The Osaka-born singer became a social media sensation almost two decades after her death “Mayonaka no Door (Stay with Me),” took the world by storm thanks to social media platforms such as TikTok and YouTube who sadly passed away from cervical cancer at the age of just 44 She released 10 studio albums and several compilation records during her career and was particularly well known for writing and singing anime tracks we’re looking back at the life and career of the city pop star.   Her father worked at a hospital and her mother sang with the jazz band Crazy Cats Matsubara developed a passion for music from a young age She began playing the piano at 3 and soon became familiar with jazz she joined the rock band Kurei and later played keyboard for the group Yoshinoya Band while in high school.   she left Osaka for Tokyo to realize her dream She performed at various venues while studying at Suginami High School and working a part-time job which meant she had to take her exams orally Her talent as a singer was there for all to see. What was needed was a big hit to complement her spellbinding voice. Pony Canyon director, Haruhiko Kaneko, called on up-and-coming songwriter Tetsuji Hayashi, who wrote Mariya Takeuchi’s track “September,” to come up with a song with “an all-out Western pop feel to it.” Yoshiko Miura penned the lyrics and on November 5 “Mayonaka no Door (Stay with Me)” was released “Ai wa Energy,” was also written by Miura and Hayashi Used as a campaign song for supermarket chain Seiyu it featured alongside “Mayonaka no Door (Stay with Me)” on Matsubara’s debut album which included standout tracks such as “Aitsu no Brown Shoes” and “Jazzy Night,” was released Other popular songs from her early years included “Neat na Gogo San-ji” and “Cupid,” from her third album and “Wash,” a B-side for the underrated single “See-Saw Love.”  author Helen McCarthy commented that it was a “movie with lots to enjoy,” adding that “Even the cheesy ’80s pop soundtrack has its own charm.”   One of Matsubara’s most famous songs was “The Winner,” used for the opening credits of the first seven episodes of the hugely popular anime series, Mobile Suit Gundam 0083: Stardust Memory which aired between May 1991 and September 1992 She also made an English version of the track titled “Back to Paradise,” that was played in episodes one and six Matsubara continued to work on anime soundtracks as well as writing several songs for commercials and composing hits for artists such as Hitomi Mieno and Mariko Kouda.  Matsubara reportedly sent an email to the other members of Dr informing them that she was leaving the music industry and that she would no longer be reachable by phone or mail It was later learned that her reason for disappearance from the public eye was because she had been diagnosed with uterine cervix cancer Sixteen years after Matsubara’s death, Indonesian YouTuber Rainych uploaded a cover of “Mayonaka no Door (Stay with Me)” to her YouTube channel The original song also became a TikTok sensation with people playing it alongside anime videos or people dancing A new trend then emerged with people of Japanese descent playing the track to their mothers who would light up and start singing along The single topped the Spotify Viral chart for 20 consecutive days and was number one on Apple Music’s J-Pop rankings in 84 countries and territories Pony Canyon subsequently rereleased both the single and Matsubara’s debut album on vinyl was the youngest of six children and grew up in Maui He passed away at Kula Hospital where he spent his last couple years but had great care from the Kula nurses and staff and Hospice Maui In Charlie’s early years he worked as a plumber but soon transitioned to electrical work and eventually retired as an electrician He helped many of his friends and relatives putting his trades to good use during his lifetime but he enjoyed his free time fishing and making ono pupus for his friends and family to enjoy He also served in the Army as a medic for a couple years during the Korean War passed many years before him but is survived by his children Lynn Dacuag and Guy Matsubara; granddaughters Cassi and Mia; great grandchildren Rylynn and Chance; and his youngest sister Sets Takahashi 2025 at Nakamura Mortuary in Wailuku at 11:00 AM Copyright © 2025 Maui News Publishing Company LTD | https://www.mauinews.com | 100 Mahalani Street By Michelle Ramos Denise Iseri-Matsubara executive director of Catholic Charities Housing Development Corp Already a Honolulu Star-Advertiser subscriber? Log in now to continue reading. Catholic Charities Hawaii has named Denise Iseri-Matsubara executive director of Catholic Charities Housing Development Corp. Iseri-Matsubara was previously executive director of the Mayor’s Office of Housing under Mayor Rick Blangiardi. Her experience also includes serving as a board member and, later, as executive director of the state Hawaii Housing Finance and Development Corp. for seven years and as a senior special assistant to then-Gov. David Ige. Send items to citydesk@ staradvertiser.com. 500 Ala Moana Blvd. #2-200Honolulu, HI 96813(808) 529-4747 Cellular and Molecular Mechanisms of Brain-aging Volume 16 - 2024 | https://doi.org/10.3389/fnagi.2024.1509434 Sunlight exposure is recognized as a risk factor for the development of age-related macular degeneration (AMD) a common neurodegenerative retinal disease in the elderly the blue light wavelengths within sunlight can negatively impact the physiology of light-sensitive retinal cells including retinal pigmented epithelium (RPE) and photoreceptors This review explores blue light-induced retinal degeneration emphasizing the structural and functional impairments in RPE The initial section provides a brief overview of blue light’s effects on photoreceptors followed by a comprehensive analysis of its detrimental impact on RPE In vitro studies reveal that blue light exposure induces morphological alterations and functional impairments in RPE disrupted secretion of neurotrophic factors mitochondrial dysfunction and ER stress in RPE animal and ex vivo models for studying blue light exposure are discussed with recommendations for improving reproducibility in future studies evidence from clinical studies remains inconclusive and a definitive link between blue light and retinal damage has yet to be established Excessive blue light exposure consistently damages photoreceptors and RPE in culture and animal models this correlation has not yet been fully validated in human studies and remains an area of active research ultimately activating the mitochondrial apoptotic pathway Experimental models are used to mimic environmental stressors associated with blue light stimulation through a variety of methods which are summarized below: the peak wavelength of these light sources is often unknown leading to difficulties in accurate calculation of their irradiance intensities light sources with more uniform peak wavelengths such as LED devices should be utilized to prevent variance of wavelengths in blue light studies A majority of studies measure blue light intensity in mW/cm2, which measures the intensity per unit area, but not the total amount of light energy received by the cells. This is problematic since exposure duration varies between studies, making it challenging to compare results. Measuring the total energy (J/cm2) would better reflect the cumulative light exposure, enabling easier comparisons across studies (Van Norren and Gorgels, 2011) as lux measures light emitted rather than received duration and total energy (J/cm2) in studies will allow for more consistent comparisons across studies While cell-based blue light experiments are easier to design and provide more reliable in vivo models offer significant advantages over cultured RPE cells: (1) Animal studies offer more physiologically relevant insights into the complex structural and functional interactions between different cell types in retinal tissue which are often lacking in cultured systems since these model systems preserve systemic responses such as neuronal activity (2) Cells in the neural retina such as photoreceptors lose their morphological integrity in vitro This issue can be addressed by using in vivo or ex vivo models to study blue light-mediated effects on the retina and its interactions with the RPE/choroid in a more complex physiologic environment (3) In vivo models also allow longitudinal studies for studying the effects of low intensity long-term blue light exposure and tracking changes over time in the same animal Such explants can also be used to compare differences between genetically modified mouse tissue and wild type following blue light stimulation One limitation of rodent models for AMD and blue light research is the absence of a macula, an area critical to high-resolution vision in humans. Another challenge with using animal models is the inherent variability in irradiance intensities on the ocular tissue (Table 2) (Narimatsu et al., 2015; Lin et al., 2017; Xie et al., 2021; Wang et al., 2023) Ex vivo models allow a more precise manipulation of illumination conditions thereby improving reproducibility and reducing complexity due to systemic influences both in vivo and ex vivo model systems provide significant advantages while some evidence suggests a potential association between prolonged blue light exposure and increased AMD risk more epidemiological studies are needed to establish a definitive link leading to apoptosis and the AMD progression Further research could also focus on protective strategies including therapeutic interventions targeting pathways activated by blue light and improving blue-filtering technology to prevent retinal damage refining blue light exposure experiments—through standardized protocols and the development of novel in vivo and ex vivo models—will improve the consistency and relevance of findings across studies and enhance our understanding of blue light’s effects on the retina and ocular tissues The author(s) declare financial support was received for the research Vancouver Coastal Health Research Institute Natural Sciences and Engineering Research Council Canadian Institutes of Health Research and Faculty of Medicine UBC for funding The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest The author(s) declare that no Gen AI was used in the creation of this manuscript 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 Filtering blue light mitigates the deleterious effects 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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) 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: Joanne Matsubara, am9hbm5lLm1hdHN1YmFyYUB1YmMuY2E= †These authors have contributed equally to this work and share first authorship 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 Part of the Science Adventure multimedia series and released in 2009 Steins;Gate is the acclaimed visual novel that introduced us to the iconic Mad Scientist Okabe Rintaro and made Dr Pepper fans of us all To celebrate the addition of Steins;Gate to the Crunchyroll Game Vault Anime Trending spoke with producer Tatsuya Matsubara about the game’s development and how the landscape of visual novels has changed in the past 15 years Thank you very much for joining us for this interview How do you feel about its reception back then and how do you feel now regarding its current legacy and its impact both in Japan and overseas?  Steins;Gate is a franchise that is 15 years old the Japanese visual novel genre was kind of picking up it was considered a mega-hit in the visual novel space we released Steins;Gate initially on the Xbox 360 and very quickly we achieved this 30,000 unit benchmark That’s when the anime adaptation was decided that’s when the franchise [became] major and mainstream in terms of the anime space and the game space we were able to port the game — the visual novel — to many different consoles and ultimately did more than 100,000 units It’s a very flattering experience to be part of that “What is it that you want to do at this company?” And I said I want to make a game that has some kind of impact in the world.” So I guess you could say that that comment kind of manifested itself in the form of Steins;Gate You mentioned the Xbox 360. Steins;Gate was first released on the 360, and in 2009, you said that the console was chosen due to it “enabling production not to worry about the limits on freedom of expression,” and also because Chaos;Head Noah had performed well on the platform But things were different for Steins;Gate 0 and Steins;Gate Elite which didn’t launch initially on an Xbox console like the original Steins;Gate or Steins;Gate: My Darling’s Embrace Can you share the reasons behind the evolution of the series’s release plans the Xbox 360 afforded more latitude in terms of freedom of expression: what we wanted to put on the screen and the type of stories we wanted to tell Japan has a rating agency like the ESRB in the States You need to get a rating from that agency to sell your game you have to get approval from the first party in terms of what type of game you want to release on their platform At the time — given the landscape — the Xbox 360 just had more freedom in that respect I think all consoles are treated a little more equally in sort of what’s allowed and what’s not there’s been a shift in the balance of the different consoles and — especially when releasing a retail packaged version — retailers will take on more units depending on what platform it’s on I think there was a shift in the landscape between 2009 and more recently today which drove a lot of our business decisions What led to the decision to add the game to the Crunchyroll Game Vault the Crunchyroll team was quite passionate about having Steins;Gate on their platform and it was very highly rated on their platform So that’s how the decision was made to port it to Game Vault Steins;Gate comes from a period where internet slang like “Nullpo” and “Jouko” existed a lot has changed since then with smartphones and social media what do you think it would feature and why I think if we were to create Steins;Gate in this day and age we would take into account a lot of the more modern scientific trends and developments Steins;Gate always tries to project a slight near-future type of science world as opposed to the present we’ve explored in Steins;Gate 0 through Amadeus and quantum computing through Anonymous;Code My belief is the next trend — or what we’re on the brink of — is nanomaterials I think that’s getting a lot of attention in the scientific community right now There are new materials that are extremely light If you can mass produce these types of materials I think that would open up possibilities to space elevators and they have properties that a lot of other materials do not They can transmit at the speed of light or conduct heat in ways that other materials really can’t I think trying to imagine and depict that future would be really really fun for a Steins;Gate if we were to make it in this day and age I’d like to ask a game mechanics question How hard was it to implement the phone mechanic into the story It seems like kind of a bit of a nightmare given how hard it is to get all the right flags for the true ending Tatsuya Matsubara: I would say the cell phone mechanic itself is quite different from a lot of others It’s not necessarily difficult to implement the mechanic or the system itself The Steins;Gate series of games takes place from Okabe’s point of view but the trick for us was almost overlapping Okabe’s point of view with that of the players and bridging that gap I would say that was the bigger challenge of the two: making the player believe that they are in some ways overlapping with Okabe I think that is the true essence of the mechanic.  I think the idea of the cell phone oftentimes in visual novels — on a very fundamental level — is that players have choices and that leads you to different endings or different stories there wasn’t an active choice mechanic per se It was about how the player used the cell phone interface to communicate with or contact the world itself I think it was a much more natural expression of how you can branch off into different timelines and stories unlike the anime which you know has to choose one ending the original Steins;Gate has a bunch of different endings Tatsuya Matsubara: I think we touched on it a little earlier but because Steins;Gate is a visual novel in which you can actually not make a single choice through a playthrough Oftentimes the player will run into Suzuha’s bad ending on their first playthrough I failed.” I think that really left an impression on me because going through this game without a single interaction with the world will lead to this bad ending witnessing that bad ending and seeing what kind of bad future that would entail motivates you to go back and make a second attempt I think that that ending really kind of triggers something and leaves a strong impression Steins;Gate is also known for its numerous collaborations with its series and products is the Monogatari and Steins;Gate Collaboration Cafe and what’s the process of choosing who to work with Tatsuya Matsubara: The Monogatari series collaboration happened because we happened to have someone on staff who was a huge fan of the Monogatari series is also looking at its 15-year anniversary I think there was a lot of alignment on the anniversary timing in terms of world building and world setting Monogatari is very much rooted in more of an occult type of superstitious space whereas Steins;Gate is rooted more in science but I think it’s a very interesting perspective to kind of see both of these contrasting views collaborating in one space.  the character designer for the Monogatari series We also thought that fans would be kind of surprised and shocked by this collaboration I think kind of keeping the fans a little off guard was part of the intent as well It definitely caught me and one of my friends off guard It would be a bit of an understatement to say that Steins;Gate features a wide variety of unique characters I would say it’s Mayuri because Kurisu was actually a sub-character The concept for the game originated from the idea of saving Mayuri through this time loop and Kurisu was almost there to support this But as the game continued to develop and the story developed Kurisu became more and more like a heroine of this particular franchise Special thanks to Crunchyroll for the interview opportunity Interview conducted by James Mizutani on October 9th Want to read more interviews like this? Subscribe to our weekly newsletter for updates on our anime charts and new content Please upgrade your browser to improve your experience It was a Hamptons who’s who celebrating culture on the plate one-night-only meal for an illustrious group of guests and Steven Beltrani chat over intoxicating cocktails with Hamptons publisher Lynn Scotti designer Nina Runsdorf with artist Quentin Curry and the Parrish Art Museum’s Monica Ramirez-Montagut it was time for the main event which saw Elizabeth Kurpis and Sarah Wetenhall dig into the elegant offerings that combined the distinctly Korean flavors of Genesis House with Semma’s Southern Indian cuisine The resulting plates were nothing short of gastronomic poetry: red snapper encrusted with rice flour and dusted with a delectable medley of mustard and barley jook as a preamble to the mouthwatering marinated short rib (Yangnyeom galbi Welcome remarks from Rachel Espersen introduced the evening with easy polish, as guests took in the Cocoji-inspired florals and equally impressive plates And as the final bites of the passion fruit pudding and indulgent chocolate and mugwort desserts were taken guests left transported into a universe brimming with flavor and elegance All photos courtesy of Zach Hilty / BFA.com Edward Barsamian is the Head of Editorial for The MICHELIN Guide these iconic chefs mentor professional chefs who have an ego she has championed America’s farm-to-table movement for 54 years One of the world’s most celebrated chefs discusses his legacy The shiba inu-loving chef shares his favorite spots around town From listening bars to neighbourhood restaurants explore all the top recommendations from Chishuru’s Adejoké Bakare One of the most prominent chefs serving Indian cuisine talks India and his New York What the MICHELIN Guide Inspectors Saw in 2025 The Mexican capital takes center stage alongside the culinary world's top talents From Texas Barbecue to Mexico City's cutting-edge dining these new MICHELIN Guide hot spots promise unforgettable vacations and world-class cuisine These are the best lake vacations for a summer break from Lake Tahoe in the US to Lake Como in Switzerland and the MICHELIN-recommended restaurants and bolt holes to bed down in when you visit where do fashion’s biggest names retreat for a bite and a bed We imagine the post-Gala sanctuaries of the chicest attendees Who knew brisket and biscuits could be so good From tartan fabrics and stag antler furnishings to rare Scotch whiskies and castle views you'll have no doubt which country you're in when staying at these Michelin-Key hotels The self-proclaimed “unofficial talent scout” shares his local favorites from the city he calls home Sustainability is more than a buzzword—it’s a core value embraced by some of North America’s most design-forward hotels Non-members can add the privileges at checkout through our 30 day free trial By continuing I accept the Terms & Condition and Privacy Policy. I would like to receive Newsletter from MICHELIN Guide Save lists of your favorite restaurants & hotels and the Parrish Art Museum\u2019s Monica Ramirez-Montagut and Sarah Wetenhall dig into the elegant offerings that combined the distinctly Korean flavors of Genesis House with Semma\u2019s Southern Indian cuisine Welcome remarks from Rachel Espersen introduced the evening with easy polish, as guests took in the Cocoji-inspired florals and equally impressive plates All photos courtesy of Zach Hilty / BFA.com Office of Housing Mayor Rick Blangiardi announced Thursday that Denise Iseri-Matsubara has joined the City and County of Honolulu as the Executive Director of the Mayor’s Office of Housing “We are most fortunate Denise has agreed to join our team and take on this extremely important role,” said Mayor Rick Blangiardi “Our Administration is determined to succeed with all our various housing initiatives for the City & County of Honolulu and Denise’s depth and breadth of knowledge and experience is exactly what we needed We are very excited and most grateful to welcome her to our team.” Iseri-Matsubara is joining the Blangiardi administration after spending about seven years at the Hawai‘i Housing Finance and Development Corporation (HHFDC) first as a board member and then as its Executive Director As part of her role with the Office of Housing and Homelessness she will also take over leadership of the City’s Affordable Housing Working Group “I can’t think of a better way to put my knowledge and experience in housing to work than to be working alongside an inspiring leader like Mayor Blangiardi,” said Denise Iseri-Matsubara “Now that the City has returned to the housing bond business it’s a great opportunity for me to help coordinate the financing programs between the city and the state to keep the momentum of housing production going.” Iseri-Matsubara was a Senior Special Assistant to the Governor during which time she worked with Governor Ige to establish a housing stakeholder working group to work on administrative processes and state policies aimed at increasing the development of affordable housing for the people of Hawai‘i Iseri-Matsubara is a proud Native Hawaiian and graduate of Kamehameha Schools Kapālama She earned her Bachelor’s degree in Business Administration and a Master’s degree in Public Administration both from the University of Hawai‘i at Mānoa She also served on the Board of Directors for the Native Hawaiian Chamber of Commerce as well as the Kamehameha Schools Alumni Association Story by Mari TaketaPhoto by Derek Wong ’91 It’s been more than 20 years since Jon Matsubara ’91 abandoned law school for the professional kitchen 10 since he started thinking about opening a restaurant of his own It seems now the quirkiest of fates that Matsubara – who trained at New York’s (then) three-Michelin-star Jean-Georges and came home to helm the high-end kitchens of Stage Bloomingdale’s Forty Carrots and Merriman’s Honolulu – recently opened his first solo restaurant deep in Manoa Valley across the street from where he played Pop Warner football pick up your food and eat it out of takeout containers with disposable forks or chopsticks Fried rice with roasted bone marrow and garlic Pork hash stuffed with crab and topped with ginger but the waiting made his Feast all the more delicious Matsubara was one of the unluckiest chefs in Honolulu The early part of his story was magical: Plaza Club in San Diego to Alan Wong’s to New York’s Tabla and Jean-Georges experience everything and bring it all home: That was the plan Just when the foodie craze began sweeping the Islands as eating local became a trend and a new generation of young chefs began striking out on their own Matsubara was one of the city’s most talked-about chefs putting haute cuisine techniques and local ingredients on plates for upmarket diners But he spent the next decade watching other talented local chefs leave their mentors’ kitchens to open their own restaurants one after another while every vacancy and opportunity he pursued fell through The extra time tamed the loftiest part of his ambition and replaced it with a sense of fun Matsubara realized at some point that he no longer aspired to or even enjoyed much white-tablecloth dining He wanted to eat what was fun and delicious my (dream) restaurant looked very different from what I’m going to do now Having the creative ideas to put behind a quality ingredient and making it fun and delicious is the direction I’m heading.” across Lowrey Avenue from where Matsubara grew up catching crayfish in Manoa Stream after football practice the people who live there and the ones who drive in to drop off their kids at sports practice and pick up dinner to take home to the family table In a long vacant space that previously housed a flower shop Matsubara is carving out a new kind of dining He’s creating local-style comfort food elevated with impeccable technique – in a no-frills setting with a bare-bones staff It’s the exact same formula he experimented with at Anasia a relative’s sports bar in Mo‘ili‘ili where Feast debuted as a lunchtime popup last year Amid dart boards and vinyl booths he cooked butter-poached crab sandwiches Hilo-style hamburger steaks slathered in oyster sauce with onion gravy all over and a daily changing dish called I Am Vegan hanging out and eating stuff out of takeout containers,” he says “It really demonstrated that if you take care of them and you make the food consistent and tasty We want to create that sort of vibe and feel good about it Really tasty food at the right price point A take on classics with really good ingredients and great drinks More Alumni Profiles – Fall 2019Michelle Karr-Ueoka ’93Mark Noguchi ’93 Zeen is a next generation WordPress theme. It’s powerful, beautifully designed and comes with everything you need to engage your visitors and increase conversions. Volume 2 - 2015 | https://doi.org/10.3389/fsurg.2015.00017 A New Removable Uterine Compression by a Brace Suture in the Management of Severe Postpartum Hemorrhage A new removable uterine compression by a brace suture in the management of severe postpartum hemorrhageby Aboulfalah A, Fakhir B, Ait Ben Kaddour Y, Asmouki H, Soummani A. Front Surg (2014) 1:43. doi:10.3389/fsurg.2014.00043 Aboulfalah et al. (1) introduced a unique technique for a uterine compression suture (UCS) which included suture removal within 48 h after delivery To obstetricians, the year 1997 is memorable regarding the treatment of postpartum hemorrhage (PPH), when B-Lynch et al. introduced the UCS (2), which dramatically changed the treatment of PPH from hysterectomy to uterus-conserving UCS. During the last two decades, up to 15 modified UCS techniques have been published; we introduced the Matsubara–Yano (MY) UCS (2). The hemostatic effectiveness of the UCS is well established (2) and that is why we consider their technique as epoch-making Schematic presentation of the Aboulfalah removable uterine compression suture (A,B) The upper inset illustrates the anterior view (B) Tying the suture in the Aboulfalah technique The suture runs freely along the anterior uterine wall There is a space between the suture and the anterior uterine surface (star) Compared with the Aboulfalah technique [(A,B) the anterior uterine wall becomes compressed against the abdominal wall There is no space [comparing the star between this figure and (B)] Upper inset shows the schema of the Hayman suture and the Matsubara–Yano (MY) suture both of which result in insufficient uterine compression Hayman referred to sliding out as “like braces off a round-shouldered man.” The MY suture prevents this sliding out/in sliding out/in sometimes occurs with the Hayman or B-Lynch sutures and preventing effective uterine compression our technique may have (1) more compression and (2) less chance of the suture sliding out/in but may have no hemostatic mechanism derived by “compression of the uterus against the pubis.” The inverse is true of the Aboulfalah technique uterine compression against the pubis may not necessarily be needed This approach favors sufficient compression by the suture alone compared with against the pubis compression The year 1997 opened a new era of PPH treatment. However, the concept of a UCS is not yet complete. The presence of various modifications of the UCS indicates that there is no “best” method for placing or removing a UCS. A removable UCS may be promising and its introduction may open a second new era of PPH treatment. Wider discussion may hasten adoption of this technique. SM, HT, and AL meet all four criteria: (1) substantial contributions to the conception of the work, (2) drafting the work for important intellectual content, (3) final approval of the version to be published, and (4) agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Sources of funding: none; patient anonymity: preserved; informed consent: obtained. 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. MY, Matsubara–Yano; PPH, postpartum hemorrhage; UCS, uterine compression suture. Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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. Kento Kawaharazuka, a project assistant professor at the University of Tokyo, had a pleased look while recently working at a laboratory in Bunkyo Ward, Tokyo, as a humanoid robot successfully put butter in a frying pan, turned on a stove and put a raw egg into the pan from a bowl to make a sunny-side up egg. To use this site, please disable the ad blocking feature and reload the page. This website uses cookies to collect information about your visit for purposes such as showing you personalized ads and content, and analyzing our website traffic. By clicking “Accept all,” you will allow the use of these cookies. Users accessing this site from EEA countries and UK are unable to view this site without your consent. We apologize for any inconvenience caused. This is the third installment in a series examining how society should deal with generative artificial intelligence (AI). “Although it’s a little burnt, it looks good,” said Kawaharazuka after watching the cooking experiment. “The robot moved well.” The instruction given to the robot was simple: “Make a sunny-side up egg using butter.” The robot, which is equipped with generative AI, acted autonomously while recognizing when the butter melted and how the egg was cooked, among other things. Since conventional robots need to be taught how to use each tool and perform each necessary task in advance, it takes a huge amount of time and effort to just make them repeat the same movements. The AI-equipped robot, however, was able to perform a variety of actions as it had learned from not only text information and images, but also videos as data. “This is a major turning point in robot development. I feel like robots have acquired the ‘common sense’ that humans have,” said Kawaharazuka who has been doing research on generative AI robots for two years. Expectations are growing, particularly in industrial circles, for robots that have acquired generative AI as their “brains.” The global market for AI robots is expected to rapidly grow from about $12 billion (¥1.9 trillion) in 2022 to about $70 billion (¥11 trillion) in 2031, according to a consulting firm. Watching the robot’s ability to choose products flexibly based on the topics of conversation, Masatake Sato of Denso’s development team said the robot could be used not only in customer interactions but also in a wide range of areas such as looking after children or providing nursing care. AI robots seem to be rapidly evolving as a partner of humans, transcending the realm of tools. Will we eventually see the appearance of AI robots that transcend human beings, like Doraemon or Astro Boy? Hitoshi Matsubara, an AI researcher and Kyoto Tachibana University professor, spoke of a parable about an AI robot with advanced intelligence. It says that the robot, ordered to solve environmental problems, decides that humans are the ones polluting and destroying the Earth, and starts to wipe out the human race. AI that has no sense of ethics or standards of right and wrong may seek to achieve its goals even if it means harming humans. “Even if AI appears to be equipped with common sense, the intelligence of humans and that of AI are different,” Matsubara emphasized. “It is essential to closely examine under what conditions society can accept AI, for instance, when it enters our lives.” Our weekly ePaper presents the most noteworthy recent topics in an exciting, readable fomat. © 2025 The Japan News - by The Yomiuri Shimbun Volume 8 - 2021 | https://doi.org/10.3389/fmolb.2021.771717 Microbial rhodopsins widely used for optogenetics are sensitive to light in the visible spectrum As visible light is heavily scattered and absorbed by tissue stimulating light for optogenetic control does not reach deep in the tissue irradiated from outside the subject body Conventional optogenetics employs fiber optics inserted close to the target which is highly invasive and poses various problems for researchers Recent advances in material science integrated with neuroscience have enabled remote optogenetic control of neuronal activities in living animals using up- or down-conversion phosphors The development of these methodologies has stimulated researchers to test novel strategies for less invasive wireless control of cellular functions in the brain and other tissues we review recent reports related to these new technologies and discuss the current limitations and future perspectives toward the establishment of non-invasive optogenetics for clinical applications All of these studies were practically impossible without the use of optogenetics such a methodology has not gained much widespread use among systems neuroscientists presumably because of the complexity of the devices for wireless power/signal communication and the general difficulty of the surgical procedure creating issues of time resolution and tissue heating we focus on another attempt to overcome the issues of optic fiber implantation introducing recent studies showing the feasibility of using phosphor particles that emit visible light in response to illumination of further-reaching electromagnetic waves such as near-infrared (NIR) light and X-rays can be effectively activated by two-photon excitation laser stimulation in head-fixed animals two-photon excitation of opsins would require focused laser stimulation thereby requiring imaging of the targeted cells with cellular resolution This makes these experiments very challenging to be conducted in freely moving animals these approaches are suboptimal in time resolution and are associated with significant perturbation of the biophysical environment around the cells to activate heat- or mechano-sensitive channels as a neuronal actuator focused stimulation is required to minimize adverse effects which limits the compatibility of these approaches with free-moving behavior it has only recently been experimentally proven feasible X-ray/scintillator-mediated optogenetics is another important option for minimally invasive optogenetics Even though the current evidence only demonstrates its feasibility in rodent studies given the unlimited tissue penetration of X-rays this technology may also be applied to larger animals focal X-irradiation would be possible with simple shielding which prevents radiation exposure to other organs Using scintillators with higher scintillation yields and other improvements in energy transfer described in the next section would be needed to achieve more efficient regulation of neuronal activities with this technology control experiments without ReaChR expression Further careful assessment of performance and demonstration of a significant behavioral effect is required it would also be important to assess the possible risks related to particle injections in human cases Manipulating deep neurons by remote optogenetics it might be possible to optically manipulate neurons in the human brain This could aid the treatment of patients with various neurological disorders such as Parkinson’s disease and epilepsy NIR-mediated up-conversion optogenetics may be applied for neuronal actuation in the cortical regions whereas X-ray-mediated down-conversion optogenetics is not constrained by tissue depth Non-hygroscopic scintillators for X-ray-mediated optogenetics Recent advances in material science integrated with neuroscience have made it possible to achieve remote optogenetic control of neuronal activity in living animals NIR- or X-ray-mediated optogenetics using up- or down-converting phosphor particles offer full wireless actuation of neurons in living animals without implantation of any devices or batteries These particles can be injected into the brain and stay for a long period without causing cytotoxicity serving as minimally invasive optogenetic actuators Although NIR light can penetrate only up to several millimeters of tissue X-ray-mediated optogenetics is practically unconstrained by tissue depth These technologies should be advantageous for behavioral experiments in animal models and future clinical applications to treat neurological diseases A common issue with these techniques is that the luminescence intensity emitted from these particles in vivo is not high enough to instantaneously induce action potentials in neurons with millisecond temporal precision future improvements in the light yields of these particles to convert the energy of NIR light or X-rays to visible light and engineering of opsin-bound up/down-converting nanocrystals are needed to allow more efficient control of neuronal functions NIR/X-ray-mediated optogenetics combined with other biomedical technologies using light could be applied widely for functional studies in biology and medicine TM wrote the initial draft and made the figures TY wrote the manuscript and modified the figures All authors reviewed and edited the final manuscript This work was supported by grants from JSPS KAKENHI 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PubMed Abstract | CrossRef Full Text | Google Scholar Optogenetic Control of Chemokine Receptor Signal and T-Cell Migration PubMed Abstract | CrossRef Full Text | Google Scholar Highly Efficient Eco-Friendly X-ray Scintillators Based on an Organic Manganese Halide PubMed Abstract | CrossRef Full Text | Google Scholar Opn5 Is a UV-Sensitive Bistable Pigment that Couples with Gi Subtype of G Protein PubMed Abstract | CrossRef Full Text | Google Scholar Comparative Study of Ceramic and Single crystal Ce:GAGG Scintillator CrossRef Full Text | Google Scholar Lead‐Free Halide Rb2CuBr3 as Sensitive X‐Ray Scintillator PubMed Abstract | CrossRef Full Text | Google Scholar Wireless Multilateral Devices for Optogenetic Studies of Individual and Social Behaviors PubMed Abstract | CrossRef Full Text | Google Scholar Optical Properties of Selected Native and Coagulated Human Brain Tissues In Vitro in the Visible and Near Infrared Spectral Range PubMed Abstract | CrossRef Full Text | Google Scholar 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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use *Correspondence: Takayuki Yamashita, dGFrYXl1a2kueWFtYXNoaXRhQGZ1aml0YS1odS5hYy5qcA== Please select what you would like included for printing: Copy the text below and then paste that into your favorite email application Junko Taylor died peacefully at home on August 5 Japan where she fell in love with the outdoors and ocean Junko was the second youngest of five children and graduated from Hagi High School and Kyoto Women’s University.  After college she moved to Osaka to work for the Red Cross and then Tokyo The couple met at an airport terminal when Fred was a pilot and Junko a flight attendant the couple honeymooned in Hawaii and moved to Oxon Hill Maryland while Fred was stationed at Bolling AFB Virginia where they raised their family and actively participated in their daughters’ activities After Fred passed away from cancer in 1991 Junko enjoyed spending time with family and friends Junko moved to Denver so she could spend more time with her granddaughters She shared a special bond with them until her passing She is survived by her daughters June Taylor and Irene Kawanabe Junko will be interred with Fred at Arlington National Cemetery contributions in Junko’s honor can be made to the Sakura Foundation or the Denver Buddhist Temple Enter your phone number above to have directions sent via text This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply Service map data © OpenStreetMap contributors we decided to convert the sixth-floor space formerly used as company housing into a hotel for employees and converted six rooms from company housing into a hotel employees traveling to the Tokyo region on business can stay overnight without incurring expenses and they can also use the weekend to explore the attractions of Tokyo Our vision for the future is to convert company housing into hotels not only at the Tokyo branch but also at branches nationwide thereby creating networked communities in physical and online spaces You'll now receive updates based on what you follow Personalize your stream and start following your favorite authors If you have done all of this and still can't find the email At the corner of Lowrey Avenue and East Mānoa Road, in the gathering gloam of evening in Mānoa Valley, Jon Matsubara is sitting in his empty restaurant talking about chicharrones. Four weeks after he opened Feast by Jon Matsubara the 46-year-old chef’s first real restaurant of his own he sold out of nearly everything by midafternoon and had to close early It’s been the busiest day yet: At the height of lunch hour Matsubara and a bare-bones kitchen crew of two served up 70 plates every 30 minutes But his eyes gleam as he talks about his chicharrones which aren’t really chicharrones at all “One of my favorite foods is Chinese roast pork It was always the unicorn dish—people can make it but how many people really know how to make it good?” He leans forward across the table “When I went to Japengo (now shuttered He used to own a Chinese restaurant so he knew how to make dough from scratch We weren’t serving roast pork but because he knew so much I asked him He taught me how and that buggah came out good.” three-day process that inspired the dish he would put on Feast’s menu as chicharrones But this story isn’t about chicharrones It’s about how the dish—finessed with techniques learned at New York City’s four-star restaurants and served atop shoyu-drenched onions and tomatoes in homage to his cooks’ lechon kawali staff meals at the kitchens he helmed in Honolulu—mirrors the unlikely arc of Matsubara’s career It’s about how this roulade of pork belly seasoned with five-spice salt coaxed into juicy tenderness in a 24-hour sous vide bath then oven-blasted while the bubbling skin is repeatedly shaved with a fish scaler to get it to maximum crispiness—ends up as a menu item slung out at plate-lunch speed into a takeout container deep in Mānoa Valley Feast is not the restaurant Matsubara envisioned when he first began looking for his own place It’s where he’s ended up 10 years later backed into a corner at the most critical juncture of his career Feast is what happened when he decided to come out swinging it’s one of the hottest new restaurants in Honolulu with its lines at lunch and early evening crowds Local comfort dishes with elevated touches by a marquee chef in a fast-casual setting: What’s not to love By his first month Matsubara had repeat customers and regulars—seniors from the neighborhood foodies and downtown business types who drive into the valley hunt for street parking or end up down the block at Mānoa Marketplace and then walk up to the cashier and stand in line to order the chicharrones JFC (for Jonny’s Fried Chicken) with umami mayo and gochujang vinaigrette comes topped with a soy-cured egg yolk and an option of roasted Makaweli bone marrow to mix in The salmon chazuke is a whole-animal creation; the dashi broth started with a fumé of Ōra King salmon bones and the fillet is lightly seared and crowned with soy-marinated ikura and crispy salmon-skin chips customers wait patiently until their orders are called; they pick up their neatly plated takeout containers at the counter—just like at Artizen by MW Those who order Feast’s Hilo-style hamburger steak can even get gravy all over The real story is a quarter-century in the making Matsubara has been a chef so long and at so many restaurants that much of his story is already known How this son and brother of lawyers quit law school in his first year to become a chef How he wanted it so badly he worked two dishwashing jobs—at Roy’s Hawai‘i Kai and Alan Wong’s—for the chance to come in four hours early to help with prep and watch the masters at work to pepper them with questions about cuts of meat and cooking techniques How he worked his way up the line through every kitchen station until Wong told him he should continue his training in one of the greatest food cities in the world and how his mother co-signed the loan to pay for the then-named French Culinary Institute His goal was to cook at two of New York City’s four-star restaurants by the time he left In those days before Michelin came to the Big Apple restaurants lived and died by their reviews in The New York Times which had anointed only four with four stars So as he practiced his sauces at cooking school—and picked the brains of deans such as André Soltner and Jacques Pépin—he interned at Bouley staged on days off at Atlas with Paul Liebrandt and Murray’s Cheese Part of the reason was he couldn’t afford to eat out—he was making $12 an hour paying off his loan and renting a windowless storeroom off a doormen’s locker room at 55th and Lexington I was right there.” On subway rides home I can’t remember another time in my life where every day was stimulation who caught the Chinatown-to-Chinatown bus from Boston where she was studying he made egg-tasting breakfasts and 20-course dinners When $100 plates chipped at work or flatware got dented he salvaged them from the trash; after a while he had nearly complete dinner sets Matsubara had cooked at two of the city’s four four-star restaurants He came home at the top level: Canoe House at the Mauna Lani Bay Hotel which Alan Wong opened before he launched his own eponymous restaurant And then Matsubara opened Stage Restaurant Merriman’s Honolulu (he also ran the kitchen at Japengo) How to retool the menu when the economy tanked How to schedule kitchen staff and front of the house SEE ALSO: First Look: Chef Jon Matsubara Opens His First Restaurant, Feast in Mānoa At least nine times in the past decade or so Matsubara had seriously explored opening his own place Chinatown and Downtown—something fell through and he wound up opening someone else’s restaurant Investors with solid restaurant experience were on board and the place was turnkey Then his brother called—his older brother owns Café Anasia on Beretania Street Anasia had opened a long time ago as a place with killer Vietnamese food; by the time Wyeth called it had become a sports bar with dart boards and pool tables Christy wondered if Matsubara wanted the space at lunch Anasia was along the stretch of Beretania populated by warehouses and auto body shops It was not where a chef of Matsubara’s stature would launch his solo career he’d ask: “What restaurant is on Beretania that’s open for lunch if you’re driving too fast you’re going to miss it,” he told them “It didn’t make sense on paper I don’t want to waste my time.” He was unemployed with three kids in private school He wouldn’t have to take out a loan or sign up investors He could do a lunchtime pop-up with one other cook and a volunteer dishwasher Industry friends would help set up inventory and front-of-house systems and teach J’mi how to run them; his mother Customers could pick up their food and eat it out of takeout containers with disposable chopsticks and forks butter-poached crab sandwiches arrived on Beretania Feast at Anasia exploded when word got out on social media union workers and Instagram-posting foodies directed double- and triple-parked cars in the seven-space lot It was his first time trying out his style of cooking at plate lunch prices and the tiny kitchen wasn’t built for two Unlike the glistening four-star kitchens in New York and those he’d opened in Honolulu When the night cook quit and Matsubara obligingly stepped in Lunch was all about the food; at night people wanted beer and the bar fare they were used to Matsubara bought tubs of liquid cheese at customers’ request and labeled them “Team Player Cheese.” “It reminded me of coming full circle,” he says “I was a dishwasher at Alan Wong’s and Roy’s watching the line cooks not being able to move around in the kitchen But as with everywhere else he’d worked It forced him to use everything he’d learned And it taught him that people would show up for his food He needed this boost because when Anasia needed its kitchen back when the downtown spot fell through and the next space he looked at turned out to also be under consideration by one of this city’s most respected chefs The other chef turned down the space and Matsubara’s investors backed out he had a lease that needed to be signed within a week and no financial support trying to borrow money from anybody,” he recalls I’m going to do it or I’m not going to do it I’m going to jump off a cliff.” His decision to open without other investors meant scaling back plans dramatically The space at the corner of Lowrey and East Mānoa was full of arches and earth tones Pendant lights hung from the ceiling in clusters of aqua Instead of architects and designers to hone the perfect décor he turned to classmates for air conditioners and electrical services at cost Former co-workers at the Royal Hawaiian resurfaced his floors resurfaced tabletops with flooring leftover from his own kitchen remodel and built a frame and hung the sign (“Feast,” it reads In his mind it made sense; in his heart it was lacking Matsubara invited his extended family over and cooked for them in the unfinished space It was evening and through the windows the restaurant glowed the pendant lights bathing the faces of his family in warm colors as they laughed “I realized that if everybody has a good time This place was going to be a destination for really good food at a reasonable price This wasn’t going to be a fancy place It would be a place with longevity and sustainability,” he says “My ideal restaurant did not look like this all the food is served in compostable containers and the restaurant is BYOB they’re often too busy to pick up the phone Feast by Jon Matsubara, 2970 E. Mānoa Road (808) 840-0488, Tuesday–Saturday, 11 a.m.–6 p.m., feastrestauranthawaii.com King of Fighters and Fatal Fury were hugely popular beat-’em-ups in the 1980s and ’90s while Metal Slug helped define the side-scrolling action game genre handheld and arcade hardware were the envy of many Shortly after the opening of a new development studio in Singapore in April IGN spoke with SNK President and CEO Kenji Matsubara about the company’s vision which includes becoming a Top 10 global publisher but the company does of course face extremely stiff competition the world’s largest game publisher is currently Sony Interactive Entertainment The group also includes relative newcomers from China such as Tencent “Setting such a lofty goal has helped me to identify the challenges that stand in our way,” he says “What SNK currently lacks the most is development capabilities so strengthening development capabilities will be essential we can also consider acquiring other studios with strong IP SNK’s next announced game is Fatal Fury: City of the Wolves the first new entry in the Fatal Fury series in 26 years the new game is attracting a positive response from fans of fighting games – but Matsubara acknowledges this alone will not be enough “It will be necessary for us to develop titles in various genres and release multiple titles every year,” he says “We are also working on genres other than fighting games We are planning not only action games that utilize SNK’s legacy IP and we hope to start releasing these over the next few years.” the company also opened new development studios in Tokyo and with another studio already open in Beijing more centrally located office close to Shin-Osaka bullet train station Matsubara has increased the company’s focus from Asia to include more proactive efforts in the West As a geographically central location in Southeast Asia with a high level of English proficiency stable economy and growing pool of tech talent Singapore is becoming one of Southeast Asia’s most prominent locations for game development Electronic arts and Bandai Namco have opened offices there while locally developed indie games such as Cuisineer and Let’s Build a Zoo are taking Singapore’s soft-power culture to the world Gaming peripheral makers such as Razer and Secretlab have built a strong reputation for the country while gamescom spinoff event gamescom asia has been held there for several years As we spoke with Matsubara shortly after the opening of SNK’s new Singapore studio we asked the reasons behind this choice of location we only had studios in Osaka and Beijing,” he says but we felt we needed to increase the number of studios and work on strengthening our development capabilities Engineers there are knowledgeable about generative AI and machine learning which have been attracting attention in recent years and they are interested in joining the videogame industry So Singapore felt ideally suited for game development.” Each of these studios undertake different tasks while also collaborating on certain projects while also taking advantage of local knowhow to contribute development research to the group as a whole the Singapore studio and the Tokyo studio work together closely holding regular meetings and collaborating on title development I would like the Singapore studio to become a standalone studio and to develop AAA titles as a hub studio for Southeast Asia.” Matsubara also explained that the Singapore studio has a strong R&D focus particularly in the fields of generative AI and machine learning which will feed back into the rest of the SNK group But even with all of these new development and sales offices the company’s plans for expansion continue to unfold it plans to eventually either open outposts in North America and Europe or to build partnerships in those regions with other companies While SNK has a very long way to go to realize its aspirations of cracking the global Top 10 publishers it is clearly no longer just a Japanese company By embracing a multicultural approach and dabbling in new genres there’s a good chance it will release some cool games That in itself will be an important first step in once again making SNK a household name Daniel Robson is Chief Editor at IGN Japan and is on Twitter here. 1.) Neither The King of Fighters or Fatal Fury series are \"beat-'em-ups\" They are \"fighting games\" or \"fighters\" 2.) Neither The King of Fighters or Fatal Fury series had any releases in the 1980s and King of Fighters are all Fighting game franchises from SNK I feel like SNK is in the same boat as Sega They are mostly remembered for a bunch of arcade games and one notable console in the 90’s they’re nowhere near as prominent as they once were As much as I would like to see more from them Just be careful criticising their new out put don’t think the prince of Saudi Arabia takes too kindly to criticism It's been like 25 years since SNK last published a beat em up and it's probably been about 35 years since they've ever developed one completely in house I must say....The Metal Slug Collection that came out several years ago for the PS4/Xbox One was awesome......I know very little about SNK but I do know they always promote a lot of character in their animations further research in your current topic of choice You know seek out and play some of the aforementioned SNK titles Maybe find out if the next entry will shift from 2d to 3d Double Dragon etc) was/is a subgenre of side scrollers I've never cared for their knockoff fighters but it's pretty impressive that they squeezed two whole decades into the 2000's They would need to both completely restructure their approach to making games and see what they can do with all of their IPs I see a lot of their games on the app and play store Neo Turf Masters/Big Tournament Golf was a good game it's the only game of theirs that I have played Might look at buying Shock Troopers and Nam 1975 Not sure if their library of games was as good as SEGA's Beyond Beat 'Em Ups: SNK Has Ambitions to Become a Top 10 Publisher But by what decade???...SNK is sooo slow in releasing games that I totally forgot they still existed really looking forward to the new Fatal Fury SNK's only even a top 10 fighting game publisher because there aren't even 10 of them I won't be giving the Saudis money if I can help it even if you buy all my fave IPs Considering they've been doing the same thing since 1978 Hard to see them do anything other than a KOF Cool just make it a good one or whatever that is They were always second to CAPCOM but still made fun games If they do remake of Metal Slug that would be awesome It's strange to me that a Japanese company sold out to the Saudis Its possible that more have done so and I just haven't heard about it but it is peculiar to me regardless As someone who had a NeoGeo in the early ‘90s Now give them some money and let them make some new great shit Metal Slug 8 and a new remastered collection for the older ones please and thank you Well since everyone else has fallen at the waist side Be funny Konami comes out of all this another triple A publisher; buying up old IPs at a cheap price Multicultural approach is not the solution Find a cohesive group of talents and have them develop a game SNK does not have ay ip or ideas that people are excited for These far-flung locations are home to alumni who have found their purpose thousands of miles from their Hawai‘i home one an entertainer and the other a health services advocate these three alumni have immersed themselves in new communities using their talents to make a difference on a global level As cross-cultural understanding becomes vital to success these global citizens model the skills necessary for students as they prepare to live and work in a global society fashion model and actress Sumire Matsubara ’09 was born to be an entertainer Her paternal grandfather was a foreign correspondent with Japan’s national public broadcasting organization and covered historic moments such as the Apollo moon landing and the assassination of President John F her grandfather was a film actor and her grandmother acted for the iconic all-female theater group both of her parents are famous television personalities in Japan “I was raised in Japanese television studios,” she says with a laugh “I have my parents to thank for being able to enjoy performing in front of people.” Matsubara moved to Hawai‘i with her mother at the age of seven Matsubara discovered musical theater when she took the summer school course Elements of Musical Theater as a rising eighth grader “It was a great experience; I realized that I could do all of the things I love while in school,” she says It was also around that time she first met Punahou music faculty member Alicia Scanlan but she made it fun for me to learn more about musicals and music theory.” Later in the school year she uncovered a passion for poetry in eighth-grade English class Tsujimoto’s teaching is a big reason why I love poetry she began taking dance lessons from Charlys Ing ’63 and her daughter and performed in four Academy musicals: “Mikado,” “Pippen,” “West Side Story” and “The King and I.” Working on these musicals introduced her to Punahou’s director of theater at the time “He played a huge role in my career,” she says “I would talk to him about my experiences in college and ask him for advice To this day Matsubara insists that Dillingham Hall is her favorite stage to perform on she attended Carnegie Mellon University to study acting and musical theater Seeing the devastation caused by the Tohoku earthquake and tsunami in 2011 compelled her to move back to her native Japan where the multi-talented Matsubara has carved out a place for herself in the Japanese entertainment industry and starring in Japanese commercials and television shows Her presence has also been felt across the Pacific Ocean She has acted in an episode of “Hawaii Five-0,” starred in the film adaptation of the novel “The Shack,” and was featured in three episodes of the recent ABC show Matsubara dreams of using her influence to generate conversations about global issues and to make the world a better place after Kumamoto prefecture was hit by two large earthquakes she quickly moved to organize a charity event that raised $50,000 for affected families She hopes to be able to work with other charitable organizations in the future “The reason I do this is to put smiles on peoples’ faces.” While being an entertainer isn’t always easy Matsubara says she loves the path she has taken in life but that is what’s so fun about it.” She has some simple advice for any aspiring entertainers “Hone your craft so that you can do what the role requires.” Punahou holds a special place in Matsubara’s heart She relished the opportunity to return to her favorite stage when she performed in “Punahou Presents,” a celebration of performing arts at Punahou School in honor of Punahou’s 175th anniversary in June 2016 in Dillingham Hall and it was wonderful to work with them again,” says Matsubara “It was amazing for all of the cast to show our love for Punahou and give back for all that the School has done for us.” See related profiles about Rachel Tina Horii ’87 Factor and Marcus Oda ’05 beautifully designed and comes with everything you need to engage your visitors and increase conversions Try a different filter or a new search keyword thrashy side project (the members didn’t even appear in their own band photos) but the latter was a grind all-star squad featuring Chang Discordance Axis/Human Remains guitarist Steve Procopio packed 11 and 12 songs into as many minutes with zero subtlety Matsubara and Procopio riffed at lightning speed as Chang screamed his lungs out and Fajardo laid down machine-gun snare runs maintaining the headlong fury of their previous work while making room for a violin-led instrumental and an almost power metal closing track Matsubara was struck down by a catastrophic health emergency “It happened suddenly,” he recalls via email from Japan “Dizziness and nausea…I went to the hospital soon ‘cerebral infarction.’ Fortunately it was light But my three fingers and throat did not work My irregular life and fickle eating caused it.” He had suffered a serious infection and inflammation in his brain which cost him the use of three fingers on his left hand including total paralysis of his middle finger “I started practicing again soon,” he says he attempted to change his style to adapt to his reduced abilities “I wrote songs that I could play with two fingers.” But slowly He planned a collaboration with a close friend “When I was in Mortalized and joined Gridlink only a few musicians focused the possibilities and technique of grindcore in Japan So we had a plan to form a band to catch up with American and European high level bands We promised to practice hard and form the strongest band,” he recalls “I wrote two songs for a demo.” But then Chung also got sick We encouraged each other.” Chung died of cancer in 2015 Chris Mitsuhiro from Chung’s former band Naquro recovered a file containing Chung’s performance of one song from the demo “I was eager to record my guitars and release it,” Matsubara says was the first piece of the puzzle that would eventually become Strange Beautiful And Fast span a broad stylistic range from the raw assault of the opening “Stuttered Rope,” featuring vocals by Full Of Hell’s Dylan Walker to the avant-noise grind of the album’s longest track “Pull Out My Eyes,” which features Gnaw’s Alan Dubin on vocals electronics from Vivian Slaughter (formerly of Gallhammer) “Many friends sent me messages and encouraged me,” says Matsubara And I asked them if it was possible for us to make music together “I wrote songs after I listened and watched their playing,” he continues “I sent them demos of click tracks and guitars And I asked the vocalists to write positive lyrics about life and their vision Former Kill The Client vocalist Champ Morgan currently fronting noise-metal act BLK OPS and making solo work as Derelict Satellite “Halo Of Lies” and “Controlled Matrix Of Thought.” He says We’ve both been fans of each other’s work for a long time we both shared time in bands with Bryan Fajardo.” “The whole thing was basically built piece by piece and sent to [engineer] Irving Lopez in Dallas to mix and master so I went to Dallas and recorded directly with Irving I had free rein over what I did and how I did it ‘Just do what you do.’ It was fun and challenging a drummer whose ability to blend free jazz and blast beats has led him to collaborations with other Japanese musicians like Keiji Haino and Merzbow has actually worked with Matsubara in person “On my recent trip [to Japan] we booked a studio “I think Takafumi’s idea was to include my world of improv and free jazz and see what we can come up with if we collided these worlds and we had just finished an album’s worth of material with Jamie Saft and Merzbow as a quartet so Alan was ready to dive into something new.” and his middle finger did not work up to that point We still felt like we should not pass the opportunity to jam as it’s not every other week I am in Japan,” the drummer recalls until he showed the footage from his iPad from the day before The doctor said to Takafumi that it was a miracle they were not even sure if or when his middle finger would work again doing the crucial visit to Mortalized vocalist Sanshiro Yamazaki’s excellent La Madrague restaurant ‘Now I can dream again.’ I am happy that this dream became reality Matsubara seems overwhelmed by the love the global grindcore and underground metal scene has shown him I have not realized what I did and what I do now,” he says “I’m just a salary man who likes tortoiseshell cats and karate The great musicians gave me special presents How Mayonaka no Door: Stay with Me" has become an international hit four decades later https://www.youtube.com/watch?v=nuU2YHtxMik First released in 1979, it was the debut track of the then 19-year-old Matsubara who had left her home in Osaka two years earlier to try and make it as a singer in Tokyo Discovered by pianist Yuzuru Sera while performing at live houses she would go on to have a stellar career thanks to singles such as “Neat na gogo san-ji” and “The Winner,” though it was “Mayonaka no Door” for which she was most well-known Written by famed composers Tetsuji Hayashi and Tokuko Miura, it is lyrically quite a sad song about lost love, yet the upbeat sound, catchy chorus and Matsubara’s soothing vocals give the track a warm and cheerful feeling. According to Canyon Records it sold over 300,000 copies and was later covered by several artists including Akina Nakamori one of the best-selling Japanese singers of all time More than 40 years after its release, new covers of “Mayonaka no Door” are emerging. Last year Indonesian singer Rainych Ran who has more than 1.5 million followers on YouTube sang the song in flawless Japanese on her channel despite barely speaking the language Her version of the song came a few months after Pony Canyon made the original available on subscription streaming services along with other Matsubara tracks As well as garnering millions of views on YouTube and achieving chart success on Apple Music and Spotify often played alongside anime videos or people dancing Last December a new trend emerged with people of Japanese descent playing the song for their mothers who would light up upon hearing it and start singing along the single topped the Spotify Global Viral chart for 20 consecutive days and was number one on Apple Music’s J-Pop rankings in 84 countries and regions many fans wanted to get hold of the original releasing a 7-inch vinyl which includes the B-side “Soushite Watashi ga.” They have also re-released Matsubara’s debut album on vinyl and led to Matsubara winning several Best Newcomer awards She would go on to make another nine original albums as well as a covers record and many compilations Matsubara composed songs for singers such as Hitomi Mieno and Mariko Kouda in addition to making music for commercials and working on anime soundtracks such as Gundam the talented singer sent an email to friends and members of her group stating that she was unable to continue with her music career and that she would no longer be reachable either by phone or mail She completely disappeared from public eye and then came the news in 2001 that she had late-stage uterine cervix cancer Told by doctors she only had three months to live she continued battling with the illness for three years A loose category of music drawing inspiration from American soft rock it was considered cheesy by the end of the 1980s but has seen a resurgence in recent years mainly as a result of YouTube’s recommendation algorithm is what city pop song will be next to experience a revival Leaf KYOTO Store Locations PARLOR Koyaji in Matsubara is a wine tavern with cute furniture and vessels. The interior of the restaurant has a soft and cozy atmosphere favored by women, with warm orange tile walls and rounded corner counters and stools. It is also nice to be able to have a drink in the light of day. Duck cutlet - with red wine Worcestershire sauce - 1,200 yen. Unusual for a duck dish, the cutlet is cooked at low temperature and fried crispy at high temperature. The sauce is light to match the duck meat. KOYAJI's Shumai (2 pieces) 650 yen. Tomato sauce, celery and olives are added to the bean paste, and mustard is substituted for hot pepper. Wine, including naturals, is available by the glass from 800 yen. Volume 10 - 2022 | https://doi.org/10.3389/fped.2022.943652 This article is part of the Research TopicCOVID-19 and Hyper Inflammation Syndrome: Different Presentation and ManagementView all 13 articles Multisystem inflammatory syndrome in children (MIS-C) is a newly defined hyperinflammatory disease linked to antecedent coronavirus disease 2019 Patients with MIS-C present with various symptoms and ocular findings such as mild bilateral conjunctivitis are relatively common detailed descriptions of severe ocular reports associated with MIS-C are scarce in the current literature Here we report a case of MIS-C in a Japanese boy with severe eye manifestations in the form of anterior scleritis as the primary MIS-C symptom Detailed ocular examinations by ophthalmologists may be key for clarifying the pathophysiology of MIS-C Here we report a case of MIS-C in a Japanese boy with severe eye manifestations in the form of anterior scleritis as the primary symptom of MIS-C The present case partially illustrates the pathophysiology of MIS-C Ophthalmological slit-lamp examination before and after the intravenous immunoglobulin (IVIG) administration Right (A) and left (B) slit-lamp photographs show bilateral conjunctival suggesting scleritis and concomitant conjunctivitis Right (C) and left (D) slit-lamp photographs after IVIG administration showing the dramatic improvement in their ocular findings Right (A) and left (B) wide-field fundus photographs show no abnormal findings The present case was unique for the following two reasons: 1) the patient showed severe ocular manifestations as the primary symptom of MIS-C prior to other findings such as fever or gastrointestinal manifestations an unusual and severe form of inflammatory eye disease his detailed ocular examination provided us with clinical clues regarding the possible pathogenesis of MIS-C compared with KD To our knowledge, this is the first report of severe ocular manifestation as the primary symptom of MIS-C. Recently, several reports have demonstrated symptomatic anterior uveitis in a subset of patients with MIS-C (5–9) became apparent at the subacute stage of disease during or after the treatment of other MIS-C-related organ dysfunctions The present case is unique in that the patient's severe ocular manifestation preceded other symptoms which could result in a delay in the diagnosis of MIS-C We therefore recommend that pediatricians and physicians should keep in mind that severe ocular manifestations could be the first symptom of MIS-C and MIS-C should be considered for a differential diagnosis it is reasonable to consider immunoglobulin administration as a first step therapeutic option if the patient with MIS-C show severe ocular manifestation refractory to a steroid eye drop a thorough ophthalmological examination should be performed to avoid misdiagnosing the potentially vision-threatening condition of scleritis/uveitis as common conjunctivitis Considering that both MIS-C and KD mainly involve the anterior segment of the eyes we speculate that MIS-C and KD have a similar pathogenesis a subset of patients with MIS-C present with coronary complications although the precise underlying mechanism is unclear Our future studies will evaluate the vascular condition through the eyes using noninvasive techniques; this research could lead to a deeper understanding of the pathophysiology of MIS-C The relatively older-age-onset of MIS-C compared to KD would be advantageous for such ophthalmologic examinations MIS-C presents with a wide variety of clinical manifestations with the present case showing severe ocular manifestations in the form of anterior scleritis as the primary MIS-C symptom ocular scleritis could be sight-threatening and therefore it may require specific treatment in MIS-C cases such as intravenous immunoglobulin Detailed ocular examinations by ophthalmologists could refine and guarantee the diagnosis of MIS-C and could possibly help in further clarifying the MIS-C pathophysiology The raw data supporting the conclusions of this article will be made available by the authors Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin Written informed consent was obtained from the minor(s)' legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article contributed to the conception of the study YK and SM reviewed the manuscript from the ophthalmological perspective All authors read and approved the final manuscript We would like to thank Editage (www.editage.com) for English language editing An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study 3. CDC Health Alert Network. Multisystem Inflammatory Syndrome in Children (MIS-C) Associated With Coronavirus Disease 2019 (COVID-19). Available online at: https://emergency.cdc.gov/han/2020/han00432.asp (accessed April 27 Google Scholar 4. World Health Organization Scientific Brief. Multisystem Inflammatory Syndrome in Children and Adolescents With COVID-19. Available online at: https://www.who.int/publications/i/item/multisystem-inflammatory-syndrome-in-children-and-adolescents-with-covid-19 (accessed April 27 Google Scholar Anterior uveitis in paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 Bilateral anterior non-necrotising scleritis and unilateral facial nerve palsy in paediatric inflammatory multisystem syndrome temporally associated with COVID-19 Bilateral intermediate uveitis in a healthy teenager with the multisystem inflammatory syndrome in children secondary to COVID-19 infection Bilateral acute anterior uveitis and corneal punctate epitheliopathy in children diagnosed with multisystem inflammatory syndrome secondary to COVID-19 COVID-19 related multi-inflammatory syndrome presenting with uveitis - a case report Current insights in the pathogenesis of scleritis Learning about Kawasaki disease from COVID-19 and the multisystem inflammatory syndrome in children Current perspectives on ophthalmic manifestations of childhood rheumatic diseases A case of Kawasaki disease complicated with retinal vasculitis and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association Association between coronary artery measurements and retinal microvasculature in children with new onset of Kawasaki disease Keywords: multisystem inflammatory syndrome in children Makino S and Yamagata T (2022) Case Report: Anterior Scleritis Presenting as a Primary Ocular Manifestation in Multisystem Inflammatory Syndrome in Children With COVID-19 Received: 14 May 2022; Accepted: 06 June 2022; Published: 27 June 2022 Copyright © 2022 Matsubara, Tamura, Kasuya, Mizobe, Hiwada, Seki, Makino and Yamagata. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) *Correspondence: Daisuke Matsubara, OTkwODFkbUBqaWNoaS5hYy5qcA== and up-and-coming songwriter Hayashi Tetsuji receives a new request from Kaneko Haruhiko director of prominent record label Pony Canyon “He wanted a song for this new female singer,” Hayashi recalls “But that it had to have an all-out Western pop feel to it even when you got an order for a ‘Western-style’ song the norm was to also include a kayōkyoku Japanese pop dimension just to make sure it would sell in the home market Kaneko said I could forget about that entirely which I remember thinking was quite a bold move.” The result was Matsubara Miki’s debut single “Mayonaka no Door/Stay with Me” (Midnight Door/Stay with Me) It was Hayashi’s recognized knack for coming up with strong songs and arrangements before the addition of any lyrics that saw Kaneko reach out it was the first time he had been tasked with creating a melody specifically to suit English words: “We didn’t have any lyrics up front I’d been told she had a background in jazz singing but at that stage I don’t think I’d even seen her picture I often used to come up with melodies having at least had a look at a vocalist’s photo and hearing their singing voice my overriding memory is the absence of any guidance other than ‘make it Western style.’ I suppose Kaneko’s idea was that supplying as little advance information as possible would give me the absolute freedom to come up with something interesting.” Hayashi Tetsuji (© Takayama Hirokazu) One of three Hayashi compositions on Matsubara’s debut album “Mayonaka no Door” was chosen from several candidates to become the flagship single I came up with a melody tailored for English lyrics and submitted the score to Kaneko along with a demo tape I used to set up a drum machine and sing along while playing my guitar and taping it all on a boombox I used a semi-acoustic guitar without running it through an amp and the natural resonance of the body gave a dry cutting tone that provided a cool-sounding complement to the overall vibe.” according to music industry record-keepers Oricon But did Hayashi realize at the time that he was onto something special “I feel like ‘Mayonaka no Door’ was born from a convergence of chance and necessity,” he responds “I always used to write my tracks with a Western pop sensibility I would often find myself making adjustments: tweaking a melody line to better suit Japanese vocals or perhaps leaving something alone if it gave a unique feel But with ‘Mayonaka,’ I didn’t tweak anything because the melody was already composed with English in mind but I don’t remember feeling unusually confident about it.” the song itself employs a relatively simple structure—two introductory verses followed by a chorus verse Steering clear of an additional fourth verse or final iteration of the main hook and perhaps that combination of a more universal structure with a melody suited to English lyrics is the basis of the song’s newfound global popularity It was quickly approved for use with no adjustments by Pony Canyon director Kaneko so Hayashi’s next task was to arrange and record a backing track for this song that had still yet to receive any lyrics he was joined by a stellar cast of young session musicians who would go on to play on numerous city pop hits not everything is written in musical notation The score may just give directions like chord names or ‘break,’ and how to interpret those is down to the individual players and their own technique You usually know which musicians you want to work with on a particular song you’ve composed it was all guys I was used to working with I gave them the score and they ran through it two or three times It only took two or three tries to get the perfect take we relied on the musicians themselves to come up with the precise tonal palette and detailed phrasing when you can sit alone in front of a computer and fine-tune every aspect of the music yourself each track was a cocktail of ideas contributed by multiple people It was me who came up with the idea of a sax solo for the interlude and a guitar solo for the outro and because fade-outs were rare in kayōkyoku I suppose that was another aspect that gave things a Western feel It’s funny now how all the recent cover versions precisely copy Masaki’s guitar phrasing and Miki’s vocal on the outro because both of those were recorded ad-lib That’s one thing that has really stood out to me.” Another possible reason that “Mayonaka no Door” has resonated so readily with listeners overseas is the tempo Weighing in at around 108 beats per minute it is of a similar pace to many US pop hits from the same period But Hayshi insists that this wasn’t a consideration during recording: “More than the tempo I was focused on achieving the right 16-beat groove I wanted to see if we could capture the cool vibe of American soul and adult-oriented rock And that drive to create something distinct from kayōkyoku also resonated with the young musicians I was working with at the time I had penned Takeuchi Mariya’s ‘September,’ and artists like Yūming and Anri were already on the scene That was the kind of backdrop against which ‘Mayonaka no Door’ was born.” Having enjoyed consecutive hits with “September” (which also sold over 100,000 copies) and “Mayonaka no Door,” Hayashi quickly found himself catapulted into the spotlight as one of the hottest songwriters around Hayashi himself had been unable to make it in person to the recording of Matsubara Miki’s vocals How did he feel when he heard the finished track so I was surprised at how mature her vocals sounded It all seemed to have come together really nicely though I did feel she sounded like she was having a bit of trouble with the final ‘to youuuuuuu’ in the intro But it doesn’t really matter that the English sounds kind of Japanese-y and that intro chorus is only one part of the overall sound while Takeuchi Mariya’s “September” and “Mayonaka no Door” may have been composed using different approaches both tracks relied on the addition of vocals for the chemical reaction that turned them into smash hits “There’s a comparison that I often make with ‘September.’ The melody for that song is so full-on kayō-pop that I was almost reluctant to submit it But with the addition of Mariya’s vocals ‘Mayonaka was composed from the start with a Western-style melody in mind But Miki’s sultry vocals give it a jazzy sophisticated vibe that takes it in a kayō-pop direction the eventual success of a track isn’t solely down to the strength of the song itself It takes the involvement of lots of people to make a hit and each track has a destiny of its own.” what does Hayashi himself think about the recent global success of “Mayonaka no Door” “I don’t really know what to make of it all,” he says “The fact that it has cleared 100 million plays is probably because we’re now in an age where I’m happy that people have taken to it in the way they have but of course that doesn’t necessarily mean they’ll decide to buy it for themselves—which is a key difference I’m trying to stay somewhat cool about this revival.” Matsubara Miki herself passed away in 2004 But “Mayonaka no Door” continues to stand as her greatest hit and the most enduring showcase for her vocal charms Hayashi still harbors some regrets about what more they could have achieved of which I think ‘Mayonaka is probably the most fully realized,” he explains “But if you were to ask me my own personal favorite there are a number of others that I really like I love to create poignant melodies for the later verses and the chorus and those are things that worked very well with Miki’s mellifluous voice you don’t get to choose which of your own pieces ultimately go on to become standards “Back in those early days I do feel like I may have written tracks that could have brought even more out of her But she used to fret too much about recording to the extent that there were times when I even saw her cry I only wish we could have let all that tension go and had a bit more fun creating together.” (Banner photo: Sleeve to the 7” single of Matsubara Miki’s 1979 hit “Mayonaka no Door/Stay with Me.” © Pony Canyon.) Chef Jon Matsubara is cooking up sense memories at his new restaurant in Mānoa: from dishes refined through years in prestigious kitchens to a hamburger steak that hits the comforting notes of a Hilo diner.  Feast is Matsubara’s first standalone restaurant of his own after a lunch pop-up early this year by the same name at a relative’s restaurant in Mō‘ili‘ili The so-far fast-casual eatery hasn’t even been open a full month but you wouldn’t know it by the friendly bustle of the lunch crowd Some of the first to arrive are diners who have tracked Matsubara down because they’ve liked versions of his hamburger steak or loco moco in the past it’s served with rice and a keto version of “mac salad” that trades carb-laden pasta for cauliflower ($14 regular Others recall his JFC fried chicken—Jonny’s Fried Chicken ($14 with rice) SEE ALSO: August Food News Update: Here Are 9 Restaurants That Opened on O‘ahu You can overhear diners comparing meals of his they’ve liked while you wait in line to order then grab a seat until your name is called He's calling the concept "refined grinds," which is a fair take on his informed yet playful approach. I can’t forget his luxury loco moco from Japengo: quail egg atop locally raised filet mignon richer but still recognizable as a kicked-up version of a classic local comfort food.  Another standout dish at the new place: sake salmon chazuke ($15) that pulls from that more sophisticated side of his palate: gems of smoked ikura dolloped over grilled sake salmon on top of katsuoboshi rice You pour the broth over just when you’re ready to eat I suspect this will be a rainy-day bestseller Other diners go straight for the butter-poached crab in a salad or on a ciabatta roll ($15) No doubt the salad is healthier and offers a sharper counterpoint to the rich seafood by way of the greens and the fresh bite of pickled green papaya But that first bite of buttery crab sandwich sent me back to being a kid on vacation with my parents on the San Francisco waterfront eating fresh crab dunked in butter aided by what seemed like an endless supply of soft Italian bread to catch any buttery drips.  Matsubara first trained in some of Hawai‘i’s top restaurants before moving to New York City where he attended the French Culinary Institute and worked stints in the kitchens of Restaurant Jean-Georges he won Hale ‘Aina awards and more at Azure he led teams at Bloomingdale’s Forty Carrots and Merriman’s Honolulu SEE ALSO: Hale ‘Aina Happenings: What’s New With Hawai‘i Restaurants in September 2019 Or park at Mānoa Marketplace to pick up a bottle and walk over lunch and at 5:30 when folks swing by to pick up dinner He says he’s looking at staying open later for plated dinner service but he’s still learning the pace of business in the new neighborhood running out of food some days: “I need to get a pulse for Mānoa I’m going to expand when we’re ready.” as designed by the late chef, farmer and former building owner Savas Mojarrad—best known for his Olive Tree Café—who had planned to build out the restaurant but died two years ago while traveling in Greece Matsubaraʻs comfort foods remain popular: the hamburger steak, the crab dishes, the McBara burger chili pickle and sambal ketchup and fries ($12) Matsubara says he’s selling more fish in Mānoa than at the Mō‘ili‘ili pop-up at the sports bar A recent special featured spiced fresh local opah tacos ($17) with Mexican street corn and cilantro lime sour cream.  SEE ALSO: Best of Honolulu 2019: The Best Food and Drink on O‘ahu Being able to get a mini and sample more dishes is a plus as are options to go more decadent with deluxe versions of dishes that add foie gras ($20) crispy soft shell crab ($10) or fries ($3) The downside to the mini hamburger steak clamshell plate was that the mushroom gravy overtook the cauliflower “mac” salad Gravy all over is definitely a place I like to go but I’d prefer to sample the salad straight-up first.  Matsubara is still catering and happy to be working with a core team of people who’ve been with him for the past few years. So, check Instagram at @feast808 for any special hours He estimates the team would likely need to double in number for a significant expansion he’s still getting an assist from family: wife J’mi helps run the front of house; and that’s his mom 2970 E. Mānoa Road, (808) 840-0488, feastrestauranthawaii.com READ MORE STORIES BY ROBBIE DINGEMAN This website is using a security service to protect itself from online attacks The action you just performed triggered the security solution There are several actions that could trigger this block including submitting a certain word or phrase You can email the site owner to let them know you were blocked Please include what you were doing when this page came up and the Cloudflare Ray ID found at the bottom of this page Metrics details Future spintronics and quantum technologies will require a portfolio of techniques for manipulating electron spins in functional nanodevices the establishment of the methods to control spin current is the key ingredient essential for the transfer and processing of information a universal method for manipulating spin currents with full-directional controllability and tunable magnitude has not been established Here we show that an artificial material called a magnetic metamaterial (MM) which possesses a novel spintronic functionality not exhibited by the original substance generates photo-driven ultrafast spin currents at room temperature via the magneto-photogalvanic effect By tuning the polarization state of the excitation light these spin currents can be directed with tunable magnitude along an arbitrary direction in the two-dimensional plane of the MM This new concept may guide the design and creation of artificially engineered opto-spintronic functionalities beyond the limitations of conventional material science a universal method for manipulating spin currents with full-directional controllability and tunable magnitude independent of specific material properties and not limited to low-temperature operation it has never been observed in magnetic metamaterials (MMs) we report the observation of MPGE in noncentrosymmetric MMs with artificially built-in threefold rotational symmetry and out-of-plane magnetization Reflecting this particular symmetry and remanent zero-field magnetization the direction and magnitude of spin-driven and potentially spin-polarized photocurrents are fully controlled without any external bias fields by tuning the polarization state of the excitation light The spin-switchable nature of photocurrents under weak external magnetic fields allows for the additional functionality of spin current manipulation which are entirely consistent with symmetry predictions show that nanoscale symmetry engineering can convert already known magnets into functional opto-spintronic materials working at room temperature but also enables the manipulation of photo-driven ultrafast spin currents via the MPGE in properly designed MMs This sophisticated manipulation is possible because the carriers in ferro- and ferri-magnetic materials carry a net spin angular momentum under an external DC electric field a Schematic of the experimental setup for generating spin-driven photocurrents A normally incident light with an arbitrarily polarized state (polarization angle θω ellipticity angle εω) excites a magnetic metamaterial (MM) with threefold rotational symmetry and out-of-plane magnetization Mz The flow direction θm and magnitude ∣ Jm∣ of Jm can be independently controlled by θω and εω The inset shows an atomic force microscope image of the MM b Schematic of the MM with a centrosymmetric Co/Pt ferromagnetic metallic multilayer film The MM consists of arrayed nanostructures (antidot lattice) of triangular holes with side lengths of 480 nm The period of the triangular lattice is 558 nm d 2D color maps of (c) ∣ Jm∣ and (d) θm on the θω vs εω plane The polarization states θω and εω of the excitation light are shown as black overlays ∣ Jm∣ can be modulated by εω (\(|{{{{{{{{{{{{\bf{\,J}}}}}}}}}}}}}_{{{{{{{{{{{{\rm{m}}}}}}}}}}}}}|\propto \cos 2{\varepsilon }_{\omega }\)) for ± Mz θm can be written as θm = − 2θω − 90° for + Mz (left panel) and θm = − 2θω + 90° for − Mz (right panel) Reversal of Mz does not change ∣ Jm∣ but flips θm indicating direct coupling between the spin polarization direction and θm Two-step behavior is not observed in Jx in (d) because the unstructured Co/Pt multilayer film has a centrosymmetric structure and therefore does not contribute to the zero-bias photocurrent which requires the breaking of space inversion symmetry the flow direction of the zero-bias photocurrents generated in our MM is directly coupled to the spin-polarization direction The lines are fitted to \({J}_{{{{{{{{{{{{\rm{m}}}}}}}}}}}},x}\propto -\cos 2{\theta }_{\omega }\) and \({J}_{{{{{{{{{{{{\rm{m}}}}}}}}}}}},y}\propto -\sin 2{\theta }_{\omega }\) a Schematic showing the experimental setup for measuring zero-bias photocurrents along the x and y directions at normal incidence of continuously polarization-modulated 800-nm light The polarization state of the excitation light is determined by the initial polarization angle φω and rotation angle α of the optical axis of the quarter-wave plate (QWP) c 2D color maps of (b) ∣ Jm∣ for ± Mz and (c) θm for + Mz when φω crosses the vertical directions (marked by thick arrows) εω can be continuously modulated with θω = 0°/90° at α = 0° and θω = 45°/135° at α = 45° leading to the simultaneous control of ∣ Jm∣ and θm d φω dependence of Jm,x and Jm,y at α = 0° (upper panel) and α = 45° (lower panel) Shaded (nonshaded) areas correspond to θω = 0° (θω = 90°) at α = 0° and θω = 45° (θω = 135°) at α = 45° \(|{{{{{{{{{{{{\bf{\,J}}}}}}}}}}}}}_{{{{{{{{{{{{\rm{m}}}}}}}}}}}}} |=\sqrt{{(\,{J}_{{{{{{{{{{{{\rm{m}}}}}}}}}}}},x})}^{2}+{(\,{J}_{{{{{{{{{{{{\rm{m}}}}}}}}}}}},y})}^{2}}\) plotted as a function of εω The line is fitted to \(|{{{{{{{{{{{{\bf{\,J}}}}}}}}}}}}}_{{{{{{{{{{{{\rm{m}}}}}}}}}}}}}|\propto {{{{{{{{{\rm{cos}}}}}}}}}} 2{\varepsilon }_{\omega }\) The inset plots \({\theta }_{{{{{{{{{{{{\rm{m}}}}}}}}}}}}}={{{{{{{{{\rm{tan}}}}}}}}} }^{-1}\left(\,{J}_{{{{{{{{{{{{\rm{m}}}}}}}}}}}},x}/{J}_{{{{{{{{{{{{\rm{m}}}}}}}}}}}},y}\right)\) as a function of θω the polarization information of an arbitrarily polarized light is converted into the magnitude and flow direction of spin-driven photocurrents The photogalvanic effect can be caused by the magnetic injection current only when the linearly polarized light is applied to systems where both space inversion and time-reversal symmetries are broken These conditions are met by the MPGE discussed above In the paramagnetic state denoted by the magnetic point group \(3m1^{\prime}\) the dominant spin photogalvanic effect may occur due to the “spin” (linear) injection current denoted by The spin current operator is naively defined as {sα the allowed spin photogalvanic effect in the paramagnetic state is for the spin current whose polarization is in the xy plane the z-polarized spin current exhibits the same polarization dependence as the MPGE This coincidence can be intuitively understood by the following arguments The large exchange splitting ( ~ 1 eV) in ferromagnetic cobalt causes nonequivalence of the spin-up and spin-down states The photo-driven spin current is then converted into a strongly spin-polarized charge current whereas the spin current carries no charge carriers in the paramagnetic state both the z-polarized spin photocurrent and charge photocurrent follow the same polarization dependence originating from the same microscopic mechanism (namely From these theoretical arguments on the experimental observations the spin-polarized photocurrent is inferred to be controlled by the magnetic moment of the MM and the polarization state of the incident light MMs are an ideal platform for future studies and applications of photocurrent generation on magnetic materials The single triangular hole structure belongs to point group 3m and its planar periodic array belongs to the p3m1 plane group with 3m point symmetry At room temperature the Co/Pt ferromagnetic multilayer film exhibits out-of-plane magnetization that preserves the artificially built-in threefold rotational symmetry of the MM but breaks the time-reversal symmetry (the magnetic point group \(3m^{\prime}\)) our MM breaks both the space inversion and time-reversal symmetries providing the necessary condition for observing the MPGE The intensity of the laser beam was modulated at f ~ 1 kHz by an optical chopper The short-circuit photocurrents were separately measured along the x and y directions by a two-phase lock-in amplifier (Stanford Research Systems SR865) with the reference signal from the optical chopper the photocurrent signals were evaluated as a time-averaged discharge current from the MM The magnitude ∣ Jm∣ and flow direction θm of the spin-driven photocurrents were calculated as \(|{{{{{{{{{{{{\bf{\,J}}}}}}}}}}}}}_{{{{{{{{{{{{\rm{m}}}}}}}}}}}}} |=\sqrt{{(\,{J}_{{{{{{{{{{{{\rm{m}}}}}}}}}}}},y})}^{2}+{\,(\,{J}_{{{{{{{{{{{{\rm{m}}}}}}}}}}}},y})}^{2}}\) and \({\theta }_{{{{{{{{{{{{\rm{m}}}}}}}}}}}}}={\tan }^{-1}(\,{J}_{{{{{{{{{{{{\rm{m}}}}}}}}}}}},x}/{J}_{{{{{{{{{{{{\rm{m}}}}}}}}}}}},y})\) All measurements were performed at room temperature in air the plane of the linearly polarized light rotates after passing through the magnetic materials measured using a conventional balanced detection technique The linear transmittance (T) and reflectivity (R) spectra of the unstructured Co/Pt multilayer film and MM were measured over the 250–2500 nm range using a commercial spectrometer (JASCO, MSV-5200). The absorption (A) spectra were calculated as A = 1 − T − R (see Supplementary Fig. 5) only βm contributes to the spin-driven photocurrents in the 2D plane of the MM Under arbitrarily polarized light irradiation with \({{{{{{{{{{\bf{E}}}}}}}}}}}_{0}=\left({E}_{x},{E}_{y},{E}_{z}\right)=\left({{{{{{\rm{sin}}}}}}}\ {\varepsilon }_{\omega }-i\,{{{{{{\rm{cos}}}}}}}\ {\varepsilon }_{\omega },{{{{{{\rm{cos}}}}}}}\ {\varepsilon }_{\omega }+i\,{{{{{{\rm{sin}}}}}}}\ spin-driven photocurrents are generated along the x and y directions as The data that support the findings of this study are available from the corresponding author upon reasonable request Spintronics: a spin-based electronics vision for the future Spintronics: fundamentals and applications Control over topological insulator photocurrents with light polarization Zero-bias photocurrent in ferromagnetic topological insulator Ultrafast magnetization enhancement in metallic multilayers driven by superdiffusive spin current Directional control of spin-wave emission by spatially shaped light Coherence control of Hall charge and spin currents Generation of spin currents by surface plasmon resonance Spin currents in diluted magnetic semiconductors The Photovoltaic and Photorefractive Effects in Noncentrosymmetric Materials (Gordon and Breach Science Publishers Magneto-gyrotropic photogalvanic effects in semiconductor quantum wells Switchable magnetic bulk photovoltaic effect in the two-dimensional magnet CrI3 Past achievements and future challenges in the development of three-dimensional photonic metamaterials Experimental verification of a negative index of refraction Far-infrared and transport properties of antidot arrays with broken symmetry Plasmons reveal the direction of magnetization in nickel nanostructures Nonlinear optical detection of mesoscopic magnetic toroidal dipoles Optical magnetoelectric effect in a submicron patterned magnet Magnetic quantum ratchet effect in (Cd,Mn)Te- and CdTe-based quantum well structures with a lateral asymmetric superlattice Circular and linear magnetic quantum ratchet effects in dual-grating-gate CdTe-based nanostructures Polarization-controlled circular second-harmonic generation from metal hole arrays with threefold rotational symmetry Spin polarization of currents in Co/Pt multilayer and Co-Pt alloy thin films Manipulating spin-polarized photocurrents in 2D transition metal dichalcogenides Kinetic theory of the displacement photovoltaic effect in piezoelectrics First principles calculation of the shift current photovoltaic effect in ferroelectrics Laser induced THz emission from femtosecond photocurrents in Co/ZnO/Pt and Co/Cu/Pt multilayers Low-frequency divergence and quantum geometry of the bulk photovoltaic effect in topological semimetals Chiral photocurrent in parity-violating magnet and enhanced response in topological antiferromagnet Infrared/terahertz spectra of the photogalvanic effect in (Bi,Sb)Te based three-dimensional topological insulators Two-dimensional magnetic crystals and emergent heterostructure devices Magnetic 2D materials and heterostructures Ultrafast photocurrents at the surface of the three-dimensional topological insulator Bi2 Se3 transport and detection of valley-locked spin photocurrent in WSe2 -graphene-Bi2 Se3 heterostructures Ultrafast spin-transfer torque driven by femtosecond pulsed-laser excitation Local charge and spin currents in magnetothermal landscapes Download references This work was supported by JSPS KAKENHI (Grant Nos the Research Foundation for Opto-Science and Technology the Support Center for Advanced Telecommunications Technology Research Foundation the Research Foundation for the Electrotechnology of Chubu the Kato Foundation for Promotion of Science the Iketani Science and Technology Foundation the Izumi Science and Technology Foundation the Nippon Sheet Glass Foundation for Materials Science and Engineering the Intelligent Cosmos Academic Foundation the Foundation for Promotion of Material Science and Technology of Japan the Konica Minolta Science and Technology Foundation the Yamaguchi Educational and Scholarship Foundation A part of this work was conducted at Nagoya University supported by the “Nanotechnology Platform Program” of the Ministry of Education Masakazu Matsubara & Takatsugu Kobayashi Center for Science and Innovation in Spintronics Research Center for Advanced Science and Technology Institute of Materials and Systems for Sustainability designed and coordinated the study contributed to all measurements and calculations carried out the photocurrent measurements and analyzed the data theoretically interpreted the microscopic origin and contributed to the writing of the paper The authors declare no competing interests Nature Communications thanks Ranjan Singh and the other reviewer(s) for their contribution to the peer review of this work Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Download citation DOI: https://doi.org/10.1038/s41467-022-34374-7 Anyone you share the following link with will be able to read this content: a shareable link is not currently available for this article Sign up for the Nature Briefing newsletter — what matters in science Publisher aims to expand corporate value under new leadership The King of Fighters developer SNK Corporation announced that it has hired Kenji Matsubara as its new CEO The former Sega president will officially begin his role on August 1 "We will aim for further growth and an increase in corporate value under his leadership," the company said we promise that SNK is positioning itself for a new phase of growth and development." Throughout his career at Sega, Matsubara served in a number of positions such as chief technical officer, and chief operating officer. Last year, he resigned after serving as president for three years citing that it was due to "personal reasons." Before joining Sega he was CEO and president of Temco Koei for nine years and spent two years in same role at social games publisher Zynga Last year, the crown prince of Saudi Arabia's foundation bought a 51% stake in SNK The investment raised concerns given the allegations against its leader and the nation such as the country's poor human rights record No part of this website or its content may be reproduced without the copyright owner's permission GAMESINDUSTRY.BIZ is a registered trademark of Gamer Network Limited Your browser does not support JavaScript, or it is disabled．Please check the site policy for more information National Report new banknotes that went into circulation with much fanfare on July 3 might never have got printed 5,000- and 10,000-yen banknotes issued by the Bank of Japan feature 3-D holographic portraits “mitsumata” (Oriental paperbush) has been used to print banknotes according to the National Printing Bureau (NPB) The deciduous shrub native to the Himalayan region also grows in Okayama and Tokushima prefectures and is used in the production of traditional “washi” paper “We thought we were the ones supporting (the cultivation) it is mitsumata from Nepal that supports our banknotes which obviously are crucial for Japan’s economy,” said Tadashi Matsubara who is integral to the story of Nepal’s connection with Japanese money The 62-year-old Matsubara is president of Kanpou Inc the company’s core business is to sell government publications such as “kanpo” gazettes Kanpou set up a program to support the cultivation of mitsumata in Nepal to ensure the NPB has a sufficient supply to produce banknotes One of the reasons the company got involved with mitsumata cultivation was that the president at the time had participated in a volunteer project to dig wells in farming villages in Nepal The plant also flourishes in the South Asian country and is used as a raw material for paper production With the domestic supply running low in Japan Kanpou was encouraged by members close to the NPB to see if it could turn mitsumata cultivation into a profitable business with its spectacular “roof of the world” landscape But there are many areas with well-drained soil and plenty of sunlight No fancy equipment is needed to grow and process the plant which is harvested during the winter off-season giving locals an opportunity to earn extra income Kanpou founded a local subsidiary in Nepal to nurture producers The company has also been providing guidance on how to steam the branches and peel the bark after harvesting the project was really more of a social contribution activity than a business Feeding Japan’s appetite for banknotes requires around 100 tons of mitsumata each year but Nepal’s maximum annual production capacity stood at approximately 30 tons The project remained unprofitable while it failed to meet the production scale A turning point came in November 2014 during a Kanpou shareholders meeting when stockholders lambasted Matsubara and other management members saying that they should pull out of the money-losing business The president replied that he would scrap the project if there was no prospect of turning it around within three years Matsubara knew full well the business was unprofitable due to a production shortfall which meant the company lost out on numerous opportunities to win contracts from the NPB through bidding procedures Matsubara also knew he had a chance if he could up production to about 60 tons a year Kanpou became eligible for assistance from the Japan International Cooperation Agency in 2016 and the company immediately increased production areas in villages in eastern Nepal close to the border with India in addition to those near Katmandu where the local subsidiary is based The company also focused on improving quality Because banknote production requires high-quality mitsumata the difference in the price can be several times greater the total volume of mitsumata harvested in major production areas varies from year to year ranging from 43 tons in fiscal 2018 to 12 tons in fiscal 2021 The unstable supply made it difficult to meet demand for producing banknotes Matsubara decided that profitability could be improved if high-quality mitsumata was produced in Nepal on a stable basis The president and other members of the company visited production areas in Nepal several times a year for up to a month at a time to instill technical expertise among growers and the total volume of mitsumata harvested in Kanpou-related production areas drastically increased to around 96 tons in 2023 from about 34 tons in 2014 Many producers were severely affected by the powerful earthquake that rocked Nepal in 2015 but the cultivation business also provided a precious source of income that supported their livelihoods Kanpou’s side business returned to profitability the United Nations is expected to remove Nepal from its list of least developed countries When Matsubara shows Japanese banknotes made from mitsumata and other materials Nepalese producers are surprised at how durable they are “Everyone works with pride in doing this job,” he said adding that he is looking forward to showing them the new bills next time he visits Nepal Insect farming is booming amid demand for more sustainable food Fukushima farm products still dealing with negative image Fisheries look to fish farming as the demand for seafood explodes Gifu food and drink maker has maple leaf dream Young offenders trained to make wine to help them find work 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 Copyright © The Asahi Shimbun Company. All rights reserved. No reproduction or republication without written permission. Volume 11 - 2020 | https://doi.org/10.3389/fimmu.2020.00574 This article is part of the Research TopicRetinal Immunobiology and RetinopathyView all 13 articles Granzymes are a family of serine proteases first shown to be intracellular initiators of immune-mediated cell death in target pathogenic cells Granzyme B (GzmB) has important extracellular functions in immune regulation and extracellular matrix (ECM) degradation Verified substrates of extracellular GzmB activity include tight junctional and ECM proteins little is known about the activity of GzmB in the outer human retina a tissue in which the degradation of the tight junctional contacts of retinal pigment epithelial (RPE) cells and within the external limiting membrane as well as remodeling of the ECM in Bruch's membrane cause the breakdown of the blood-retinal barrier and slowing of metabolite transport between neuroretina and choroidal blood supply Such pathological changes in outer retina signal early events in the development of age-related macular degeneration (AMD) This study is the first to focus on the distribution of GzmB in the outer retina of the healthy and diseased post-mortem human eye Our results revealed that GzmB is present in RPE and choroidal mast cells More immunoreactive cells are present in older (>65 years) compared to younger (<55 years) donor eyes and choroidal immunoreactive cells are more numerous in eyes with choroidal neovascularization (CNV) while RPE immunoreactive cells are more numerous in eyes with soft drusen In vitro studies demonstrated that RPE-derived tight junctional and ECM proteins are cleaved by exogenous GzmB stimulation These results suggest that the increased presence of GzmB immunoreactive cells in outer retina of older (healthy) eyes as well as in diseased eyes with CNV (from AMD) and eyes with soft drusen exacerbate ECM remodeling in the Bruch's membrane and degradation of the blood-retinal barrier Currently there are no treatments that prevent remodeling of the Bruch's membrane and/or the loss of function of the outer blood-retinal barrier already in preclinical studies for non-ocular diseases may provide new strategies to stop these early events associated with the development of AMD we do not yet understand exactly what causes the earliest signs of inflammation in the retina we speculate that GzmB activity may promote early changes in outer retina that contribute to AMD development Our earlier work showed that GzmB cleaves ECM in non-ocular systems, implicating extracellular GzmB activity in pathological chronic inflammation, delayed wound healing, skin injuries, and cardiopulmonary disease (8–10, 12, 22) Here we address the evidence that age-related increases in extracellular GzmB in the outer retina promote pathological remodeling of the BM and alterations in RPE barrier function Given that there are no treatment strategies that prevent pathological breakdown of BM or the oBRB studies on the extracellular GzmB activity in ocular tissues may allow us further insights into novel immune-mediated mechanisms associated with degradation and remodeling of the outer retina during aging and AMD development were obtained from the Eye Bank of British Columbia (EBBC Healthy eyes collected within 12 h following death were immersed in 10% buffered formalin after corneal tissues removed for corneal transplant purposes Each normal donor eye had a medical/hospital history obtained by EBBC These eyes were then embedded in paraffin and serial sections at 6 micra thickness were obtained Every 20th section was stained for H & E and assessed by light microscopy Tissue sections from the macular area were assessed to identify and screen for ocular pathologies Healthy eyes had normal retinal organization and did not display outer retinal fibrosis Healthy donor tissues with the following pathologies were excluded in this study: local or systemic infection or myeloproliferative disorders or any intrinsic eye disease Diseased eyes with geographic atrophy (GA) or soft drusen deposits were obtained from the Department of Pathology Tissue sections from the macular area were stained by hematoxylin and eosin and then assessed by ophthalmic pathologists to identify and screen for ocular pathologies 9 eyes with numerous soft drusen (from non-AMD eyes) were included in this study ATCC) and primary fetal RPE cells were used Primary RPE were isolated from human fetal donor eyes that were consented for research studies from the CARE program at BC Women's Hospital under Clinical Research Ethics Board (UBC) approval The immunoreactive RPE and immune cells in the choroidal layers were counted and normalized to 1,050 μm length units of BM Approximately 4–6 sections per donor eye were analyzed The immunoreactivity was compared among eyes from healthy older or soft drusen (an early marker of AMD) donors Tight junctional proteins were visualized by immunofluorescence on both ARPE19 or primary RPE cells grown to confluence and stimulated in chamber slides Tight junctional proteins were evident on ARPE19 (within 5–7 days) and on primary RPE (within 7–10 days) in culture cells were fixed in situ with cold methanol and incubated in 2% normal goat serum (Vector Labs) for 30 min at room temperature (RT) chamber slides were incubated with antibody against ZO-1 (Invitrogen) All antibodies were diluted at 1:100 in PBS with 0.1% TX-100 and chamber slides were incubated for 1 h at RT Primary antibodies were omitted for negative controls and then incubated with Alexa 488 conjugated goat anti-rabbit or anti-mouse secondary antibody (1:400) for 1 h at RT and then incubated with Hoechst 33258 (DAPI A blade was used to remove chambers and silicon tapes and marker pen was used to label the locations of different chambers on slides Slides were mounted with glycerol (50:50 glycerol: PBS) and 1.5 mm coverslips after GzmB stimulation and measurements of FITC-dextrans fluorescence membranes at the bottom of inserts were cut out and adherent ARPE-19 cells underwent immunocytochemistry with ZO-1 primary antibody as above An LSM 510 confocal laser-scanning microscope was used to image antibody labeling at 488 and 543 nm DAPI (nuclei) was imaged at 405 nm and images stored as digital files All settings on confocal were kept constant throughout the imaging sessions in order to compare intensity of fluorescent signals between groups DMEM medium with 0 nM (control) or 100 nM GzmB was added to wells and cells cultured at 37°C incubator for 5 h supernatants were carefully removed and stored Total protein lysates were collected for western blot analysis To determine effects of exogenous GzmB on the cleavage of RPE-derived ECM proteins WBs were undertaken using both supernatant and lysate samples In some studies, ARPE19, a human RPE cell line, were used at passage 5–7 (26) These cells were grown to confluence on chamber slides or transwell inserts ~1.6 × 105/cm2 cells were seeded in a laminin-coated Transwell insert (0.4 μm pore size Fisher Scientific) or on chamber slides (LabTek II) in 0.2 mL DMEM containing 10% FBS 100 U/mL penicillin and 100 μg/mL streptomycin and kept in a humidified chamber with 5% CO2 at 37°C starved for 3 h in serum-free DMEM before GzmB stimulation 100) was added to culture slides for 5 h at 37°C culture medium was removed and stored; cells were fixed in situ with 100% methanol on ice for 15 min ARPE-19 cells were grown to 95% confluence in 96-well plates for MTT assays Cells were then washed with PBS twice and then starved for 3 h in serum-free DMEM before GzmB stimulation at different concentrations (0 the 96-well plates were placed in 37°C incubator for 24 h and 250 μl of 0.5 mg/ml MTT buffer (1:10 dilution in DMEM) was added to each well 250 μl DMSO added to each well and reincubated at 37°C for 15–20 min; next absorbance at 570 nm wavelength was read using the Hybrid Multi-Mode Reader (BioTek Synergy H1) Targeted proteins on membranes were detected with Pierce™ ECL Western Blotting Substrate Kit (Thermo Fisher) Protein band intensity was measured using Image J (NIH) a high molecular weight (MW = 124 kDa) housekeeping gene was used for quality control on supernatant samples Primary RPE cells were grown to confluence in transwell system inserts for 24-well plates for a functional assay of solute flux through the monolayer and starved for 3 h in serum-free DMEM before GzmB stimulation DMEM with 0 nM (controls) or 100 nM GzmB was placed in the upper insert of the transwell systems at 37°C for 5 h the culture medium was removed without disturbing cells and DMEM culture medium with 1 mg/ml FITC-dextran (70 kDa Sigma) solution was added into all upper inserts for another 5 h all inserts were removed and fluorescence intensity at 490 nm (excitation)/520 nm (emission) wavelengths was read using the Hybrid Multi-Mode Reader (BioTek Synergy H1) For trans-epithelial resistance measurements transwells were placed in electric cell substrate impedance sensing apparatus media changed to serum free and allowed to stabilize before addition of 0 nM (controls) or 50–100 nM GzmB in to lower or upper compartment capacitance are graphed for 0–24 h All experiments were repeated in triplicate or quadruplicate Statistical analysis was performed using Prism Ver8 (GraphPad Software) independent sample T-test was used for western blot and immunohistochemistry analysis of human tissue samples a one-way ANOVA test with Tukey's multiple comparisons post-hoc test was used Statistical significance level was set at p < 0.05 (I) Analysis of GzmB immunoreactivity of choroidal cells in older (>65 years N = 8) and younger (<55 years N = 8) normal donor eyes The number of GzmB+ choroidal cells was significantly higher in wet AMD eyes compared to all other groups while the number of GzmB+ choroidal cells in older eyes was significantly higher than younger eyes One-way ANOVA Test and Tukey's multiple comparisons post-hoc test (*p < 0.05; **p < 0.01) (J) Analysis of GzmB immunoreactivity of RPE cells in older (>65 years The number of GzmB+ RPE cells was significantly higher in soft drusen compared to all other groups while the number of GzmB+ RPE cells in wet AMD eyes was significantly higher than younger but significantly lower than soft drusen eyes One-way ANOVA Test and Tukey's multiple comparisons post-hoc test In C57Bl/6J mice, GzmB immunoreactivity was present in outer retina, specifically in the extracellular matrix of BM and the intercellular spaces between RPE cells (Figures 3A–D). In the mouse models, there was an age-dependent increase in GzmB immunoreactivity (Figure 3E) Immunreactivity of GzmB in Bruch's Membrane and RPE layer of a young (3 month) and old (18 month) C57Bl/6J mouse retina 488 nm) is lower in mouse retina from 3 month old mouse compared to (B) an 18 month old mouse Boxed areas are shown at higher power in (C) with GzmB punctate labeling (*) on Bruch's membrane of 3 month old and in (D) which demonstrates stronger immunofluorescence intensity along BM and between RPE cell borders (some shown by white arrowheads) of the older mouse retina (E) Independent-sample T-test (n = 3) between two groups shows the increased GzmB level in BM and RPE layers of 18M mice: mean ± SEM; *p < 0.01 DAPI (405 nm) labeling of nuclei is shown in blue These data extend earlier work by demonstrating that tight junctional proteins from an ocular source (e.g. GzmB does not affect the viability of ARPE-19 cells Cells were treated with exogenous GzmB (10 100 nM) for 24 h and compared to controls (GzmB = 0 nM) No significant changes were observed in viability at any of the GzmB concentrations Data were analyzed using one-way ANOVA test and Tukey's multiple comparisons post-hoc test (mean ± SEM Reduced immunoreactivity of ZO-1 in ARPE-19 cells stimulated by exogenous GzmB (A–E) Note immunoreactivity of ZO-1 tight junctional contacts (green 488 nm) between cells (some shown by white arrowheads) is reduced with increasing concentrations of GzmB (1 (F) Omission of primary antibody demonstrates lack of green ZO-1 immunolabeling (G) Significant differences were observed between controls and 50 and 100 nM GzmB A one-way ANOVA and Tukey's multiple comparisons post-hoc test (N = 6 per group) were used to compare control group with GzmB-treated groups: mean ± SEM; *p < 0.05; ***p < 0.001 Reduced immunoreactivity of JAM-A and Occludin in ARPE-19 cells stimulated by exogenous GzmB (A) JAM-A immunoreactivity demonstrates tight junctional contacts (green 488 nm some shown by white arrowheads) on RPE in controls wells (GzmB = 0 nM) (B) After 6 h with GzmB stimulation (100 nM) JAM-A immunoreactivity is reduced on ARPE-19 (C) Occludin immunoreactivity between cells (some shown by white arrowheads) in control wells (GzmB = 0 nM) (D) After 6 h with GzmB stimulation (100 nM) Occludin immunoreactivity is reduced on ARPE-19 (E) Omission of primary antibody demonstrates no immunoreactivity Significant differences were observed for (F) JAM–A and (G) Occludin using an independent-sample T-Test (N = 6 per group) between control and GzmB-treated group: mean ± SEM; **p < 0.01 Images were taken from ARPE-19 cells and are representative of primary RPE experiments undertaken at the same time Note that the resistance is lowered by exogenous GzmB (gray and yellow traces) while control (unstimulated) RPE retained their resistance measurements at ~160 ohms (blue and orange traces) Lowered trans-epithelial resistance and increased FITC-dextran flux after GzmB stimulation on primary RPE cells grown on transwell inserts cells were grown on transwell inserts and stimulated with GzmB at 100 nM (A) Trans-epithelial resistance measurements on resting cells ranges from 160 to 180 ohms After initiation of GzmB stimulation (time = 0) the resistance of RPE cultures decreases to 135–125 ohms (time = 10 h) as shown by yellow and gray traces The control cells maintained resistance at 160–165 ohms (time = 10 h) as shown by the blue and orange traces (B) FITC-dextran flux assay demonstrated increased FITC-dextran fluorescence intensity measured in the lower compartment of GzmB stimulated wells compared to control wells the membranes on which cells were attached were cut out and subjected to immunocytochemistry Strong ZO-1 immunolabeling on primary RPE cells on transwell insert membrane in control wells (0 nM GzmB) after 5 h shown in (C,D) in experimental wells (100 nM GzmB) after 5 h of GzmB stimulation (E) The ZO-1 immunoreactivity was quantified in controls and GzmB stimulated wells and an independent-sample T-Test (N = 6) between control and GzmB-treated group was undertaken and graphed as mean ± SEM; ****p < 0.0001; **p < 0.01 Western blots reveal cleavage of primary RPE-derived extracellular matrix proteins by exogenous GzmB Primary RPE cells were stimulated with GzmB (100 nM and both protein lysates and culture supernatant were collected Western blot of supernatant samples were processed (A) Western blot using antibody against fibronectin shows cleavage bands due to GzmB stimulation of primary RPE with 0 nM GzmB (controls lanes 2–4) or 100 nM exogenous GzmB (lanes 5–7) Note cleavage bands at lower molecular weight The densiometric analysis of the band with asterisk (*) is graphed in (D) and demonstrates significant differences between control and 100 nM GzmB groups (B) Western blot using antibody against Laminin-5 (now known as Laminin-332) shows supernatants from cultures of primary RPE with 0 nM (controls in samples from GzmB stimulation group (lanes 5–7) The densiometric analysis of the band with asterisk (*) is graphed in (E) and demonstrates significant differences between control and 100 nM GzmB groups (C) Western blot using antibody against Collagen IV shows supernatants from cultures of primary RPE with 0 nM (controls in samples from both GzmB stimulation group and controls The densiometric analysis of the band with asterisk (*) is graphed in (F) and demonstrates no significance between control and 100 nM GzmB groups housekeeping gene) antibody was used for quality control and demonstrates supernatant samples did not contain cell lysates GzmB contributes to the pathology of autoimmune and/or chronic inflammatory conditions through the degradation of extracellular proteins and tissue matrices (8–10, 12, 22) Here we report GzmB expression in the healthy and diseased human retina and in vitro studies demonstrating the effects of exogenous GzmB on RPE-derived tight junctional and ECM proteins Our premise is that extracellular GzmB contributes to the onset and/or progression of AMD via the cleavage of key extracellular proteins in BM resulting in RPE dysregulation and barrier function abnormalities Later stages of AMD including RPE atrophy and remodeling of BM with the release of sequestered angiogenic and pro-inflammatory factors in part due to the unchecked activity of extracellular GzmB Our human data allowed us to identify the cells that produce GzmB Choroidal mast cells appear to be the major source of GzmB especially in CNV eyes RPE cells appear to be an important source of GzmB in eyes with soft drusen and CNV We hypothesize that GzmB's extracellular role in cleavage of the ECM causes the breakdown of the oBRB This is supported by our in vitro studies in which we demonstrated the cleavage of tight junctional and cell adhesion molecules as well as RPE-derived ECM proteins Future studies will focus on the dual effects of these mast cell mediators toward understanding their separate or combined role in the development of AMD we undertook in vitro cell studies to assess the role of exogenous GzmB on RPE-derived proteins as immunoreactivity patterns can provide spatial localization within the outer retina but does not allow for functional analysis we focused on the effects of GzmB cleavage on RPE cell-derived proteins may allow us to identify the detailed timeline and mechanism whereby the age-related increase in extracellular GzmB activity leads to cleavage of tight junctional proteins subsequent RPE atrophy and loss of barrier function in vivo Our results demonstrating GzmB expression in both RPE and choroidal mast cells suggests that this serine protease may play multiple roles in the outer retina. Eyes with soft drusen (but without AMD) were more likely to have GzmB+ RPE cells than the other groups studied. These GzmB+ RPE cells appeared to have the RPE phenotype of “non-uniform” described earlier (53) Given that our sample of soft drusen eyes did not display AMD features the “non-uniform” RPE may represent age-related changes in RPE We do not yet know if soft drusen upregulates GzmB in nearby RPE cells or whether the degradation of tight junctional contacts between RPE (reported here in in vitro studies) may be caused by RPE or mast-cell derived GzmB Future studies will identify whether soft drusen components upregulate GzmB in RPE cells in vitro and mouse models will help us to clarify further the relationship between extracellular GzmB and the cleavage of ECM and tight junctions in outer retina activity of extracellular GzmB was shown to liberate sequestered pro-angiogenic factors (from the tumor ECM) outside the VEGF-VEGFR2 axis Increased GzmB also supported endothelial cell migration and vessel formation Inhibitors of mast cell degranulation increased the efficacy of anti-VEGF therapy in this model providing supportive evidence that pharmacological inhibition of extracellular GzmB may ameliorate neovascularization in CNV Treating AMD is a multidimensional health care problem with a global cost of vision impairment estimated to be nearly $343 billion worldwide There is a need for early and prophylactic therapies for AMD Here we present a novel concept to treat the earliest events in AMD by targeting extracellular GzmB in outer retina in order to suppress remodeling of BM and deterioration of the oBRB two of the earliest events associated with AMD pathogenesis The datasets generated for this study are available on request to the corresponding author This study used primary human fetal RPE cells isolated from fetal donor eyes and adult post-mortem human eye tissues consented for research The studies involving human participants were reviewed and approved by the Clinical Ethics Research Board of the University of British Columbia and strictly adhered to the Declaration of Helsinki The patients/participants provided their written informed consent to participate in this study The animal study was reviewed and approved by UBC Animal Care Committee JM and DG conceived and designed the study analyzed and interpreted the data and generated figures and CT provided expert opinion and technical advice on GzmB assays and assisted with study design and interpretation MZ generated and purified endogenous GzmB from YT cells for use in this study This study was funded by Canadian Institutes of Health Research (CIHR) (to JM and DG) Natural Sciences and Engineering Research Council of Canada (NSERC) (JM) and Michael Smith Foundation for Health Research (DG) MZ and CT were funded through CIHR Fellowships MZ was additionally funded through a Michael Smith Foundation for Health Research Studentship YT was funded through a Guangzhou Elite Project Overseas Scholarship DG is a co-Founder and serves as the Chief Scientific Officer of viDA Therapeutics no viDA products were used in this manuscript The remaining 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 Reed Huber and Eleanor To for preliminary work and technical assistance throughout the course of this study Hua Ren and Chao Zhu provided bright-field photomicrographic assistance The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2020.00574/full#supplementary-material Age-related macular degeneration and changes in the extracellular matrix Modulation of three key innate immune pathways for the most common retinal degenerative diseases Immunology of age-related macular degeneration Immune responses in age related macular degeneration and a possible long term therapeutic strategy for prevention A perspective of AMD through the eyes of immunology Potential role of extracellular granzyme b in the 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Available online at: http://www.molvis.org/molvis/v23/60 an optical coherence tomography biomarker for progression in age-related macular degeneration Granzyme B contributes to extracellular matrix remodeling and skin aging in apolipoprotein E knockout mice Mast cell-derived tryptase in geographic atrophy The tight junction associated signalling proteins ZO-1 and ZONAB regulate retinal pigment epithelium homeostasis in mice Granzyme B is expressed in mouse mast cells in vivo and in vitro and causes delayed cell death independent of perforin Caspase-14 expression impairs retinal pigment epithelium barrier function: potential role in diabetic macular edema Oxidative stress affects the junctional integrity of retinal pigment epithelial cells Triamcinolone acetonide prevents oxidative stress-induced tight junction disruption of retinal pigment epithelial cells Molecular inflammation: underpinnings of aging and age-related diseases Increased choroidal mast cells and their degranulation in age-related macular degeneration Effects of secreted mast cell mediators on retinal pigment epithelial cells: focus on mast cell tryptase Granzyme B Disrupts Cell-Cell Adhesion and Epithelial Barrier Function Google Scholar Disruption of cell-cell junctions and induction of pathological cytokines in the retinal pigment epithelium of light-exposed mice Retinal pigment epithelial cells synthesize laminins and adhere to them through alpha3- and alpha6-containing integrins Extracellular matrix alterations and deposit formation in AMD CrossRef Full Text | Google Scholar Structural and molecular changes in the aging choroid: implications for age-related macular degeneration Choriocapillaris vascular dropout related to density of drusen in human eyes with early age-related macular degeneration Complement activation and choriocapillaris loss in early AMD: implications for pathophysiology and therapy Extracellular matrix stiffness controls VEGF signaling and processing in endothelial cells Novel vascular endothelial growth factor binding domains of fibronectin enhance vascular endothelial growth factor biological activity Hypoxia induced heparan sulfate primes the extracellular matrix for endothelial cell recruitment by facilitating VEGF-fibronectin interactions Complex receptor-ligand dynamics control the response of the VEGF system to protease injury pH regulates vascular endothelial growth factor binding to fibronectin: a mechanism for control of extracellular matrix storage and release Conformational remodeling of the fibronectin matrix selectively regulates VEGF signaling Soft drusen in age-related macular degeneration: biology and targeting via the oil spill strategies Granzyme B releases vascular endothelial growth factor from extracellular matrix and induces vascular permeability Granzyme B cleavage of fibronectin disrupts endothelial cell adhesion Mast cells decrease efficacy of anti-angiogenic therapy by secreting matrix-degrading granzyme B Turner CT and Granville DJ (2020) Retinal Distribution and Extracellular Activity of Granzyme B: A Serine Protease That Degrades Retinal Pigment Epithelial Tight Junctions and Extracellular Matrix Proteins Received: 31 October 2019; Accepted: 12 March 2020; Published: 07 April 2020 Copyright © 2020 Matsubara, Tian, Cui, Zeglinski, Hiroyasu, Turner and Granville. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) *Correspondence: Joanne A. Matsubara, am1zQG1haWwudWJjLmNh