia Sammut, Bertrand Grébaut, and Fany Payre, and orchestrated by the talented Marine Bidaud. This grand event, organized by the Association pour le Rayonnement de l'Opéra de Paris (AROP), served as a crucial fundraiser for the Paris Opera's activities. It was made possible through the exceptional support of Rolex, the Timepiece of the Paris Opera, and Chanel, the Major Patron of the Paris Opera, alongside the generosity of individuals and corporate donors who form the Honorary Committee. Among the galagoers were Alexander Neef, Director of the Paris Opera; José Martinez, Dance Director of the Paris Opera; and Stéphanie Childress, the conductor. The Étoile dancers of the Paris Opera Ballet, including Dorothée Gilbert, Ludmila Pagliero, and Hugo Marchand, graced the occasion with their presence. In addition, a constellation of stars from various fields added to the evening's glamour. Notable attendees included Charlotte Casiraghi, Géraldine Nakache, Rossy de Palma, and Mati Diop, to name just a few. The Honorary Committee, comprising esteemed partners and benefactors, played a pivotal role in ensuring the success of this gala. Rolex, as the Timepiece of the Paris Opera, and Chanel, as the Major Patron of the Paris Opera Ballet, have demonstrated their unwavering commitment to the world of dance and art. a foodstuff made from yam that is known for being ultralow in calories is shaking off its humble image in Japan and getting a culinary makeover as consumers embrace it as a diet-friendly superfood there is even a theme park dedicated to konnyaku where visitors can experience making konnyaku products by hand and help themselves to a buffet of konnyaku dishes free of charge "I don't feel guilty no matter how much I eat because it's so low in calories," said Mina Fujita who has successfully used konnyaku to shed weight Fujita began making konnyaku-based meals about 15 years ago after learning of konnyaku's health benefits to suppress skin conditions such as atopic dermatitis which her 22-year-old daughter suffers from also known as devil's tongue and voodoo lily in English increasingly became a family favorite as it can be cooked in various ways and has a texture they never grow tired of She started using konnyaku for her own diet several years ago such as a konnyaku "steak" and even "sashimi." She credits it with helping her lose 15 kilograms in about two and a half years A processed food made from the edible bulb of the konjac plant konnyaku is believed to have been introduced from China as a medicine around the sixth century Used in vegetarian cooking since the Muromachi period (1336-1573) it took off in popularity in the Edo era (1603-1868) a konnyaku producer in the town of Kanra in Gunma that operates Konnyaku Park says its buffet-style konnyaku has become such a hit that visitors to the amusement park occasionally see waits of up to two hours for their turn to eat which already features a mini Ferris wheel aiming to accommodate 1.5 million visitors annually with Japanese companies stepping up exports of a variety of konnyaku-based products such as noodles began to export one of its signature products and other food products about seven years ago its "konnyaku rice," containing a mixture of konnyaku and unpolished rice Nakaki held a special lecture at Nagoya Bunri University in Inazawa in November last year as part of the company's campaign to promote the domestic consumption of konnyaku Konnyaku has been primarily used in a supporting role in Japanese cooking says this dull image is quickly becoming a thing of the past "The image of konnyaku having a peculiar smell but no taste no longer applies," Nakamura said "I wanted young people to learn about the allure of konnyaku," he added He said the students were eager to learn more about konnyaku asking about its carbohydrate content and the most popular konnyaku products overseas Nakaki plans to release a retort pouch mixture of white rice and konnyaku as an alternative to white rice targeting people with diabetes and other conditions that require they restrict their carbohydrate intake It is also developing a rice alternative in which all grains are manufactured from konnyaku "We hope to make konnyaku into one of the world's dietary staples," Nakamura said According to the Japan Konjac Association in Tokyo which seeks to increase consumption of the healthy root to fight "lifestyle-related diseases," because konnyaku is low in calories and rich in dietary fiber which is usually a gray color with black specks or white "It is the savior of problems with obesity today," said an association official The soaring popularity of bonsai abroad has spurred a recent spate of thefts of the aesthetic plants across Japan for sale outside the country or miniaturized trees and other plants cultivated as a traditional Japanese art have risen in recent years thanks to increased interest in Japan and relaxed restrictions are especially susceptible to being stolen "Recently all anyone talks about in the industry is theft It's unbearable," said Tatsuharu Takeshita who works at bonsai seller Koyoen in the central Japan city of Inazawa The shop has lost a total of 15 potted bonsai trees in two incidents -- one last year and another in January in which thieves cut through a protective fence he had installed the stolen bonsai had been entrusted to his care by customers 25 thefts in 11 prefectures have been confirmed according to data collected since February 2023 by the Nippon Bonsai Growers Cooperative There was also a case of theft involving a bonsai worth over 3 million yen ($19,110) 33 bonsai potted trees with a total value of 18.8 million yen were stolen from a store in Kumamoto Prefecture Numerous eyewitness reports and other sources claim that the crimes were carried out by groups made up of foreign nationals Stolen bonsai have turned up for sale on U.S such as the 2020 lifting of a ban on exporting Japanese black pine bonsai to the European Union have significantly heightened overseas demand for the plants according to the Japan External Trade Organization JETRO figures showed that the value of bonsai exports reached around 910 billion yen in 2023 Some businesses have successfully turned the tables on thieves Local police in central Japan arrested three Vietnamese men in April and May on suspicion of stealing bonsai The trees were traced after the owner put tracking devices on them leading authorities to identify the group's base of operations Acknowledging the vulnerability to bonsai grown outdoors a senior investigator called on businesses to step up security advised owners to "regularly take photos" of their bonsai to make it easier to prove ownership Women on Thursday officially joined a so-called “naked festival” at a shrine in central Japan for the first time in the event’s 1,250-year history donning purple robes and chanting excitedly as they bore a large bamboo trunk as an offering Seven groups of women took part in the ritual which is said to drive away evil spirits and where participants pray for happiness Many women wore “Happi Coats” (robes that reach to the hips) and shorts that are typically worn at Japanese festivals although men just wore loincloths similar to those worn by sumo wrestlers so I definitely wanted to take part to help bring excitement to this town and festival,” said 59-year-old civil servant Emi Tachibana said there had never been a ban on women participating and some had even made small offerings as individuals before when a women’s group inquired last year if they could join “I believe the most important thing is for there to be a fun festival for everyone The women did not join the festival’s main event where a large group of men clash together to drive away evil spirits Tsunoda said it would be difficult to open up that part of the festival to women due to the physical aspect The Japanese government last year said that it would push to improve women’s participation in society after an annual report showed the nation was struggling to narrow the gender gap The World Economic Forum report measuring gender parity ranked Japan 125th out of 146 nations last year Metrics details X-linked mental retardation (XLMR) is a common clinically complex and genetically heterogeneous disease arising from many mutations along the X chromosome Although research during the past decade has identified >90 XLMR genes copy-number variations (CNVs) were screened in individuals with MR from 144 families by array-based comparative genomic hybridization (aCGH) using a bacterial artificial chromosome-based X-tiling array Candidate pathogenic CNVs (pCNVs) were detected in 10 families (6.9%) Five of the families had pCNVs involving known XLMR genes duplication of Xq28 containing MECP2 in three families duplication of Xp11.22-p11.23 containing FTSJ1 and PQBP1 in one family and deletion of Xp11.22 bearing SHROOM4 in one family New candidate pCNVs were detected in five families as follows: identical complex pCNVs involved in dup(X)(p22.2) and dup(X)(p21.3) containing part of REPS2 NHS and IL1RAPL1 in two unrelated families duplication of Xp22.2 including part of FRMPD4 duplication of Xq21.1 including HDX and deletion of Xq24 noncoding region in one family Both parents and only mother samples were available in six and three families and pCNVs were inherited from each of their mothers in those families other than a family of the proband with deletion of SHROOM4 This study should help to identify the novel XLMR genes and mechanisms leading to MR and reveal the clinical conditions and genomic background of XLMR only three XLMR-associated genes have been identified suggesting structural variations other than point mutations including CNVs or variants in regulatory regions to contribute to unidentified XLMR conditions The flowchart of the screening of MR-associated pathogenic CNV Asterisks indicate types of benign CNVs corresponding to asterisks in Supplementary Table S1 and an abnormal karyotype of 46,XY,der(18)t(5;18)(p13;p11.3)pat(20/20) was detected in one case Peripheral blood samples were obtained with informed consent approved by the Institutional Review Board National Center of Neurology and Psychiatry Epstein–Barr virus-transformed lymphoblast cell lines (LCLs) were established from peripheral blood cells All LCLs were cultured in RPMI1640 medium supplemented with 10% fetal bovine serum and antibiotics Fluorescence ratios were normalized so that the mean of the middle third of log2 ratio across the array was zero The thresholds for copy-number gain and loss were set at log2 ratios of 0.4 and −0.4 A genome-wide oligonucleotide aCGH was performed using 244K (Agilent Technologies USA) according to the directions provided by the manufacturer The hybridized arrays were scanned using an Agilent scanner and the CGH Analytics program version 3.4.40 (Agilent Technologies) was used to analyze copy-number alterations after data extraction filtering and normalization by Feature Extraction software (Agilent Technologies) cDNAs were synthesized from total RNA extracted from LCLs established from the patients their parents and six normal controls (three males and three females) Quantitative real-time reverse transcriptase PCR was performed with the ABI PRISM 7500 sequence detection System (Applied Biosystems USA) using TaqMan Gene Expression Assays (Hs00202185_A1 FTSJ1 Applied Biosystems) according to the manufacturer's instructions mRNA levels of the genes of interest were normalized against a housekeeping gene as an internal control to collect the relative expression data Each assay was performed in triplicate for each sample Metaphase chromosomes were prepared with adjunction of 5-bromo-2-deoxiuridine in the last 6 h of cell culture after thymidine synchronization The chromosome slides were stained with Hoechst 33258 (1 mg ml−1) (Sigma and exposed to 254-nm ultraviolet light (Stratalinker UV Crosslinker 1800; Agilent Technologies) at a distance of 20 cm for 10 min after heating at 75 °C for 10 min These chromosomes were used for FISH to estimate the ratio of inactivation of the affected X chromosome Results of array-CGH analysis with the X-tiling array in probands of 10 families in which candidate pCNVs were detected. Each dot represents the log2 ratio of a BAC, and arrows and circles indicate MR-associated duplications (ratio >0.4) and homozygous deletions (ratio <−0.7), respectively. Arrowheads indicate benign CNVs. The gray vertical lines represent the centromeric region for which no clones were available. Pedigrees of 10 families in which probable pCNVs were detected The proband indicated by an arrow was used for CGH with the X-tiling array Asterisks indicate persons having identical pCNVs among each family A slash indicates that the person has died We detected candidate pCNVs at Xp11.22-p11.23 in 2 of 144 families (1.4%; MR67H and MRF91 in Table 1), although the affected regions showed no overlap between these two families (Figure 4). Mapping of aberrations at Xp11.23-p11.22 detected in families MRF91 and MR67H Disease-associated and copy-number-sensitive genes (not drawn to scale) are described by chevrons Filled bars and gray bars indicate >99% similarity and 90–99% similarity High-density oligonucleotide array (Agilent 244K) revealed an ∼1.15-Mb duplication at Xp11.23 in MRF91 (filled bar) and an ∼2.67-Mb deletion at Xp11.23-p11.22 in MR67H (open bar) The aberration is as follows: arr Xp11.23 (48 089 045–49 246 795) × 2 mat The aberration is as follows: arr Xp11.22 (50 040 995–52 710 691) × 0 An enlarged image of the duplicated allele is shown in the upper right inset indicating that the duplicated sequence at Xp22.2 was inserted in close proximity (arrow) whereas the duplicated sequence at Xp21.3 inserted into the duplication at Xp22.2 together with the original Xp21.3 (arrowheads) A full color version of this figure is available at The Journal of Human Genetics journal online suggesting that these CNVs were benign CNVs that have not been associated with the disease the del(X)(p11.22) containing SHROOM4 might occur through a segmental duplication-dependent manner Protein-truncation mutations in NHS have been identified in patients with Nance-Horan syndrome (OMIM 302350) an X-linked developmental disorder characterized by congenital cataracts As our patients in both families did not have cataracts or dental anomalies the genomic rearrangement involved in NHS may not affect the function of this gene Although the characteristic CNVs observed in two patients of two unrelated families were identical the severity of MR was different between patients: one patient had severe MR but the other had moderate MR suggesting this complicated genomic rearrangement to vary in penetrance among individuals It has not yet been clarified whether the complex CNV was transmitted from a single founder or occurred independently Further analysis such as genomic DNA sequencing and/or screening among different ethnic groups will be needed to disclose the full details of it it is possible that the duplication of disrupted FRMPD4 caused the mild MR and autistic features in our case suggesting segmental duplications to be involved in the generation of the duplication It is possible that the deletion alters expression levels through some mechanism such as a defect in binding of transcription factor(s) and alteration of the chromatin structure such as large CNVs observed second alterations other than the risk CNVs serve as ‘second hits’ that convert the risk CNV from a risk factor to a determinant or modifier of the developmental phenotype which need second-site genomic events to produce a severe phenotype Further detailed analyses including whole-genome sequencing will be needed to clarify this possibility Nomenclature guidelines for X-linked mental retardation large-scale resequencing screen of X-chromosome coding exons in mental retardation The genetic landscape of intellectual disability arising from chromosome X Use of array CGH in the evaluation of dysmorphology Submicroscopic duplications of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures Construction of a high-density and high-resolution human chromosome X array for comparative genomic hybridization analysis Clinical and molecular cytogenetic characterization of two patients with non-mutational aberrations of the FMR2 gene A new assay for the analysis of X-chromosome inactivation based on methylation-specific PCR A simple G-banding technique adaptable for fluorescent in situ hybridization (FISH) and physical ordering of human renin (REN) and cathepsin E (CTSE) genes by multi-color FISH Detection of genomic copy number changes in patients with idiopathic mental retardation by high-resolution X-array-CGH: important role for increased gene dosage of XLMR genes X-chromosome tiling path array detection of copy number variants in patients with chromosome X-linked mental retardation Structural variation in Xq28: MECP2 duplications in 1% of patients with unexplained XLMR and in 2% of male patients with severe encephalopathy Submicroscopic duplication in Xq28 causes increased expression of the MECP2 gene in a boy with severe mental retardation and features of Rett syndrome Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males and mental retardation caused by duplication of MECP2 and adjacent region in Xq28 An International System for Human Cytogenetic Nomenclature Disruptions of the novel KIAA1202 gene are associated with X-linked mental retardation X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment Complex rearrangements in patients with duplications of MECP2 can occur by fork stalling and template switching Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism Mutations in the gene encoding the Wnt-signaling component R-spondin 4 (RSPO4) cause autosomal recessive anonychia a secreted protein implicated in Wnt signaling Complex segmental duplications mediate a recurrent dup(X)(p11.22-p11.23) associated with mental retardation Mutations in the polyglutamine binding protein 1 gene cause X-linked mental retardation a novel polyglutamine tract-binding protein inhibits transcription activation by Brn-2 and affects cell survival Interaction between mutant ataxin-1 and PQBP-1 affects transcription and cell death PQBP-1 increases vulnerability to low potassium stress and represses transcription in primary cerebellar neurons PQBP-1 transgenic mice show a late-onset motor neuron disease-like phenotype Expression of human PQBP-1 in Drosophila impairs long-term memory and induces abnormal courtship Segmental duplications arise from Pol32-dependent repair of broken forks through two alternative replication-based mechanisms A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders Mutations in the small GTPase gene RAB39B are responsible for X-linked mental retardation associated with autism Characterization of a novel chromo domain gene in xp22.3 with homology to Drosophila msl-3 Homeobox genes in vertebrate forebrain development and disease which encodes a ubiquitin E3 ligase subunit cause an X-linked mental retardation syndrome associated with aggressive outbursts Mutations in ionotropic AMPA receptor 3 alter channel properties and are associated with moderate cognitive impairment in humans A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay High resolution ordering of DNA markers by multi-color fluorescent in situ hybridization of prophase chromosomes Download references We thank the patients and families for their generous participation in this study N Murakami for cell culture and EBV-transformation A Takahashi and R Mori for technical assistance This work is supported by grants-in-aid for Scientific Research on Priority Areas and Global Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstitution of Tooth and Bone from the Ministry of Education Japan; a grant from the New Energy and Industrial Technology Development Organization (NEDO); and by a research grant for Nervous and Mental Disorders from the Ministry of Health This study was supported by the Joint Usage/Research of Medical Research Institute S Honda is supported by Research Fellowship of the Japan Society for the Promotion of Science (JSPS) for Young Scientists Medical Research Institute and School of Biomedical Science National Center of Neurology and Psychiatry (NCNP) Department of Mental Retardation and Birth Defect Research Grobal Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstitution of Tooth and Bone This work is part of an ongoing study by the Japanese Mental Retardation Research Consortium Supplementary Information accompanies the paper on Journal of Human Genetics website Interdisciplinary Graduate School of Medicine and Engineering Yokohama City University Graduate School of Medicine Research Center for Bioscience and Technology Hokkaido University Graduate School of Medicine Download citation The Purpose: Official mascot of Japan’s Ministry of Tourism The Occasion: 1994 Asian Games in Hiroshima Wally McNamee/Corbis****Year Invented: 1998 The Occasion: The 1998 Winter Olympics in Nagano The Occasion: The 2005 World Exposition in Aichi The Occasion: Sento-kun and Manto-kun were created for the 1,300th anniversary of the city of Nara, Japan’s ancient capital city. Cuteness factor: 3/10 (Sento-kun), 8/10 (Manto-kun) The Occasion: The 50th anniversary of Inazawa City in Aichi Prefecture The Story: Inaapi is a green-haired, gnome-like creature whose pill-shaped body has become the physique of choice for many Japanese mascot designers. Meant to be a “tree guardian,” and dressed in a traditional fundoshi, or sumo loincloth, Inaapi has taken on the role assigned to many of Japan’s city critters: encouraging eco-tourism. Find him stamped across government-issued posters advertising Inazawa as a “city of trees,” or present in costume form at various tree-planting ceremonies. Courtesy Ishikawa JET blogYear Invented: 2008 The Occasion: Promoting tourism on the Noto Peninsula Courtesy National Cultural FestivalYear Invented: 2011 The Occasion: The National Cultural Festival in Kyoto up-to-the-minute voice in all things travel Condé Nast Traveler is the global citizen’s bible and muse We understand that time is the greatest luxury which is why Condé Nast Traveler mines its network of experts and influencers so that you never waste a meal or a hotel stay wherever you are in the world Guangzhou customs authorities hold a press conference to brief the media on drug smuggling cases in the third quarter of 2018 Japanese version Today's print edition Home Delivery including spiral escalators and elevators with doors bearing elegant Islamic designs made at Mitsubishi Electric Corp.'s Inazawa Works As the domestic market approaches saturation Mitsubishi Electric is using the eye-catching and unique products made at its plant in Inazawa as advertisements to boost offshore sales.googletag.cmd.push(function() { googletag.display('div-gpt-ad-1499653692894-0'); }); The spiral escalator uses a special system that combines both rotating and vertical movements In a time of both misinformation and too much information quality journalism is more crucial than ever.By subscribing Your subscription plan doesn't allow commenting. To learn more see our FAQ Sponsored contents planned and edited by JT Media Enterprise Division NEOWIZ has released the music video for a new song in DJMAX Respect called “Only for You.” The music video is the first in a series of new music video and song debuts NEOWIZ is planning DJMAX Respect is due out worldwide for PlayStation 4 in July Watch the “Only for You” music video below Reproduction in whole or in part in any form or medium without acknowledgment of Gematsu is prohibited Use of this site is governed by all applicable laws Website by 44 Bytes Women will take part in the hadaka matsuri in Inazawa in which thousands of men dressed in next to nothing drive away evil spirits Women in Japan have been permitted to take part in an ancient ceremony Every February, thousands of men dressed in next to nothing take part in the hadaka matsuri at a Shinto shrine in Inazawa, a town in central Japan, to drive away evil spirits over the coming year. The festival has been regarded as off-limits to women since it was first held in the town about 1,250 years ago, but organisers will allow a group of about 40 women to take part on 22 February, according to Japanese media reports. will make ritual offerings of bamboo grass but will not be part of the festival’s momiai climax in which men dressed only in fundoshi – a type of traditional loincloth – tabi socks and hachimaki bandanas clash with each other as they attempt to transfer their bad luck to a “chosen man” by touching him before he is withdrawn to the safety of the shrine who campaigned for the unofficial ban on women to be lifted said she had wanted to take part in the festival since she was a child “I could have participated had I been a boy,” she told reporters according to the Yomiuri Shimbun newspaper Suzuki added that she would use the opportunity to pray for her family’s safety and for people affected by the recent deadly earthquake on the Noto peninsula Organisers of Japan’s myriad festivals have come under pressure to open them up to all-comers amid concern that rural depopulation could put an end to events traditionally dominated by local men women took part in the Katsube fire festival in Shiga prefecture for the first time in its 800-year history But organisers of the Somin-sai – which also features minimal clothing – in the north-east town of Oshu announced last month that the event would be held for the final time this year chief priest at the temple that hosts the 1,000-year old festival told the Mainichi Shimbun that the decision had been prompted by the advanced ages of many local men and a lack of people to oversee the event Fujinami dismissed suggestions that the festival be opened up to people living outside the town saying it would not be in keeping with “core rituals” that had been handed down by generations of locals While some have welcomed the revamped naked festival as a modest step forward for gender equality other areas of traditional life in Japan are still off limits to women including the dohyo ring used in the country’s sport of sumo While women compete in amateur sumo they cannot fight professionally and are banned from even stepping on to the dohyo – a dirt-covered circle marked out with half-buried rice-straw bales – used in the six main tournaments held every year The rule has occasionally caused embarrassment to organisers of the centuries-old sport Sumo authorities battled allegations of sexism in 2018 after several women rushed on to a sumo ring to administer first aid to a local mayor who had collapsed after suffering a stroke the referee repeatedly ordered them to leave the ring JAPAN: A young and determined team of Singapore bowlers turned initial disappointment into victory at the Nov 1-4 Japan Open Bowling Championships in Inazawa originally set its sights on the Asian Indoor and Martial Arts Games was shaken by the event’s cancellation in August their drive remained unshaken as they debuted at the prestigious event held at the Inazawa Grand Bowl The competition which saw 216 men’s and 108 women’s teams from across the globe marked a major achievement for Singapore’s up-and-coming bowlers earning ¥200,000 (S$1,730) worth of merchandise vouchers secured second place and ¥120,000 in vouchers finishing second in the women’s all-events narrowly losing to Japan’s Haru Suzuki by just one pin She also took home third place in the women’s doubles alongside Chang while Cheah Ray Han claimed second in the men’s singles Lim Shi En also impressed with a fourth-place finish in the women’s singles Jason Yeong-Nathan, technical director of the Singapore Bowling Federation especially considering they had just a month to bond and adapt to a new team dynamic “These were young teams that we were preparing for the Asian Indoor Games,” Yeong-Nathan said “They had never bowled a team event together before but they handled the challenges and conditions superbly.” who has had a standout year with victories at the World Youth Championships and Thailand Open Masters “It’s a satisfying feeling to know that the hard work is paying off I’m proud to represent my family and friends back home.” Fellow team member Ning Tay expressed her pride in the team’s resilience and teamwork despite this being their first time competing together With their eyes now set on the 54th Singapore Nationals and 9th National Youth Championships later this month the young bowlers are eager to apply their lessons from Japan hoping the team’s adaptability and sharp decision-making will propel them forward in future competitions Featured image by Depositphotos (for illustration purposes only) Get your groove on and nail the beat with the Hi-Fi Rush soundtrack and song list full of big names in rock music to accompany the fast-paced action