Find Clues in the Teppo Factory Stop the Gunpowder ShipmentFind Clues in the Teppo Factory place a marker in the middle of the glowing blue circle on your map and head there You'll be near the southwestern wall of the Teppo Factory but don't worry—the clue you need to complete this objective is close by the one next to the factory's southwestern entrance This clue reveals how The Shinbakufu's members are planning to blow up the Teppo Factory Your next move is to destroy the gunpowder shipment to stop their plans Navigate until you get close to the ship's stern you'll notice a couple of guards patrolling the area it's time to destroy all the gunpowder aboard Go inside the room in the middle of the ship and carry one of the bombs there to the ship's stern The bombs have a white target on them so you can easily identify them Place the bomb next to the red pots on the deck and take out your teppo to shoot at the bomb Metrics details A Comment to this article was published on 05 February 2025 Nocturnal urination frequency is associated with sleep blood pressure (BP) it was uncertain to what extent the sleep BP increases within individuals with each increase in the number of nocturnal urination We calculated intraindividual differences in sleep BP between nights with different urination frequencies to clarify their relationship We enrolled 2418 community residents (mean age Participants wore a cuff on the upper arm when sleeping that automatically measured BP at fixed times during a 1-week period The frequency of nocturnal urination was recorded in a sleep diary by the study participants Sleep systolic BP increased with increased nocturnal urination frequency (0 time vs and a similar association was observed for sleep diastolic BP These associations were independent of age the use of antihypertensive drugs reduced renal function and the presence of sleep-disordered breathing Sleep BP in participants who experienced nocturnal urination 0 and 2 times during the 1-week measurement period showed a linear increase with the frequency of urination (0 time vs There was an intraindividual correlation between nocturnal urination frequency and sleep BP These correlations were independent of baseline BP and participants’ clinical backgrounds Nocturnal urination frequency may be an indicator of individuals who require detailed ambulatory BP measurement Prices may be subject to local taxes which are calculated during checkout Yang WY, Melgarejo JD, Thijs L, Zhang ZY, Boggia J, Wei FF, et al. Association of office and ambulatory blood pressure with mortality and cardiovascular outcomes. JAMA. 2019;322:409–20. https://doi.org/10.1001/jama.2019.9811 Kario K, Hoshide S, Mizuno H, Kabutoya T, Nishizawa M, Yoshida T, et al. Nighttime blood pressure phenotype and cardiovascular prognosis: practitioner-based nationwide JAMP study. Circulation. 2020;142:1810–20. https://doi.org/10.1161/CIRCULATIONAHA.120.049730 Tabara Y, Matsumoto T, Murase K, Nagashima S, Hirai T, Kosugi S, et al. Seasonal variation in nocturnal home blood pressure fall: the Nagahama study. Hypertens Res. 2018;41:198–208. https://doi.org/10.1038/s41440-017-0003-3 Matsumoto T, Tabara Y, Murase K, Setoh K, Kawaguchi T, Nagashima S, et al. Association between sleep disturbance and nocturnal blood pressure profiles by a linear mixed model analysis: the Nagahama study. Sleep Med. 2019;61:104–9. https://doi.org/10.1016/j.sleep.2019.01.049 Matsumoto T, Tabara Y, Murase K, Setoh K, Kawaguchi T, Nagashima S, et al. Nocturia and increase in nocturnal blood pressure: the Nagahama study. J Hypertens. 2018;36:2185–92. https://doi.org/10.1097/HJH.0000000000001802 Tabara Y, Igase M, Miki T, Ohyagi Y, Matsuda F, Kohara K, et al. B-type natriuretic peptide is a determinant of the nocturnal increase in blood pressure independently of arterial hypertrophy and hypoxia. J Hypertens. 2016;34:2393–401. https://doi.org/10.1097/HJH.0000000000001104 Funada S, Tabara Y, Setoh K, Negoro H, Akamatsu S, Yoshino T, et al. Impact of nocturia on mortality: the Nagahama study. J Urol. 2020;204:996–1002. https://doi.org/10.1097/JU.0000000000001138 Hamada S, Tabara Y, Murase K, Matsumoto T, Setoh K, Wakamura T, et al. Night-time frequency of urination as a manifestation of sleep-disordered breathing: the Nagahama study. Sleep Med. 2021;77:288–94. https://doi.org/10.1016/j.sleep.2020.09.007 Morgenthaler T, Alessi C, Friedman L, Owens J, Kapur V, Boehlecke B, et al. Practice parameters for the use of actigraphy in the assessment of sleep and sleep disorders: an update for 2007. Sleep. 2007;30:519–29. https://doi.org/10.1093/sleep/30.4.519 Shimamoto K, Ando K, Fujita T, Hasebe N, Higaki J, Horiuchi M, et al. The Japanese Society of Hypertension guidelines for the management of hypertension (JSH 2014). Hypertens Res. 2014;37:253–390. https://doi.org/10.1038/hr.2014.20 Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53:982–92. https://doi.org/10.1053/j.ajkd.2008.12.034 Sasaki N, Nagai M, Mizuno H, Kuwabara M, Hoshide S, Kario K. Associations between characteristics of obstructive sleep apnea and nocturnal blood pressure surge. Hypertension. 2018;72:1133–40. https://doi.org/10.1161/HYPERTENSIONAHA.118.11794 Kikuya M, Ohkubo T, Asayama K, Metoki H, Obara T, Saito S, et al. Ambulatory blood pressure and 10-year risk of cardiovascular and noncardiovascular mortality: the Ohasama study. Hypertension. 2005;45:240–5. https://doi.org/10.1161/01.HYP.0000152079.04553.2c Dolan E, Stanton A, Thijs L, Hinedi K, Atkins N, McClory S, et al. Superiority of ambulatory over clinic blood pressure measurement in predicting mortality: the Dublin outcome study. Hypertension. 2005;46:156–61. https://doi.org/10.1161/01.HYP.0000170138.56903.7a Tabara Y, Matsumoto T, Murase K, Setoh K, Kawaguchi T, Nagashima S, et al. Lifestyle habits associated with nocturnal urination frequency: the Nagahama study. Neurourol Urodyn. 2019;38:2359–67. https://doi.org/10.1002/nau.24156 Kohara K, Tabara Y, Ochi M, Okada Y, Ohara M, Nagai T, et al. Habitual hot water bathing protects cardiovascular function in middle-aged to elderly Japanese subjects. Sci Rep. 2018;8:8687 https://doi.org/10.1038/s41598-018-26908-1 Navasiolava NM, Pajot A, Gallois Y, Pastushkova LKH, Kulchitsky VA, Gauquelin-Koch G, et al. NT-ProBNP levels, water and sodium homeostasis in healthy men: effects of 7 days of dry immersion. Eur J Appl Physiol. 2011;111:2229–37. https://doi.org/10.1007/s00421-011-1858-7 Tai Y, Obayashi K, Okumura K, Yamagami Y, Negoro H, Kurumatani N, et al. Association between before-bedtime passive body heating and nocturia during the cold season among older adults. J Epidemiol. 2023;33:398–404. https://doi.org/10.2188/jea.JE20210471 Kario K, Chen CH, Park S, Park CG, Hoshide S, Cheng HM, et al. Consensus document on improving hypertension management in Asian patients, taking into account Asian characteristics. Hypertension. 2018;71:375–82. https://doi.org/10.1161/HYPERTENSIONAHA.117.10238 Kanzaki G, Tsuboi N, Shimizu A, Yokoo T. Human nephron number, hypertension, and renal pathology. 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Hypertens Res. 2010;33:515–20. https://doi.org/10.1038/hr.2010.47 Download references We are extremely grateful to the Nagahama City Office and the nonprofit organization Zeroji Club for their assistance in conducting the Nagahama study We also thank the editors of Crimson Interactive Pvt for their help in English language editing The study was supported by a university grant and a Grant-in-Aid for Scientific Research (25293141 Science and Technology of Japan; the Practical Research Project for Rare/Intractable Diseases (ek0109070 the Comprehensive Research on Aging and Health Science Research Grants for Dementia R&D (dk0207006 the Program for an Integrated Database of Clinical and Genomic Information (kk0205008) the Practical Research Project for Lifestyle-related Diseases including Cardiovascular Diseases and Diabetes Mellitus (ek0210066 the Research Program for Health Behavior Modification by Utilizing IoT (le0110005) and the Research and Development Grants for Longevity Science (dk0110040) from the Japan Agency for Medical Research and Development (AMED); Welfare Sciences Research Grants Research on Region Medical from the Ministry of Health Labor and Welfare of Japan; the Takeda Medical Research Foundation Shizuoka Graduate University of Public Health Kyoto University Graduate School of Medicine Department of Sleep Medicine and Respiratory Care The Department of Respiratory Care and Sleep Control Medicine at Kyoto University is funded by endowments from Philips Respironics The Department of Sleep Medicine and Respiratory Care Nihon University of Medicine is funded by endowments from Philips Respironics Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law Download citation DOI: https://doi.org/10.1038/s41440-024-02085-9 Anyone you share the following link with will be able to read this content: a shareable link is not currently available for this article Ressha Sentai ToQger actors Jun Shison and Shin Nagahama reprised their roles in the latest episode of Bakuage Sentai BoonBoomger Tokusatsu actors Jun Shison and Shin Nagahama recently reprised their respective roles from Ressha Sentai ToQger (2014) in the latest episode of Bakuage Sentai BoonBoomger This episode marked the first appearance of both of their characters since the 2016 crossover movie Shuriken Sentai Ninninger vs Shin Nagahama was previously announced to be reprising his role after the premiere of episode 31 of BoonBoomger. The episode features Genba/BunOrange continuing in his pursuit of against Disrace. After Genba is defeated, he unexpectedly comes across Akira Nijino/ToQ 6 of the ToQgers. Following his return to the role of Akira, Shin Nagahama posted the following statement to his social media account; episode 32 also features the surprise return of Jun Shison as Right Suzuki/ToQ 1 Right suddenly comes to the aid of BunRed and BunViolet to defeat the Hashyrian’s and their train-themed Senro Guruma monster I am full of respect for the team who continue to create “dreams” even now Episode 32 of Bakuage Sentai BoonBoomger premiered on October 6 Hardcore Kamen Rider Dragon Knight enthusiast This site uses Akismet to reduce spam. Learn how your comment data is processed. Enter your email address to subscribe to the Tokusatsu Network and receive notifications of new posts by email Please upgrade to a more modern version to fully experience JapanToday site and for security reasons Japan is pretty flexible when it comes to sandwich fillings you’ll find plenty of examples of old standbys like ham-and-cheese or tuna with mayo but also dessert sandwiches with sliced fruit So if anything goes for Japanese sandwiches why not pour some Japanese whisky in there too which has created the Whisky Bonbon Snack Sandwich together with partner Nagahama Distillery “Snack Sandwich” is Fuji Baking’s line of pocket sandwiches of the sort that became a hit with foreign visitors to Japan during the Tokyo Olympics Snack Sandwiches first went on sale in 1975 and come in all sorts of different varieties but how did they decide to make one with whisky the manager of Fuji Baking’s Nishiharu factory in Aichi Prefecture received a bottle of whisky from his daughter as a present Deeply impressed with its quality and flavor he wondered if there was some way Fuji Baking could do a joint project with the whisky’s maker Fuji Baking and Nagahama hit upon the idea of crafting a whisky bonbon-flavor Snack Sandwich What followed was an extensive and through testing phase in which the development team repeatedly experimented with different ratios of chocolate cream to whiskey until they found the optimal combination…or maybe they found the perfect ratio right away and simply held off on telling their bosses about it for a while since it’s hard to imagine a more enjoyable work project to have running long than one that involves consuming chocolate and whisky Whisky Bonbon Snack Sandwiches are on sale at supermarkets and drugstores in Japan’s central Chubu region -- Discovered: An even better way to open Japanese convenience store rice balls【Video】 -- Dark and edgy Jujustu Kaisen teams up with bright and cheery Sanrio for new merch line【Pics】 -- Starbucks Japan releases exclusive new holiday goods at Reserve Roastery Tokyo Join the leading Asian tourist attraction to assist our diverse range of customers Because I wanted to rise to the occasion and get loafed up this article fails to mention the price of the product.. Use your Facebook account to login or register with JapanToday you will also receive an email inviting you to receive our news alerts A mix of what's trending on our other sites On the screen in front of a crowded Otakon panel room, Director Hiroshi Nagahama shows a slide featuring the cover art for the 1987 film Wicked City, directed by Yoshiaki Kawajiri of Studio Madhouse on the screen in front of a crowded Otakon panel room Who here has seen this movie?" To his surprise a good number of audience members raised their hands Nagahama explains that he first saw the film when he was only 16 years old I talked to Nagahama at Otakon 2024 and asked him a few questions about the show and its production Ah, Kawajiri... NAGAHAMA: Yes! [Yoshiaki] Kawajiri is one of the directors I respect the most image: Researchers developed a smartphone-based digital holographic microscope that can capture reconstruct and display holograms in almost real time They used the microscope to acquire cross-sectional images of a Nymphaea plant stem (left) and a pine needle (right) Tokyo University of Agriculture and Technology WASHINGTON — Researchers have developed a new smartphone-based digital holographic microscope that enables precision 3D measurements The highly portable and inexpensive microscope could help bring 3D measurement capabilities to a broader range of applications including educational uses and point-of-care diagnostics in resource-limited settings Holographic microscopes digitally reconstruct holograms to extract detailed 3D information about a sample enabling precise measurements of the sample’s surface and internal structures existing digital holographic microscopes typically require complex optical systems and a personal computer for calculations making them difficult to transport or use outdoors “Our digital holographic microscope uses a simple optical system created with a 3D printer and a calculation system based on a smartphone,” said research team leader Yuki Nagahama from the Tokyo University of Agriculture and Technology portable and useful for a variety of applications and settings.” In the Optica Publishing Group journal Applied Optics the researchers demonstrate the smartphone-based digital holographic microscope’s ability to capture The user can even use a pinch gesture on the smartphone screen to zoom in on the reconstructed hologram image “Since our holographic microscope system can be built inexpensively it could potentially be useful for medical applications such as diagnosing sickle cell disease in developing countries,” said Nagahama “It could also be used for research in various field environments or in education by allowing students to observe living organisms at school and at home.” Digital holographic microscopes work by capturing the interference pattern between a reference beam and light scattered from the sample The hologram is then digitally reconstructed which generates 3D information that can be used to measure the sample’s features Although smartphone-based digital holography microscopes have been developed previously available technologies either reconstruct the holograms on a seperate device or lack real-time reconstruction This limitation arises from the restricted computing and memory capacity of most smartphones To achieve fast reconstruction on a smartphone the researchers used an approach called band-limited double-step Fresnel diffraction to calculate the diffraction patterns This method reduces the number of data points enabling faster computational image reconstruction from holograms I worked on portable digital holographic microscopes which initially used laptops as the computing system,” said Nagahama I began exploring their potential as computing systems for broader applications and considered leveraging them for tasks like removing artifacts from observed images which ultimately shaped the development of this microscope.” the researchers created a lightweight housing for the optical system using a 3D printer They also developed an Android-based application to reconstruct the holograms acquired by the optical system The microscope generates a reconstructed image of the hologram on the image sensor of a USB camera built into the optical system This hologram can be observed by the Android smartphone which provides computational image reconstruction in real time The reconstructed hologram is then displayed on the smartphone where users can interact with it via the touchscreen The researchers evaluated their new microscopy system by using a prepared object with a known pattern and then testing whether the pattern on the object could be accurately observed with the microscope They were able to successfully observe the pattern on the test target and also used the microscope to image other samples such as a cross section of a pine needle The researchers showed that when using band-limited double-step Fresnel diffraction holograms could be reconstructed at a frame rate of up to 1.92 frames per second This enabled images to be displayed in almost real time when observing stationary objects they plan to use deep learning to improve the quality of the images generated with the smartphone based microscope Digital holographic microscopes often generate second unintended images during hologram reconstruction and the researchers are exploring how deep learning could be used to remove these unwanted images Optica Publishing Group is a division of the society, Optica It publishes the largest collection of peer-reviewed and most-cited content in optics and photonics the society’s flagship member magazine and papers and videos from more than 835 conferences our publications portfolio represents the full range of research in the field from around the globe Applied Optics publishes in-depth peer-reviewed content about applications-centered research in optics. These articles cover research in optical technology, photonics, lasers, information processing, sensing, and environmental optics. Optica Publishing Group publishes Applied Optics three times per month and oversees Editor-in-Chief Gisele Bennett, MEPSS LLC. For more information, visit Applied Optics 10.1364/AO.532972 Interactive zoom display in smartphone-based digital holographic microscope for 3D imaging are not responsible for the accuracy of news releases posted to EurekAlert by contributing institutions or for the use of any information through the EurekAlert system Copyright © 2025 by the American Association for the Advancement of Science (AAAS) Yuki Nagahama has shown how a simple optical system connected to a smartphone with suitable software can be used to capture and then reconstruct holograms (in this case of a pine tree leaf) A scientist in Japan has devised a new way of using a smartphone to capture 3D images in the form of holograms (Appl. Opt., doi: doi.org/10.1364/AO.532972) which relies on compressing the data within a digital hologram is compact and cheap and might prove useful for medical diagnosis―particularly in remote areas The idea underlying the work is to use a digital form of holography to obtain both amplitude and phase information from a microscopic sample in a single shot this involves bouncing light off the specimen and interfering the scattered beam with a reference beam Holograms are then reconstructed by using wave propagation calculations allowing the object to be viewed in three dimensions Researchers have already shown how this principle could be exploited for bio-imaging to study cell division and other cell dynamics as well as diagnose sickle cell disease But most demonstrations to date have been one-offs Some groups have instead used smartphones as part of the process of collecting and reconstructing images these systems all have their limitations―they either require a separate device for reconstructing the holograms or forego real-time image generation by doing everything on the phone Yuki Nagahama at the Tokyo University of Agriculture and Technology has found it is possible to reconstruct holograms on a smartphone in close to real time using an Android-based application that he designed The system relies on a separate optical device to record the holograms but this device can be made using a compact 3D printer and contains nothing more than a semiconductor laser and standard USB camera—neither bulky nor expensive (Using the smartphone itself to do the recording would mean removing the lens from the phone’s camera which would prevent it from taking pictures.) Key to the new scheme is a less computation-intensive form of digital holography better suited to smartphones which tend to have limited processing and memory capabilities This “band-limited double-step Fresnel diffraction” involves creating a virtual plane between the hologram and image planes and then placing that imaginary surface at whatever distance is required to yield a given sampling rate at the image plane (placing this surface nearer the object lowers the required rate but also limits the area that can be observed) To put his smartphone-based system through its paces Nagahama used it to image a leaf from a pine tree He showed that it could accurately reproduce both the object's amplitude and phase information and he found that while holography using convolution-based diffraction yielded about 0.7 frames per second the double-step method instead reached about 1.9 frames per second he also showed it was possible to zoom in on and out of the reconstructed image by pinching the phone's touch screen He enabled this feature by using what are known as scalable diffraction calculations Nagahama says that his next step is to use deep-learning techniques to remove the unwanted secondary images that are sometimes produced when reconstructing digital holograms he hopes to capture holograms of moving as well as static objects by employing multiple processors to carry out calculations in parallel―perhaps using the graphics processing unit built into a smartphone’s system on a chip he says that the most expensive material item is the USB camera Wafer‑Scale Switch Promises a Photonic Fast Lane for AI A New Color Comes into View Optical Vortices Today's print edition Home Delivery Three men were arrested on Thursday for allegedly hiding a body inside a home freezer in the city of Nagahama a court clerk at the Nagahama Summary Court a 62 year-old part-time cleaner in the city of Sakai Osaka Prefecture.googletag.cmd.push(function() { googletag.display('div-gpt-ad-1499653692894-0'); }); The three are accused of conspiring to store the body in the freezer at Iwase’s home The frozen body was found in a crouched position and is thought to have been kept in the freezer for a long time The broadcaster also reported that an examination is likely to take time due to the body's condition The suspects' responses to the allegations have not been disclosed the case came to light on Tuesday through another incident in Osaka Prefecture in which a suicide note was found at the scene The note reportedly contained information indicating the involvement of Iwase and the others in the case of the body in the freezer Police in Shiga conducted an investigation based on information provided by the Osaka Prefectural Police Shiga police are working to identify the body and are investigating the circumstances surrounding the victim’s death in detail In a time of both misinformation and too much information quality journalism is more crucial than ever.By subscribing Your subscription plan doesn't allow commenting. To learn more see our FAQ Sponsored contents planned and edited by JT Media Enterprise Division director and animator Hiroshi Nagahama was invited to attend the local San Japan 2024 convention in San Antonio He is better known for his directorial depiction of surrealism in works such as Mushishi and The Flowers of Evil but became the series director of Uzumaki‘s first episode Nagahama shared some personal stories as a creator and held an open discussion with the fans at the convention specifically praising Redline’s director Takeshi Koike for his work The “Learn The Anime Industry with Anime Director Hiroshi Nagahama” panel provided a fire chat-style discussion for Nagahama and fans to talk about their love and passion for anime It began with Nagahama asking fans to share their favorite anime he began asking the audience and having them shout out various anime titles Nagahama reminisced on why Redline was memorable with its level of detail and work and shared his respect for director Takeshi Koike at Madhouse As more fans began to shout out other familiar titles which was one of Nagahama’s early directorial anime series was in the crowd while Nagahama talked about the production and she followed up by noting  how she knew about Nagahama’s recent work Nagahama began live-sketching the Detroit Metal City character Soichi Negish partly out of nostalgia and to pay homage to Tanaka-san’s production studio Unlike many live-drawings events that include a simultaneous Q&A component to it the 20-minute sketch from Nagahama captivated the audience enough that they remained relatively quiet throughout The Uzumaki anime series premiered September 28 on Adult Swim and stream on Max in the United States The 4-episode limited anime series was produced by studios Fugaku (for Episode 1 and Episode 4) and Akatsuki (for Episode 2 and Episode 3) Colin Stetson (Hereditary) served as the music composer and Aki Itami (Forest of Piano Production I.G USA and Adult Swim co-produced the anime An official anime trailer was recently released ahead of the premiere Junji Ito‘s Uzumaki horror manga was originally serialized from 1998 to 1999 in Shogakukan’s Big Comic Spirits and is collected into three tankoubon volumes a small fogbound town on the coast of Japan the withdrawn boyfriend of teenager Kirie Goshima their town is haunted not by a person or being but a pattern: UZUMAKI the spiral—the hypnotic secret shape of the world The bizarre masterpiece horror manga is now available all in a single volume A live-action film adaptation was released in 2000 Software Communications Lighting Electrical/​Electronics RF & Microwave Electronics Semiconductors & ICs Energy Photonics/​Optics Imaging Motion Control Robotics, Automation & Control Test & Measurement Sensors/​Data Acquisition Manufacturing & Prototyping Materials & Coatings Mechanical & Fluid Systems Propulsion Transportation Automotive Current Issue Magazine Archives SUBSCRIBE Researchers have developed a new smartphone-based digital holographic microscope that enables precision 3D measurements enabling precise measurements of the sample’s surface and internal structures “Our digital holographic microscope uses a simple optical system created with a 3D printer and a calculation system based on a smartphone,” said Research Team Leader Yuki Nagahama from the Tokyo University of Agriculture and Technology portable and useful for a variety of applications and settings.” the researchers demonstrate the smartphone-based digital holographic microscope’s ability to capture “Since our holographic microscope system can be built inexpensively such as diagnosing sickle cell disease in developing countries,” said Nagahama “It could also be used for research in various field environments or in education by allowing students to observe living organisms at school and at home.” which generates 3D information that can be used to measure the sample’s features available technologies either reconstruct the holograms on a separate device or lack real-time reconstruction which initially used laptops as the computing system,” said Nagahama which ultimately shaped the development of this microscope.” Here is an exclusive Tech Briefs interview Tech Briefs: What was the biggest technical challenge you faced while developing this smartphone-based microscope Nagahama: The biggest technical challenge was the issue of calculation speed smartphones have limited computing resources and memory capacity the convolutional diffraction calculation algorithm that has been used in personal computer-based calculation systems up to now has not been able to achieve the expected calculation speed we have improved the calculation speed by adopting “Band-limited double-step Fresnel diffraction,” which is a diffraction calculation algorithm that uses fewer calculation resources the current calculation speed is still unsatisfactory we are examining whether it is possible to perform calculations at higher speeds using the GPUs built into smartphones Tech Briefs: How did this project come about Nagahama: The idea for a portable digital holographic microscope was based on a research topic conducted in my laboratory when I was a student as the performance of smartphones has improved I came up with the idea that a more sophisticated system could be created by using smartphones as the computation system Tech Briefs: Can you explain in simple terms how it works Nagahama: This digital holographic microscope system employs Gabor-type optics [see image below] one transmitted through an object (object light) and the other transmitted through an area without an object (reference light) enter the image sensor and are recorded as interference fringes These interference fringes are called holograms and information about the object light is recorded in the holograms The object is then observed by performing light diffraction calculations on the hologram to simulate the state of the object light at the position where the object is located Tech Briefs: Do you have plans for any further research/work/etc Nagahama: To improve the image quality of the observed image in this smartphone-based microscope we are first considering the removal of the unintended second image is caused by the hologram recorded by the image sensor having only light intensity information we generate holograms for which both the intensity and phase information of the light is known through simulations based on diffraction calculations of the light Smartphone-Based COVID-19 Test Smartphone System Tests for Lead in Water and we are currently investigating how to implement this method in smartphones Tech Briefs: Do you have any advice for engineers/researchers aiming to bring their ideas to fruition Nagahama: It would be good to have a prototype It is easier to get people interested in your idea and to give you advice if you have a prototype How MXenes Can Improve Air Filtration A Donut-Shaped In-Wheel Motor for Military Electric Vehicles How Will TSN Ethernet Impact the Future of Embedded Computing? A Better-Performing Sodium-Ion Cathode New Research Sheds Light on Using Multiple CubeSats for In-Space Servicing... New Atom-Based Thermometer Measures Temperature More Accurately AI and Machine Learning in Medical Device Cybersecurity Optimizing Electric Powertrains: Advanced Materials for Performance, Safety, and Efficiency Breakthrough in Infrared and Visible Imaging: One Dataset with Spatial and Temporal Alignment Improving Rocket and Flight Vehicle Testing Under Capital Constraints Advancing Automotive Manufacturing with Digital Twins Powering NewSpace Missions: Navigating the Cost vs. Reliability Challenge Medical Design Briefs Mobility Engineering Technology Service Status By submitting your personal information, you agree that SAE Media Group and carefully selected industry sponsors of this content may contact you and that you have read and agree to the Privacy Policy You may reach us at privacy@saemediagroup.com Subscriber Services Contact Us Advertise Cookie Usage Where to find and destroy the gunpowder for the Nagahama Black Powder quest Stopping the gunpowder shipment in Assassin's Creed Shadows is part of the Nagahama Black Powder quest you need to complete to track down The Mourner Shinbakufu Before you can do this though, you must find the Teppo Factory clue first, then you can start tracking down the gunpowder. We found this Assassin's Creed Shadows task much easier by being stealthy you also cannot sabotage the gunpowder if the guards are on alert - so be careful here's how to stop the gunpowder shipment in Assassin's Creed Shadows The gunpowder shipment in Assassin's Creed Shadows is on a large ship south of Teppo Factory and south-west of Nagahama castle in Nagahama (in north-east Omi) We've marked the ship's location on the map below but it should be highlighted for you on your map: head to the south dock and steal a boat (you can also swim there if you want) head for the rear side of it and then start to climb up it until you get to the deck We assassinated them silently to continue our path forward When you're on the deck at the rear of the ship You need to make your way to the second floor We did this by climbing up the outside quickly and in through the upper window we've marked on the image below: so as soon as you reach this area you need to engage quickly and take them out or they'll alert the rest of the boat to your presence look at the table on the left side of the room and collect the item on here from here exit out of the window and make your way to the front of the boat using the rooftops stay in the middle of them to remain hidden from view When you're at the front of the ship you should see a lot of gunpowder barrels here The one you need to sabotage will be a smaller black one that's marked with your quest marker you must remain anonymous or you won't be able to sabotage it wait for the large enemy below to be the only one there (sometimes two more are in the area drop down from the roof when the large enemy's back is turned and find cover again when the large enemy's back is turned stay crouched and make your way to the barrel run to the edge of the ship and dive off into the water to start swimming away A cutscene will then follow that marks the end of the quest © 2025 Eurogamer.net a brand of IGN Entertainment No part of this website or its content may be reproduced without the copyright owner's permission Eurogamer is a registered trademark of Gamer Network Limited A new easily portable digital holographic microscope could broaden a range of applications by making precision 3D measurements accessible through smartphone-powered technology The low-cost microscope features capabilities that could assist in everything from near-patient testing to educational and scientific uses By digitally recreating 3D information about objects and environments with holographic technology holographic microscopes allow researchers to make highly precise measurements of not only the surfaces of objects digital holographic microscopes are less than optimal for field use since they can only function by relying on elaborate technologies that normally require conventional desktop computers to make calculations That is all about to change with the development of a new simpler optical system by researcher Yuki Nagahama from the Tokyo University of Agriculture and Technology and her team which employs 3D printing capabilities and smartphone-based calculations to create what Nagahama says will be a new microscope that is “inexpensive The new holographic microscope is capable of functioning in close to real time according to a new paper the team published in the journal Applied Optics Similar to normal images captured with smartphone cameras once a microscopic image is produced by Nagahama’s system users can “pinch” the rendering to zoom in and view portions of the reconstruction in greater detail Nagahama says that the new application could be useful in a wide range of medical applications particularly in regions where such technologies are currently inaccessible Additional uses for the new holographic microscope include research efforts in the wild where precision 3D renderings of microscopic objects have previously never been possible the concept for this new holographic application drew from her personal experiences “When I was a student, I worked on portable digital holographic microscopes, which initially used laptops as the computing system,” Nagahama said in a statement as more and more smartphone apps extended the normal functions of mobile phones to enable novel capabilities Nagahama began looking at how they might also serve as the computers for powering applications in a wide range of areas “which ultimately shaped the development of this microscope.” digital holographic microscopes detect interference patterns that emerge between light scattered from the sample in question and a reference beam produced by the device the hologram is reconstructed using 3D information that can measure a sample The new device is not the first smartphone-based holographic microscope, and while others exist Nagahama’s is the first to feature almost real-time reconstruction capabilities by relying on what is called band-limited double-step Fresnel diffraction which enables fast calculations based on the diffraction patterns it observes The faster process is made possible by greatly reducing the amount of data required for collection during use The new system is housed within a lightweight container which includes both the microscope’s optical system and the 3D printer Holograms are reconstructed using an Android application designed specifically for use with the new technology which employ the image sensor of a camera connected to the device via USB the resulting image is displayed on the smartphone screen the new microscope can reconstruct holograms at frame rates of up to 1.92 frames per second Nagahama and the team plan to improve the new application with help from deep learning which they hope will limit the production of secondary imagery that are unintended artifacts which occasionally arise from the holographic reconstruction process The team’s findings appeared in the recent study “Interactive zoom display in a smartphone-based digital holographic microscope for 3D imaging,” published in Applied Optics on August 23 Micah Hanks is the Editor-in-Chief and Co-Founder of The Debrief. He can be reached by email at micah@thedebrief.org. Follow his work at micahhanks.com and on X: @MicahHanks The official X (formerly Twitter) account for Shinshokan's Dear+ and Cheri+ magazines announced on November 29 that Scarlet Beriko will launch a continuation for the Nagahama to Be, or Not to Be series in the March issue of Cheri+ on January 30 Seven Seas' released the original manga in English and describes the story: Beriko debuted the manga in Cheri+ in January 2023 Seven Seas released the manga in English as part of an overall project for 11 different publishers to simultaneously release the single volume in 11 territories Source: Dear+'s X/Twitter account A woman's body found in a home freezer in the city of Nagahama last week has been identified as the wife of one of the three suspects arrested in connection with the case Shiga Prefectural Police said on Wednesday The body has been identified as Mariko Nonaka who has been arrested on suspicion of abandoning a corpse.googletag.cmd.push(function() { googletag.display('div-gpt-ad-1499653692894-0'); }); Shiga police have also arrested two other suspects: Tatsuhiko Iwase Nonaka is believed to be Tatsuhiko’s uncle The Nagahama Police Station reported that an autopsy revealed no life-threatening external injuries The exact cause of death is still under investigation.​ Mariko Nonaka's body was discovered on April 2 when investigators visited Iwase’s residence following information provided by the Osaka Prefectural Police The tip-off came from a suicide note found in connection with a separate incident in Osaka Prefecture The note reportedly contained information indicating the involvement of Iwase and the others in the body abandonment case The body was found frozen in a crouched position Where to find the clue in Teppo Factory for the Nagahama Black Powder quest Finding the clue in Teppo Factory in Assassin's Creed Shadows is part of the Nagahama Black Powder quest which you'll need to complete while chasing down The Mourner Shinbakufu If you've not explored much of Omi, the first challenge is finding Teppo Factory itself as Omi is a very big place and, in true Assassin's Creed Shadows style here's the Assassin's Creed Shadows Teppo Factory clue location you can find Teppo Factory in west Nagahama This is west of Ibu Highlands and south of Goshiki Outlands We've marked the location on the maps below: For the 'Nagahama Black Powder' quest in Assassin's Creed Shadows you can find the clue in Teppo Factory in the south-west corner of the factory When you get to the area marked on the map above look for the raised wooden platform that's facing the water Use Observation to find the blue dot here if you're not sure you're in the right place Climb this wooden platform and the clue will be laying on the table here. Walk over to it and 'read' it to collect the clue. This will then lead you to the next part of this quest, stopping the gunpowder shipment The staff of Otakon revealed on Friday that it will host director Hiroshi Nagahama and voice actress Uki Satake (pictured at right) at this year's event He began his career at Madhouse, where he was the concept designer for Revolutionary Girl Utena. He was also the storyboarder, the animation director, and key animator for Sexy Commando Gaiden: Sugoi yo!! Masaru-san. He was also the chief director of Jubei-Chan 2: The Counter Attack of Siberia Yagyu She made her voice acting debut as Podungo and female Kite in Hunter x Hunter Satake has since voiced characters in various anime including QT in Space Dandy, Ellen Tadano in Crayon Shin-chan Spin-off: Aliens vs. Shinnosuke, Tsubomi in Mob Psycho 100, and Lox Stella in ACCA: 13-Territory Inspection Dept. She also voiced Uki in Nagahama's THE REFLECTION Otakon 2024 is scheduled for August 2-4 at the Walter E. Washington Convention Center in Washington, D.C. Last year's event took place in July 2023 Source: Press release (link 2) which was originally published in Japanese language on 4 Mar a member of 〈Sakuranbo Kyouseien〉 in Sagae City a student at the main campus of the Murayama School for Special Needs Education ‘Kizashi and Manazashi’ is an open call exhibition that has been held in Yamagata since 2019 It focuses on the “expressions” (kizashi) of people with disabilities and the “gaze” (manazashi) that follows them TAKEDA Kazue is one of the people working behind the scenes on the exhibition She visits welfare facilities and individuals all over Japan to ask about expressive activities that are currently taking place there was a person who would take equipment outside and line it up in the parking lot on a near-daily basis from the perspective of those who wanted to use the equipment continued to take photographs and document it from their own honest point of view: “Why are they doing this?” They saw in this person’s collection of “mischievous” activities an expression of the person’s will “Actions seen as problematic behavior could This is why the ‘Kizashi and Manazashi’ exhibition introduces the ‘expressions’ (kizashi) that emerge from such relationships,” says Takeda appeared in the distance as we drove along the national highway We passed golden rice paddies dancing with dragonflies and orchards growing apples we arrived at the main campus of the Murayama School for Special Needs Education The school building was surrounded by trees and was illuminated by soothing natural daylight Students’ cheerful voices echoed through the hallways and classrooms NAGAHAMA Tetsuya (who goes by “Tecchin”) is a senior in high school here He spends every lunch break drawing in the classroom “He draws things up so fast—dozens of pictures every day without fail,” says his mother who works as a teacher at a nursery school She showed us some of the works he had created so far The tote bags and paper bags filled with bundles of drawings that she handed to us were incredibly heavy “I think Tecchin’s drawings make use of techniques he developed himself.” I recalled Takeda’s words before the interview: Tetsuya is autistic and is not very good at speaking he was unable to express his emotions and often threw tantrums or cried in panic he learned to communicate what was on his mind by showing people pictures and words on a magnetic drawing board such as “I want to eat chocolate ice cream.” Then after participating in an open call exhibition when he entered junior high school he began to express his feelings and desires “I was worried that he might not be interested in other people since he had been playing by himself for so long I realized how rich and expansive Tecchin’s world is,” says Naoko there is a drawing he made of many people and animals smiling and waving their hands I could tell that he was happy to see all the daycare members and staff waving goodbye to him as he rode home from the after-school daycare program He doesn’t show what he’s feeling outwardly Drawing has now become Tetsuya’s means of everyday communication Shiho has long been an observer of Tetsuya’s quest for self-expression and ingenuity in the way he lives his life I became acutely aware of how we can compensate for our weaknesses in order to create a more livable society,” Shiho says How can we empathize with the minds of other people which she developed naturally while growing up with Tetsuya is also useful in her own work with children Follow us on social media for notifications about The Nippon Foundation DIVERSITY IN THE ARTS events Metrics details Cross-sectional relationships between nocturia and sleep problems have been well evaluated but the risk association for each incidence is scarcely reported This analysis included 8076 participants of the Nagahama study in Japan (median age 57 31.0% male) and associations between nocturia and self-reported sleep-related problems (poor sleep) were evaluated cross-sectionally Causal effects on each new-onset case were analyzed longitudinally after 5 years Three models were applied: univariable analysis demographic and lifestyle variables) and full adjustment for basic and clinical variables The overall prevalences of poor sleep and nocturia were 18.6% and 15.5% while poor sleep was positively associated with nocturia (OR = 1.85 Baseline nocturia was positively associated with this incident poor sleep (OR = 1.49 Baseline poor sleep was positively associated with this incident nocturia (OR = 1.26 p = 0.026); such associations were significant only in women (OR = 1.44 p = 0.004) and under-50-year-old groups (OR = 2.82 Nocturia and poor sleep associate with each other Baseline nocturia can induce new-onset poor sleep while baseline poor sleep may induce new-onset nocturia only in women and showed the bidirectional effects of self-reported large-scale reports have since explored such longitudinal relationships the aim of this study was to complete a longitudinal study on interlocking factors between nocturia and self-reported sleep-related problems in a large Japanese cohort over 5 years while focusing on gender differences the relationship between nocturia and self-reported sleep-related problems at baseline by cross-sectional analysis is demonstrated also discovering links between new-onset nocturia/baseline self-reported This study was designed in compliance with the Declaration of Helsinki and was approved by the Kyoto University Graduate School and Faculty of Medicine Ethics Committee (No the Ad Hoc Review Board of the Nagahama Study and the Nagahama Municipal Review Board of Personal Information Protection informed consent to participate and allow their data to be used in the present study Hyperglycemia was defined based on medical history and glycated hemoglobin levels (A1c ≥ 6.5%) Obstructive sleep apnea was determined based on medical history Mental health was assessed by the Mental Health Inventory-5 (MHI-5) a screening questionnaire for anxiety and depressive symptoms The definition of new-onset nocturia refers to individuals who did not report nocturia at baseline but developed the condition during the 5-year follow-up period new-onset poor sleep refers to individuals who did not report poor sleep at baseline but developed sleep-related problems during the follow-up period Factors independently associated with nocturia and poor sleep were assessed using multivariable logistic regression analysis with three models: (1) univariate analysis (2) adjustment for baseline basic variables (i.e. and (3) adjustment for baseline basic and clinical variables (hyperglycemia A p value less than 0.05 was considered statistically significant All statistical analyses were performed using the commercially available software package JMP 14.2.0 (SAS Proportion of participants who reported poor sleep by nocturnal urinary frequency Sanky diagram visualizing the prevalence flow of nocturia and poor sleep among participants In the present cohort study of a relatively healthy population nocturia and poor sleep were significantly associated with each other in a cross-sectional analysis nocturia was clearly a significant risk for incident poor sleep while poor sleep was a statistically significant but weak risk for incident nocturia any studies evaluating relationships between poor sleep and nocturia should be inclusive of both sexes and stratify results by sex whenever possible Regarding the risk of nocturia causing poor sleep in the under-50 cohort about half of men with nocturia developed poor sleep but women did not experience this to the same degree these data suggest men under 50 with nocturia as a special risk population for poor sleep pathogenesis using 50 years of age as a stratification cutoff was useful in eliminating some of these causes for younger-middle-aged men in the analysis Since only a few factors in younger people contribute to the incidence of nocturia (other than poor sleep) the true effect of poor sleep on incident nocturia may be more evident in these younger populations Proactive interventions for poor sleep caused by stress and lifestyle disturbances would also be desirable in terms of prevention of nocturia only sleep quality (yes/no) and presence/absence of sleeping pills were analyzed while the degree and classification of sleep disorders were not evaluated the causal association between the degree of poor sleep and nocturnal urinary frequency remains unknown Follow-up is ongoing with more quantifiable evaluation methods and future studies are expected although participants with a history of dialysis or undergoing treatment for obstructive sleep apnea (which may be directly related to nocturia) were excluded therapeutic interventions for nocturia and poor sleep during the 5-year course of the study were not evaluated The cross-sectional analysis excluded participants who were not available for follow-up to be evaluated in the same population as the longitudinal analysis stratified by gender age cutoffs from a clinical view while interactions were evaluated in the multivariable analyses The prevalence of nocturia itself is low among participants younger than 50 years of age this is an epidemiological study and the mechanism of the associations between nocturia and poor sleep is not known; however the gender and age differences highlighted in this study may shed light on approaches to fully understanding such mechanisms sleep-related problems were closely related to each other with differences in their effects depending on gender and age Nocturia was clearly associated with risk of developing self-reported sleep-related problems in both men and women sleep-related problems were associated with the risk of nocturia onset in women only The datasets generated during and/or analysed during the current study are not publicly available due to the cohort data of the Nagahama study group but are available from the corresponding author on reasonable request International Continence Society (ICS) report on the terminology for nocturia and nocturnal lower urinary tract function The impact of nocturia on falls and fractures: A systematic review and meta-analysis The impact of nocturia on mortality: A systematic review and meta-analysis Impact of nocturia on mortality: The Nagahama study Epidemiology of insomnia: What we know and what we still need to learn sleep disturbance and general health-related quality of life: Is there a relation? Sleep disturbances in older adults are associated to female sex The mediating role of sleep quality in the association between nocturia and health-related quality of life Differences in the association of nocturia and functional outcomes of sleep by age and gender: A cross-sectional Sleep disturbance has a higher impact on general and mental quality of life reduction than nocturia: Results from the community health survey in Japan and causes of sleep interruption in a Danish population of men and women aged 60–80 years Quantitative association between nocturnal voiding frequency and objective sleep quality in the general elderly population: The HEIJO-KYO cohort Association of sleep disorders with nocturia: A systematic review and nominal group technique consensus on primary care assessment and treatment Sex differences in insomnia: From epidemiology and etiology to intervention Sex differences in insomnia: A meta-analysis Sleep related problems and urological symptoms: Testing the hypothesis of bidirectionality in a longitudinal vitality and utility in a group of healthy professionally active individuals with nocturia A multinational study of sleep disorders during female mid-life A Longitudinal study of bidirectional relationships between sleep disorder and frequency of nocturia: Results from the Iwaki health promotion project Short-wavelength light exposure at night and sleep disturbances accompanied by decreased melatonin secretion in real-life settings: A cross-sectional study of the HEIJO-KYO cohort Association between melatonin secretion and nocturia in elderly individuals: A cross-sectional study of the HEIJO-KYO cohort Chronobiology of micturition: Putative role of the circadian clock Clinical guidelines for male lower urinary tract symptoms and benign prostatic hyperplasia Effects of walking exercise on nocturia in the elderly Tai, Y. et al. Association between before-bedtime passive body heating and nocturia during the cold season among older adults. J. Epidemiol. https://doi.org/10.2188/jea.JE20210471 (2022) Diurnal rhythms of urine volume and electrolyte excretion in healthy young men under differing intensities of daytime light exposure Efficacy and safety of desmopressin in women with nocturia: A systematic review and meta-analysis of randomized controlled trials Download references We are extremely grateful to the Nagahama City Office and non-profit organization Zeroji Club for their help in performing the Nagahama Study The Nagahama Study group executive committee is composed of the following individuals: Yasuharu Tabara Fumihiko Matsuda (Center for Genomic Medicine Kyoto University Graduate School of Medicine) Shinji Kosugi (Department of Medical Ethics and Medical Genetics and Takeo Nakayama (Department of Health Informatics The Nagahama study was supported by a university grant and the Research Program for Health Behavior Modification by Utilizing IoT (le0110005) from Japan Agency for Medical Research and Development (AMED); the Takeda Medical Research Foundation; the Mitsubishi Foundation; the Daiwa Securities Health Foundation; and the Sumitomo Foundation This study was also supported by the Takeda Science Foundation The authors declare no competing interests Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Download citation DOI: https://doi.org/10.1038/s41598-023-36707-y Sign up for the Nature Briefing newsletter — what matters in science « Back Metrics details constitutes a major health problem due to the large number of patients Intermittent hypoxia caused by SDB induces alterations in metabolic function metabolites characteristic for SDB are largely unknown we performed gas chromatography-mass spectrometry-based targeted metabolome analysis using data from The Nagahama Study (n = 6373) SDB-related metabolites were defined based on their variable importance score in orthogonal partial least squares discriminant analysis and fold changes in normalized peak-intensity levels between moderate-severe SDB patients and participants without SDB We identified 20 metabolites as SDB-related these metabolites were frequently included in pathways related to fructose Multivariate analysis revealed that moderate-severe SDB was a significant factor for increased plasma fructose levels (β = 0.210 generalized linear model) even after the adjustment of confounding factors We further investigated changes in plasma fructose levels after continuous positive airway pressure (CPAP) treatment using samples from patients with OSA (n = 60) diagnosed by polysomnography at Kyoto University Hospital and found that patients with marked hypoxemia exhibited prominent hyperfructosemia and their plasma fructose levels lowered after CPAP treatment These data suggest that hyperfructosemia is the abnormality characteristic to SDB the metabolic pathways that are characteristically associated with SDB remain unclear a large obstacle in the metabolic characterization of SDB patients is the confounding factors possessed by the majority of SDB patients These factors can strongly affect metabolic characteristics and interfere with the evaluation of specific associations between SDB and metabolic pathways One strategy to control for these confounding factors is to perform a study that includes large number of participants with diverse background and adjust for those factors studies conducted so far included a relatively small number of patients and it has been difficult to adequately control for confounding factors In this study we hypothesized that SDB is associated with specific metabolic pathways downstream of intermittent hypoxia and independent from other confounding factors By using targeted plasma metabolome data measured by gas-chromatography mass-spectrometry (GC–MS) in a large-scale community-based cohort we compared individuals with and without SDB for differences in metabolite levels we investigated changes in the identified metabolite after continuous positive airway pressure (CPAP) treatment using our institutional cohort data Participants were included in the present study when data from at least 2 nights were available Participants were excluded if plasma samples were not available for analysis or if they were already receiving treatment for OSA (e.g. continuous positive airway pressure (CPAP) treatment or oral appliance) Participants were instructed to skip the meal before the visit We also analyzed an institutional retrospective longitudinal cohort of clinically stable patients older than 20 years diagnosed with OSA by polysomnography at the Sleep Laboratory of Kyoto University Hospital between 2012 and 2014 The patients in this institutional cohort underwent polysomnography at diagnosis and a follow-up study three months after CPAP treatment to assess the treatment efficacy Patients lacking samples at the time of the diagnosis or the follow-up study were excluded as were those with acute infection or active malignancies The meals during hospital stay were decided prior to admission based on their age They did not have choices of contents that might change the amount of nutrients (e.g Patients finished the evening meal before 7 pm and then undergo polysomnography written informed consent was obtained from all participants The Ethics Committee of Kyoto University Graduate School of Medicine approved these two cohort studies (G0278 and E1475) These studies were performed in accordance with the Declaration of Helsinki Participants were divided into three groups based on their Acti-ODI3% values according to the American Association of Sleep Medicine guidelines: normal group: < 5/h mild group: 5 to < 15/h and moderate-severe group OSA in the institutional cohort was diagnosed according to the American Association of Sleep Medicine guidelines based on polysomnography results Plasma samples in the Nagahama study were collected at study visits and stored at − 80 °C until analysis Information including the participants’ sex and the timing of the last meal were collected and pulse rate were evaluated at the study visit We measured the maximum value of intima-media thickness of the common carotid artery (CCA-IMT-max) by ultrasonography through the lateral approach plasma samples were collected at the time of diagnosis and at each follow-up study Plasma samples were collected after the completion of polysomnography and before breakfast we evaluated the concentration of fructose in each sample using a single-point calibration curve derived from concentration-determined D-Fructose 13C6 (ISOTEC criteria were waist circumference ≥ 85 cm (male) or ≥ 90 cm (female) accompanied by two or more of the following factors: 1 systolic blood pressure ≥ 130 mmHg and/or diastolic blood pressure ≥ 85 mmHg; 2 plasma triglycerides ≥ 150 mg/dl and/or plasma HDL levels < 40 mg/dl and their waveform processing were performed using Shimadzu GC/MS solution software Version 2.71 (Shimadzu Corp. Small polar metabolites were identified using a commercially available GC–MS Metabolite Mass Spectral Database (Shimadzu Corp. Peak area of each metabolite was calculated and then normalized using the internal standard peak In the analysis of the institutional cohort we evaluated the actual concentration of each sample by using a single-point calibration curve derived from concentration-determined D-Fructose 13C6 (ISOTEC Raw peak intensity levels of plasma fructose and uric acid were compared between groups by the Kruskal Wallis test and Holm’s post-hoc test was used to compare two out of three groups To adjust the effects of confounding factors for the elevation of plasma peak intensity levels of these metabolites we used a generalized linear model by setting the link function as family = Gamma(log) Model 1 included the following factors as explanatory variables: age Model 2 included metabolic syndrome instead of diabetes and otherwise included the same variables as model 1 The association between CCA-IMT-max and normalized plasma fructose peak intensity values were assessed with the Spearman’s rank correlation test we compared the changes in plasma fructose levels before and after the introduction of CPAP treatment by the Wilcoxon signed-rank test Patients’ backgrounds were compared by Fisher’s exact test Correlations between changes in plasma fructose levels and the following factors were analyzed by Spearman’s test: baseline plasma fructose levels and total time of SpO2 < 80% during sleep A P-value of < 0.05 was considered as significant The circle indicates pathways which include fructose These results highlighted fructose as a characteristic metabolite in patients with SDB We further performed multivariate analyses for plasma levels of hypoxanthine and uric acid by using models with the same explanatory variables and revealed that moderate-severe SDB was also significantly related to high hypoxanthine and uric acid levels These results suggested that SDB was a specific factor for the increased plasma levels of fructose and its related metabolites Associations between fructose levels and the degree of hypoxemia (A): Association between baseline plasma fructose levels and lowest SpO2 levels during sleep at diagnosis (B): Associations between changes in plasma fructose levels and baseline plasma fructose levels (upper left) lowest SpO2 levels during sleep at diagnosis (upper right) changes in lowest SpO2 levels during sleep (lower left) and changes in AHI (lower right) SDB is accompanied by a broad range of abnormalities in plasma metabolites we have newly identified fructose as a critical metabolite related with SDB SDB was significantly associated with elevated levels of plasma fructose even after the adjustment of participants’ background factors and complications CPAP treatment was also found to lower plasma fructose levels especially in OSA patients with high plasma fructose and low SpO2 levels during sleep We found a number of large differences in the factors of participants’ background between their dataset and our dataset which might have affected the results of the analyses Future studies might examine metabolic features specific and universal among participants with different backgrounds fructose levels in OSA patients could be normalized through treatment This study suggests the potential significance of a therapeutic intervention targeting the SDB-fructose axis restricting the intake of fructose-containing foods (such as soft drinks) may be strongly recommended for patients with SDB inhibition of fructose uptake from the intestine may help prevent the progression of atherosclerosis progression in SDB patients Future studies should address these questions and to establish the significance of fructose as a plasma biomarker for SDB First is that detailed information about food intake by participants in the Nagahama Study was not available In order to minimize the effect of food intake on the data the participants were instructed to skip the meal before their visit to the test site and we found that there was no difference between the duration after the last meal nutritional intake by individual participants such as the amount of daily calorie consumption each patient was served meals in which components were carefully calculated according to meet the nutritional principles during the hospital stay These meals remained the same before and after CPAP treatment which suggests that nutrition intake was controlled in these patients The second is that the institutional cohort included only patients with OSA; 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Heart J. 40, 1149–1157. https://doi.org/10.1093/eurheartj/ehy624 (2019) Download references The authors express gratitude to the Nagahama City Office and the nonprofit organization Zeroji Club for their assistance in conducting the Nagahama study This study was funded by a University Grant a Grant-in-Aid for Scientific Research from the Ministry of Education and the Global University Project from Japan Science and Technology Agency Japan Agency for Medical Research and Development (AMED) under Grant Number wm0425018 the Intractable Respiratory Diseases and Pulmonary Hypertension Research Group from the Ministry of Health Labor and Welfare of Japan (H29-intractable diseases-general-027 and 20FC1027) the Takeda Medical Research Foundation (Grant Number not applicable) Mitsubishi Foundation (Grant Number not applicable) Daiwa Securities Health Foundation (grant number not applicable) Sumitomo Foundation (Grant Number not applicable) the Research Foundation for Healthy Aging (grant number not applicable) Labour and Welfare Sciences Research Grants Research on Region Medical (H28-iryo-ippan-016 The Department of Respiratory Care and Sleep Control Medicine is funded by endowments from Philips-Respironics Fukuda Denshi and Fukuda Lifetec-Keiji to Kyoto University Department of Respiratory Care and Sleep Control Medicine Department of Advanced Medicine for Respiratory Failure Department of Primary Care and Emergency Medicine National Hospital Organization Kyoto Medical Center Department of Biomedical Statistics and Bioinformatics performed GC–MS analysis and data interpretation data interpretation and revision of the manuscript cellular experiments and revision of the manuscript T.Ha and T.Hi contributed to data interpretation and review of the manuscript supervised cellular experiments and data analysis contributed to the study design and revision of the manuscript is the guarantor and accepts full responsibility for conducting the whole project prepared the manuscript and controlled the decision to publish All authors gave final approval of the manuscript Yoshinari Nakatsuka reports grants from Philips-Respironics outside the submitted work; Kimihiko Murase reports grants from Philips-Respironics outside the submitted work; Kazuhiro Sonomura is an employee of Shimadzu during the conduct of the study; Yasuharu Tabara reports grants from Japan Agency for Medical Research and Development (AMED) grants from Daiwa Securities Health Foundation during the conduct of the study; Tadao Nagasaki reports grants from Philips-Respironics outside the submitted work; Satoshi Hamada reports grants from Teijin Pharma outside the submitted work; Hirofumi Takeyama reports grants from Philips-Respironics outside the submitted work; Hironobu Sunadome reports grants from Philips-Respironics outside the submitted work; Naomi Takahashi reports grants from Philips-Respironics outside the submitted work; Tomohiro Handa reports grants from Teijin Pharma outside the submitted work; Taka-Aki Sato is an employee of Shimadzu during the conduct of the study; Takeo Nakayama reports personal fees from Ohtsuka Pharamaceutical co. personal fees from Dainippon Sumitomo Pharmaceutical co. personal fees from Ono Pharamaceutical co. personal fees from Chugai Pharamaceutical co. personal fees from Takeda Pharamaceutical co. personal fees from Janssen Pharmaceutical K.K personal fees from Boehringer Ingelheim International GmbH other from HANSHIN Dispensing Holding Co.,Ltd. personal fees from Nikkei Business Publications personal fees from Mitsubishi Tanabe Pharma Corporation outside the submitted work; Fumihiko Matsuda reports grants from Kyoto University grants from Japan Agency for Medical Research and Development (AMED) grants from The Takeda Medical Research Foundation during the conduct of the study; Kazuo Chin reports grants from the Japanese Ministry of Education grants from the Intractable Respiratory Diseases and Pulmonary Hypertension Research Group from the Ministry of Health grants from the Center of Innovation Program Japan Agency for Medical Research and Development grants from the Research Foundation for Healthy Aging during the conduct of the study; grants and personal fees from Philips-Respironics grants and personal fees from Fukuda Denshi grants and personal fees from Fukuda Lifetec Keiji and Tokyo grants and personal fees from Teijin Pharma grants from Nippon Boehringer Ingelheim Co. grants and personal fees from GlaxoSmithKline Toyohiro Hirai and Yoichiro Kamatani have nothing to disclose Download citation DOI: https://doi.org/10.1038/s41598-023-40002-1 thin-noodled ramen found in stalls through Fukuoka similar to Hakata ramen (which also has roots in Fukuoka) they have to eat really fast,” Yamada says “I’ve been to those ramen shacks so many times Yamada is now the one running a Nagahama ramen shop Yamada and chef Taka Terashita opened Wu-Rons in the former Noraneko space specializing in Nagahama-style tonkotsu ramen Hip hop plays on the speakers as Portlanders order noodles from the counter the ramen itself isn’t some sort of Portland-Japanese fusion; Terashita wanted to stay true to what’s sold in Yamada’s hometown The tonkotsu broth boils for around eight to 10 hours before landing in a bowl with a pile of thin A layer of sesame seeds mingles with floating scallions swirling around thick sliced-and-seared slabs of chashu pork the key to nailing tonkotsu isn’t about the toppings; it’s about the broth “The secret is the balance: some use more ham bone or more back bone.” The secret to Wu-Rons’s broth is still under lock-and-key but the resulting broth remains light in texture Wu-Rons menu is extremely simple: Nagahama ramen and a vegetarian tantan made with both dried and fresh mushrooms the restaurant may introduce snacks like karaage and Terashita and Yamada are picking out sakes for the shop and making sure the energy of the shop feels right “I want people to walk in and feel pumped.” • Wu-Rons [Official]• Wu-Rons [Instagram] Metrics details Little is known about the association of prolonged cough We aimed to clarify this association using data from the Nagahama cohort a prospective study of participants from the general population Self-report questionnaires on prolonged cough were collected at baseline and 5-year follow-up assessments Blood tests at follow-up were used for gas chromatography-mass spectrometry-based metabolomics The association between metabolites and prolonged cough was examined using the partial least squares discriminant analysis and multiple regression analysis 632 had newly developed prolonged cough at follow-up which was defined as “new-onset prolonged cough” Low plasma citric acid was significantly associated with new-onset prolonged cough even after the adjustment of confounding factors including the presence of asthma and gastroesophageal reflux disease (GERD) A similar association was observed for isocitric acid The analysis of these four metabolites revealed that citric acid had the strongest association with new-onset prolonged cough This significant association remained even when the analysis was confined to participants with UACS or GERD at baseline or follow-up and these associations were also observed in participants (n = 976) who had prolonged cough at follow-up regardless of baseline status low blood citric acid may be associated with prolonged cough are well-known to often underlie prolonged cough some participants complain of prolonged cough without these underlying diseases the mechanisms that underlie prolonged or chronic cough remain largely unclear but metabolites that are relevant to prolonged or chronic cough remain unknown This study aimed to identify the metabolomics pathways that are related to prolonged or chronic cough Flow of baseline and follow-up measurement of Nagahama cohort. In the period of baseline, serum IgE were measured. In the period of follow-up, questionnaires about the presence of various diseases and triggers of cough, and other blood collection were conducted. Patients with new-onset prolonged cough are highlighted in yellow, and those with a prolonged cough at follow-up are marked with a red line. Underlying disease with new-onset prolonged cough group at follow-up Variable importance projection (VIP) score calculated from Partial least-squares discriminant analysis (PLS-DA) VIP scores of metabolite profiles generated by GC–MS data of new onset prolonged cough at follow-up measurement by using Metaboanalyst 4.0 were measured Heat map with red or blue boxes indicates high or low abundance ratio of metabolites with new-onset prolonged cough and 3-hydroxybutyric acid showed VIP score 1.5 or over PLS-DA: Partial least squares discriminant analysis Univariate analysis of plasma citrate in association with (a) sex the role of plasma citric acid for cough continuation in participants with cough triggers was examined Lower plasma citric acid level was associated with new-onset prolonged cough and prolonged cough at follow-up among the 3375 subjects who had at least one of the 3 triggers without asthma and blood collection time after meals (Table S4b) this is the first report to show an association of plasma metabolites with prolonged cough in the general population and HIBA were risk factors for prolonged cough in this large population-based study citric acid was the most closely associated with prolonged cough and independent of the presence of asthma low plasma citric acid level was a risk of new-onset prolonged cough in participants with cough-triggering factors in the absence of these 3 diseases decreased citric acid may accelerate cough in participants with underlying diseases Reduced activity of TCA cycle may result in reduced ATP production in neurons which might change the sensitivity of P2X3 receptor an important receptor responsible for cough hypersensitivity a decrease in plasma citric acid can be explained by intracellular consumption to regulate mitochondrial oxidative stress as an inflammation consequence lower blood citric acid could be a therapeutic target for prolonged cough as it induces cough by its weak acidic nature whether citric acid intake could be a friend to prolonged and chronic cough should be further examined decreased BHB may not prevent neuroinflammation and may contribute to cough hypersensitivity which is defined to last for 8 weeks or longer cough-specific interviews were not conducted as part of the Nagahama study which involved a large number of comprehensive questionnaires covering various organ diseases information regarding the presence of cough at the time of the interview and impact on the participants' quality of life remains unknown Approximately half of the participants with a new-onset prolonged cough or prolonged cough at follow-up reported having sputum symptoms An analysis of the data revealed no significant relationship between plasma citric acid levels and the sputum symptoms (data not shown) this study included only residents who were willing to participate and it is possible that potentially health-conscious participants may have been selected this analysis focused on plasma metabolites and whether metabolite level in plasma reflects the intracellular dynamics of participants is unclear and further research is needed metabolite levels were measured only at follow-up; thus determining a causal relationship with new-onset prolonged cough is impossible It is also difficult to determine precisely when plasma citric acid dropped in patients with a history of prolonged cough because blood samples were taken after the onset of cough Studies on changes in plasma citric acid following therapeutic interventions are warranted this study revealed that low plasma TCA cycle intermediates were risk factors for prolonged cough in a large sample of the general population Elucidating the roles of citric acid in the pathogenesis of prolonged/chronic cough including the effects on the airway sensory nerve The present study excluded current smokers and participants with missing essential GC–MS data The presence of prolonged cough was asked with this questionnaire at baseline and follow-up assessments: Have you ever experienced a cough for 3 weeks or more Participants who had newly developed prolonged cough at follow-up were defined as “new-onset prolonged cough” and those who had prolonged cough at follow-up regardless of baseline status as “prolonged cough at follow-up.” Citrus consumption and cough-triggering factors at follow-up were also examined we performed PLS-DA using Metaboanalyst 4.0 (details are presented in the Supplemental file) data were analyzed using JMP version Pro 15 (SAS Institute Inc. Two groups were compared using a t-test or one-way analysis of variance Logistic regression analyses were performed to investigate contributing factors to the new-onset prolonged cough and prolonged cough at follow-up The Pearson’s correlation coefficient was used to test the strength of associations between the metabolites The Bonferroni correction was performed to reduce the risk of type I errors associated with multiple comparisons of metabolites Citizens were not directly involved in the design of this study but their opinions for the length and volume of the questionnaires were taken into account The Nagahama Zeroji Cohort is a collaboration between Nagahama City (government agency), Kyoto University, and a non-profit organization whose board members and members are mostly Nagahama citizens. 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Meas. 1, 385–401. https://doi.org/10.1177/014662167700100306 (1977) Download references We are incredibly grateful to the Nagahama City Office and nonprofit organization Zeroji Club for their help in conducting the Nagahama Study The Nagahama Study group executive committee comprises the following individuals: Yasuharu Tabara and Fumihiko Matsuda from the Center for Genomic Medicine Kyoto University Graduate School of Medicine (YaT FM); Department of Health Informatics (YoT TN); Department of Medical Ethics and Medical Genetics (SK) This study was supported by a University Grant and Grant-in-Aid for Scientific Research from the Ministry of Education by the Practical Research Project for Rare/Intractable Diseases the Comprehensive Research on Aging and Health Science Research Grants for Dementia R&D the Program for an Integrated Database of Clinical and Genomic Information and the Practical Research Project for Life-Style related Diseases including Cardiovascular Diseases and Diabetes Mellitus from Japan Agency for Medical Research and Development (AMED) and by the Takeda Medical Research Foundation Department of Respiratory Medicine and Allergology analyzed and interpreted the data and wrote the draft collected the data and revised the work critically contributed to the design of the Nagahama cohort study provided overall supervision and critically revised the manuscript Download citation DOI: https://doi.org/10.1038/s41598-023-40878-z Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology Fukuoka Prefecture is renowned by noodle aficionados around the world as birthplace of Hakata ramen It takes its name after the neighborhood in Chūō Ward where it was first introduced by a small stall named Nagahama-ya—along with the concept of kaedama Nagahama-ya catered to fishery workers who typically had time only for a quick meal With thin noodles and thick soup of pork bone broth it soon became popular and the line between Hakata and Nagahama has been steadily growing thinner there are numerous “Nagahama-ya” in Fukuoka today including those founded by former employees of the original several of them claiming to be the ganso (“original”) it now requires a huge hassle to seek out the one true The confusion went on as the original closed in 2008 due to the major roadwork in the area leaving only its (officially sanctioned) branch open to rival the impostors the branch closed permanently as the original returned to a new location On its former site now stands a number of neon signs arrows and banners indicating the new location declaring that it is the only original “original” Nagahama-ya many locals consider it to be Fukuoka’s most significant cultural heritage A regular serving of ramen at Ganso Nagahama-ya currently costs ¥550 and you can get a second helping of noodles for ¥100 First buy a ticket from the vending machine and place it on the table; your ramen will be ready as soon as you take a seat Diners have been slurping 'fool's noodles' at this shop for more than 70 years This time-honored eatery near Hoàn Kiếm Lake serves the classic pairing of rice vermicelli soup and savory sticky rice Slurp sesame noodles at the third-generation family-run establishment that invented them Sample specialties from Xinjiang at this Shinjuku neighborhood gem A microbiologist-chef is slinging noodles with hyperlocal Nordic ingredients One of Kyoto's oldest food establishments has supplied soba noodles to temple priests and the Imperial Palace Metrics details Subjects with subclinical respiratory dysfunction who do not meet the chronic obstructive pulmonary disease (COPD) criteria have attracted attention with regard to early COPD intervention Our aim was to longitudinally investigate the risks for the development of airflow limitation (AFL) and dyspnoea in a large-scale community-based general population study The Nagahama study included 9789 inhabitants and a follow-up evaluation was conducted after 5 years AFL was diagnosed using a fixed ratio (forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) < 0.7) We enrolled normal subjects aged 40–75 years with no AFL dyspnoea or prior diagnosis of asthma or COPD at baseline 310 subjects had subclinical respiratory dysfunction (FEV1/FVC < the lower limit of normal; n = 57 and FEV1 < 80% of the predicted value (preserved ratio impaired spirometry); n = 256) A total of 5086 subjects attended the follow-up assessment and 449 and 1021 subjects developed AFL and dyspnoea Baseline subclinical respiratory dysfunction was independently and significantly associated with AFL with dyspnoea development within 5 years Subjects with subclinical respiratory dysfunction are at risk of developing COPD-like features and require careful monitoring the clinical impact of asymptomatic PRISm is unclear We hypothesized that these types of subclinical respiratory dysfunction together with smoking status and comorbidities could be risk factors for the development of COPD The specific goal of this study was to identify the risk factors for the development of AFL; respiratory symptoms subjects with AFL and dyspnoea could be diagnosed with COPD; therefore this investigation may contribute to the early detection of COPD in the general population Of the 9804 participants recruited for the Nagahama study, 5865 individuals aged 40–75 years who did not have AFL (FEV1/FVC ≥ 0.7) or dyspnoea (modified Medical Research Council [mMRC] dyspnoea scale = 0) at baseline were included in the current analysis (Fig. 1). Flowchart of the data extraction process of the Nagahama Study mMRC modified Medical Research Council (mMRC) dyspnoea scale At baseline, 310 subjects had subclinical respiratory dysfunction (based on Japanese predictive equations from the Japanese Respiratory Society (JRS); 57 subjects had FEV1/FVC < LLN and 256 subjects had %FEV1 < 80%) (Table1) Compared with subjects with normal respiratory function (FEV1/FVC ≥ LLN and %FEV1 > 80%) subjects with FEV1/FVC < LLN were younger (mean 49 years vs and had a lower body mass index (BMI) (21.4 kg/m2 vs whereas subjects with %FEV1 < 80% (PRISm) were older (62 years vs and more likely to have a smoking history (41% vs After 5 years, 5086 subjects underwent follow-up assessments (Fig. 1) The baseline characteristics of the subjects (N = 779) who were lost to follow-up are presented in Supplementary Table S1 Among the 5086 subjects who attended the 5-year follow-up AFL was newly identified in 449 subjects (9%); 1021 subjects (20%) had newly developed dyspnoea (mMRC ≥ 1) and 100 subjects developed both AFL and dyspnoea concurrently (AFL with dyspnoea) Compared with subjects without AFL or dyspnoea at follow-up, subjects who developed AFL were older (mean 63 years vs. 58 years), more likely to be male (55% v 31%), and more likely to smokers (current or former) (49% vs. 28%) at baseline (Table 2) while subjects who developed dyspnoea were older (61 years vs and were more likely to be current smokers (13% vs was observed in both AFL patients and dyspnoea patients than in normal controls (29% Subjects with AFL with dyspnoea were older (64 years vs 31%) and more likely to be current smokers (27% vs They also had higher prevalence rates of hypertension and cardiovascular disease (30% vs dyspnoea and both among subjects who underwent follow-up assessment and both (AFL with dyspnoea) at follow-up in groups with normal respiratory function and subclinical respiratory dysfunction at enrolment (N = 5086) A GOLD grade ≥ 2 was defined as the development AFL with %FEV1 < 80% *Two subjects had both FEV1/FVC < LLN and %FEV1 < 80% at baseline †P value < 0.05 compared with normal respiratory function PRISm and FEV1/FVC < LLN at baseline were significantly associated with the development of AFL with dyspnoea in the multivariate analysis (risk ratio [95% confidence interval]; 1.99 [1.49–2.67] and 2.71 [1.44–5.09] We investigated a population-based cohort with follow-up assessments to evaluate both respiratory symptoms and pulmonary function and found that subclinical respiratory dysfunction represented by FEV1/FVC < LLN and %FEV1 < 80% (PRISm) was independently associated with the development of AFL which is the most important COPD-like feature Given the need to promote the early detection of COPD the major finding of the present study is that subjects with subclinical respiratory dysfunction should be observed closely for the development of respiratory symptoms our results revealed the independent impacts of current smoking on the development of all AFL We also showed that comorbidities and obesity independently contributed to the development of dyspnoea and a history of cardiovascular disease had an impact on the development of AFL with dyspnoea not the development of respiratory symptoms (dyspnoea) or AFL the relationship between PRISm and the development of COPD is ill-defined especially in never smokers and those who are not yet symptomatic no study has assessed the association between FEV1/FVC < LLN but ≥ 0.7 and the development of COPD The present study builds on previous research on subclinical respiratory dysfunction by clarifying the risks for the development of AFL with dyspnoea at 5 years which were two- and threefold higher in those with PRISm and FEV1/FVC < LLN than in those with normal respiratory function our results suggest that PRISm in those with a cardiovascular burden requires special attention These factors could also contribute to the difference in the PRISm rate between the populations the specific causes of low FVC in Japanese PRISm patients could differ from those in Western patients (old tuberculosis for example) The heterogeneity of PRISm should be considered when interpreting our results this study is significant in that it suggests that patients with PRISm regardless of their symptoms or smoking status could be candidates for early COPD detection in the Japanese population We acknowledge potential bias from loss to follow-up given the lower FEV1 in subjects who were lost to follow-up than in those who were followed including the lost subjects would increase the incidence of COPD in the group with subclinical respiratory dysfunction This supports our conclusion that subclinical respiratory dysfunction is a risk factor for the development of COPD our results are important in terms of identifying the population at high risk for COPD Our study additionally revealed the importance of smoking cessation in subjects without AFL or dyspnoea in terms of prevention of both COPD and related morbidity and AFL with dyspnoea in this study comes close to fulfilling those criteria We believe that identifying subjects at risk of the development of AFL with dyspnoea would be of great benefit in the real world We found that those with subclinical respiratory dysfunction were 2- and 3-times more likely than those with normal function to develop AFL with dyspnoea We suggest that more attention should be given to these subjects we used a grade of 1 instead of 2 for the cut-off of the mMRC grade This minimized underestimation and was suitable for our purpose of promoting early identification of subjects at risk We revealed that individuals with subclinical respiratory dysfunction including FEV1/FVC < LLN and %FEV1 < 80% (PRISm) Patients with comorbidities and obesity could develop dyspnoea via mechanisms other than the progression of AFL This was a population-based observational study based on the Nagahama Cohort for Comprehensive Human Bioscience (the Nagahama Study); subjects from the general population of Nagahama in Shiga Prefecture were enrolled from November 2008 to November 2010 Residents aged 30–74 years who were able to live independently and lacked serious health or physical impairment were recruited The participants in this cohort were invited to participate in a follow-up assessment 5 years after enrolment and participants with an mMRC grade of 0 were considered to be free from dyspnoea Among the 9804 residents recruited from 2008 to 2010, 5868 subjects aged 40–75 years who did not have a history of adult asthma or COPD and who did not have AFL (FEV1/FVC ≥ 0.7) or dyspnoea (mMRC grade of 0) at the time of enrolment were included (Fig. 1) This study adhered to the principles of the Declaration of Helsinki All study protocols were approved by the ethics committee of Kyoto University Graduate School of Medicine and the Nagahama Municipal Review Board (Registry ID G0278) Pulmonary function was measured during an FVC manoeuvre with an electronic spirometer with automated quality checks (baseline; SP-350 COPD the same type of spirometer (SP-350) was used to measure FVC at baseline and at follow-up while a different type of spirometer (SP-370) was used in the remaining subjects A two-tailed P-value < 0.05 was considered statistically significant All statistical analyses were performed using JMP Pro 14 (SAS Institute Data are presented as means (± standard deviations [SDs]) for continuous variables and percentages for categorical variables We obtained written informed consent from all the participants The datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request COPD in Japan: The Nippon COPD Epidemiology study Underdiagnosis and undertreatment of COPD in primary care settings Clinical significance of symptoms in smokers with preserved pulmonary function Respiratory impairment and mortality in older persons: A novel spirometric approach Risk factors and comorbidities in the preclinical stages of chronic obstructive pulmonary disease Adibi, A. & Sadatsafavi, M. Looking at the COPD spectrum through “PRISm”. Eur. Respir. J. 55, 1902217. https://doi.org/10.1183/13993003.02217-2019 (2020) and prevention of chronic obstructive pulmonary disease: GOLD executive summary American Thoracic Society/European Respiratory Society statement on pulmonary rehabilitation and exercise capacity index in chronic obstructive pulmonary disease Wan, E. S. et al. Epidemiology, genetics, and subtyping of preserved ratio impaired spirometry (PRISm) in COPDGene. Respir. Res. 15, 89. https://doi.org/10.1186/s12931-014-0089-y (2014) Morbidity and mortality associated with the restrictive spirometric pattern: A longitudinal study Wijnant, S. R. A. et al. Trajectory and mortality of preserved ratio impaired spirometry: The Rotterdam Study. Eur. Respir. J. 55, 1901217. https://doi.org/10.1183/13993003.01217-2019 (2020) Park, H. J. et al. Significant predictors of medically diagnosed chronic obstructive pulmonary disease in patients with preserved ratio impaired spirometry: A 3-year cohort study. Respir. Res. 19, 185. https://doi.org/10.1186/s12931-018-0896-7 (2018) Lower limit of normal or FEV1/FVC < 0.70 in diagnosing COPD: an evidence-based review The ratio of FEV1 to FVC as a basis for establishing chronic obstructive pulmonary disease Characteristics and outcomes of chronic obstructive pulmonary disease in never smokers in Denmark: A prospective population study The effect of defining chronic obstructive pulmonary disease by the lower limit of normal of FEV1/FVC ratio in tiotropium safety and performance in respimat participants Overdiagnosing subjects with COPD using the 0.7 fixed ratio: correlation with a poor health-related quality of life Colak, Y. et al. Young and middle-aged adults with airflow limitation according to lower limit of normal but not fixed ratio have high morbidity and poor survival: A population-based prospective cohort study. Eur. Respir. J. 51, 1702681. https://doi.org/10.1183/13993003.02681-2017 (2018) A risk prediction model for mortality among smokers in the COPDGene(R) study Longitudinal phenotypes and mortality in preserved ratio impaired spirometry in the COPDGene Study Rapid lung function decline in smokers is a risk factor for COPD and is attenuated by angiotensin-converting enzyme inhibitor use Predictors of loss of lung function in the elderly: The Cardiovascular Health Study The chronic obstructive pulmonary disease comorbidity spectrum in Japan differs from that in western countries and prevention of chronic obstructive lung disease: The 2020 GOLD science committee report on COVID-19 & COPD Renewed Japanese spirometric reference variables and risk stratification for postoperative outcomes in COPD patients with resected lung cancer Adult life-course trajectories of lung function and the development of emphysema: The CARDIA Lung Study Lung-function trajectories leading to chronic obstructive pulmonary disease Impact of cigarette smoking on decline in forced expiratory volume in 1s relative to severity of airflow obstruction in a Japanese general population: The Yamagata-Takahata study Effect of obesity on constant workrate exercise in hyperinflated men with COPD Obesity in COPD: Revealed and unrevealed issues Dyspnea on exertion in obese women: Association with an increased oxygen cost of breathing Combined effects of obesity and chronic obstructive pulmonary disease on dyspnea and exercise tolerance stability and outcomes of the 2011 GOLD COPD groups in the ECLIPSE cohort Airflow limitation and histology shift in the National Lung Screening Trial Ogata, H. et al. Trends in the prevalence of airflow limitation in a general Japanese population: two serial cross-sectional surveys from the Hisayama Study. BMJ Open 9, e023673. https://doi.org/10.1136/bmjopen-2018-023673 (2019) Perez-Padilla, R. et al. Lung function decline in subjects with and without COPD in a population-based cohort in Latin-America. PLoS ONE 12, e0177032. https://doi.org/10.1371/journal.pone.0177032 (2017) COPD Guidelines: A review of the 2018 GOLD report Multi-ethnic reference values for spirometry for the 3–95-year age range: the global lung function 2012 equations How to utilize CAT and mMRC scores to assess symptom status of patients with COPD in clinical practice? Modified Medical Research Council scale vs Baseline Dyspnea Index to evaluate dyspnea in chronic obstructive pulmonary disease hypertension and cardiovascular disease in COPD Airflow obstruction and cardio-metabolic comorbidities Clinical Pulmonary Functions Committee of the Japanese Respiratory S: Reference values for spirometry in Japanese adults calculated with the LMS method and compared with previous values Download references We are grateful to Nagahama City Office and the non-profit organization Zeroji Club for their assistance with the Nagahama study Ryo Tachikawa and Morito Inouchi (Kyoto University Graduate School of Medicine Japan) for their assistance with data collection This study was funded by a university grant; a Grant-in-Aid for Scientific Research from the Ministry of Education 18K18450); and grants from the Center of Innovation Program and the Global University Project from Japan Science and Technology Agency Japan Agency for Medical Research and Development (AMED) (grant numbers dk0207006 This research was also supported by grants from the Japanese Ministry of Education Science and Technology; the Intractable Respiratory Diseases and Pulmonary Hypertension Research Group from the Ministry of Health Labour and Welfare of Japan (H29-intractable diseases-general-027); the Takeda Medical Research Foundation; the Mitsubishi Foundation; the Daiwa Securities Health Foundation; the Sumitomo Foundation; the Research Foundation for Healthy Ageing; and the Health and Research on Region Medical (H28-iryo-ippan-016 The Department of Respiratory Care and Sleep Control Medicine is funded by grants from Philips-Respironics S.S.: conceived and designed the study; collected and interpreted the data; wrote and edited the manuscript; and takes responsibility for all aspects of the work and H.M.: contributed to the study design; collection and interpretation of the data; and the writing of the manuscript and T.O.: contributed substantially to the interpretation of the data and the writing of the manuscript and T.N.: contributed to the interpretation of the data and critically revised the manuscript K.M.: contributed to the study design and data collection and revised the work critically T.H.: provided overall supervision and critically revised the manuscript and T.H.: contributed to the design of the Nagahama cohort study The final manuscript was approved by all the authors S reports a grant from Nippon Boehringer Ingelheim Co and ResMed that did not pertain to the submitted work ResMed and Japan Society for the Promotion of Science none of which pertained to the submitted work T reports grants from the Japan Agency for Medical Research and Development (AMED) and The Ministry of Education Science and Technology in Japan during the study period C reports grants from the Japanese Ministry of Education Science and Technology; grants from the Intractable Respiratory Diseases and Pulmonary Hypertension Research Group Japan; grants from the Research Foundation for Healthy Ageing; grants from Health Research on Region Medical; grants from the Center of Innovation Program and the Global University Project from Japan Science and Technology Agency Japan Agency for Medical Research and Development during the study period; grants and personal fees from Philips-Respironics GlaxoSmithKline and Resmed; grants from KYORIN Pharmaceutical Co. Ltd; none of these pertained to the submitted work Japan Agency for Medical Research and Development (AMED) and The Takeda Medical Research Foundation during the study period Download citation DOI: https://doi.org/10.1038/s41598-022-24657-w Metrics details This article has been updated Gut-microbiota derived metabolites are important regulators of host biology and metabolism To understand the impacts of the microbial metabolite 4-cresol sulfate (4-CS) on four chronic diseases [type 2 diabetes mellitus we conducted association analyses of plasma 4-CS quantified by liquid chromatography coupled to mass spectrometry (LC–MS) in 3641 participants of the Nagahama study Our results validated the elevation of 4-CS in CKD and identified a reducing trend in MetS we performed a phenome-wide association analysis (PheWAS) with 937 intermediate biological and behavioral traits We detected associations between 4-CS and 39 phenotypes related to blood pressure regulation including fatty acids and 14 blood pressure indices suggesting that 4-CS is a potential biomarker for MetS Consistent associations of this gut microbial-derived metabolite on multiple endophenotypes underlying distinct etiopathogenesis support its role in the overall host health with prospects of probiotic-based therapeutic solutions in chronic diseases by performing regression analyses between 4-CS and 937 human phenotypes Significant associations related to blood pressure regulation Further analyses indicated that 4-CS could be connected to CKD via ion regulation and lipid regulation Our results demonstrate the consistent impacts of 4-CS on multiple biological functions in healthy individuals and its association with indices of improved cardiometabolic health in humans only obese T2DM participants (n = 65) were selected to compare with control individuals the logistic regression indicates the absence of significant association between 4-CS and T2DM (OR = 0.90 [95% CI: 0.71 Since blood 4-CS levels could be influenced by environmental factors such as diet and medication intake we repeated statistical analyses following adjustment for additional covariates in order to re-examine 4-CS’ effects on T2DM Results showed no evidence of statistical significance between 4-CS and T2DM (OR = 0.99 [95% CI: 0.87 we investigated the impacts of 4-CS in non-T2DM individuals (n = 3279) on T2DM-related indices as well as the homeostasis model assessment of insulin resistance (HOMA-IR) we did not identify evidence of statistical significance between 4-CS on blood glucose (β = 0.01 [95% CI: − 0.02 p = 0.06) and HOMA-IR (β = − 0.02 [95% CI: − 0.06 Details of the PheWAS analysis pipeline. This pipeline was constructed in the R language with Nextflow. Manhattan plot showing the 39 intermediate phenotypes associated with plasma 4-cresol sulfate through PheWAS in the Nagahama study population A total of 937 intermediate phenotypes collected in 3641 generally healthy individuals of the Nagahama Study were used to test for significant association (p < 5.32 × 10−5) with 4-cresol sulfate R-intraocular pressure right intraocular pressure corrected by corneal pressure Results from PheWAS uncover multiple significant associations of 4-CS with a priori biologically unrelated variables (e.g. This broad-ranging pattern of associations suggests coordinately regulated biological mechanisms and pathways by 4-cresol with possible consequences on the risk of several chronic disorders This study elucidates the functional relationships between the gut microbial metabolite 4-CS and multiple phenotypes in healthy individuals We report broad-ranging associations between 4-CS and liver function blood pressure regulation and ketone and fatty acids metabolisms the latter three suggesting its impact on cardiometabolic risk Further detailed analyses on four disease endpoints identified a positive association between 4-CS and CKD and a reducing trend with MetS risk ion regulation might be the biological mechanism underlying the contribution of 4-CS to CKD risk Further investigations are required to understand the role of 4-CS in liver function results from statistical analyses after adjustment for environmental variables such as diet and medication failed to identify an impact of 4-CS on T2DM and T2DM-related traits in non-T2DM individuals showed inversed relationships with 4-CS in our study we hypothesize that 4-CS might be a potential biomarker of MetS prediction in healthy individuals These data further support the importance of the metabolic function of the gut microbiome in the susceptibility of individuals to developing chronic diseases and the opportunities to design nutritional and probiotic-mediated solutions that stimulate 4-CS levels in treating this cluster of metabolic diseases diagnostic accuracy of the three chronic diseases (T2DM T2DM was determined by self-answered questionnaires CKD diagnosis was based solely on creatinine level at a single time point and NAFLD cases were defined only by the FIB-4 score board-ranging intermediate phenotypes systematically available for all subjects in the Nagahama population study have provided important clues for analysis of disease risks association analyses were performed with few covariates and cannot assess causality nor determine the beneficial range of 4-CS required to avoid any toxic effects future mechanistic analysis carefully accounting for appropriate covariates and Mendelian randomization studies with genetic information are required to test our hypotheses replication in large population studies with various ethnic backgrounds should also be conducted before generalization this is the first PheWAS targeting a disease-predicting candidate metabolite presenting a new analytical method for metabolite analysis Our work provides supportive evidence of the beneficial role of 4-cresol metabolism on host health and continues challenging the impact of 4-CS We propose that non-toxic levels of this metabolite can positively impact human health Extension of the phenotype screening to include unexplored organ systems enables multiple hypotheses generation thus providing a high-level overview of the possible roles of this metabolite in humans our study supports the notion that microbial-derived metabolites can affect not only metabolism but also the overall health of the host and promote the development of novel therapeutic solutions for chronic diseases This study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the ethics committee of Kyoto University Graduate School of Medicine and by the Nagahama Municipal Review Board (no The status of CKD was determined by the estimated glomerular filtration rate (eGFR) level at a single time point The eGFR was calculated by eGFR [mL/min/1.73 m2] = 194 × (serum creatinine [mg/dL])−1.094 × age [years]−0.287 × 0.739 (if female) CKD was defined as eGFR < 60 ml/min/1.73 m2 The status of T2DM was determined by web-based questionnaires participants who indicated they were previously diagnosed with type 1 diabetes (n = 14) and gestational diabetes (n= 10) were excluded participants were required to answer the question “Have you had type 2 diabetes mellitus?” the responses were chosen from one of the following answers: “No disease” (n = 3352) only participants who chose “No disease” (n = 3352) or “Diagnosed “No disease” individuals with glucose ≥ 126 mg/dl after ≥ 8 h after a meal (n = 1) or HbA1c ≥ 6.5% (n = 48) or both (n = 8) or low kidney function defined as eGFR < 30 (n = 6) were excluded the remaining participants were categorized as controls for “No disease” (n = 3279) and cases for “Diagnosed The four T2DM-related traits are blood levels of glucose and the homeostasis model assessment of insulin resistance (HOMA-IR) HOMA-IR was calculated by HOMA-IR = fasting insulin [μIU/ml] × fasting glucose [mg/dl]/405 for individuals whose time after the last meal ≥ 8 h based on the questionnaire For the analysis of the four T2DM-related traits a diseased individual must have an abdominal circumference ≥ 90 cm for females or ≥ 85 cm for males one must meet two out of three following clinical conditions: (1) triglyceride level ≥ 150 mg/dl or high-density lipoprotein (HDL) cholesterol < 40 mg/dl or on anti-hyperlipidemic medications (2) systolic blood pressure (SBP) ≥ 130 mmHg and/or diastolic blood pressure (DBP) ≥ 85 mmHg or on anti-hypertensive medications (3) fasting plasma glucose ≥ 110 mg/dl (10 h or more fasting time) or on diabetes medications Applying these diagnostic criteria to the 3460 individuals previously selected for T2DM 326 individuals were assigned as cases and 3144 as controls Individuals who have drinking habits were eliminated (n = 1927) The Fibrosis-4 (FIB-4) score was calculated by FIB-4 = (age [years] × aspartate transaminase (AST) [IU/L]/(platelet count [109/L] × √ alanine aminotransferase (ALT) [IU/L]) The NAFLD control group was defined as FIB-4 < 1.30 Individuals whose Fib-4 score was 1.30 and 2.67 were eliminated to avoid ambiguity the number of cases and controls were 116 and 667 The detailed PheWAS pipeline is shown in Fig. 1 All 937 phenotypes were classified into three types: 71 binary Logistic regression was conducted between binary traits and 4-CS adjusted by sex and age they were first adjusted by sex and age to obtain residuals The residuals were normalized by inversed-normal transformation Linear regression was conducted between the transformed data and 4-CS concentration Continuous phenotypes were first transformed by inversed-normal transformation Linear regression was performed between each continuous trait and 4-CS with sex and age as covariates the significant ones were selected by p-values less than the Bonferroni correction threshold p < 5.34 × 10−5 To investigate the association between 4-CS and four metabolic diseases logistic regression was conducted between each disorder and 4-CS with sex and age as covariates we adjusted for environmental effects on 4-CS by adding additional covariates as follows: among all medications and dietary traits five 4-CS-associated traits (butter consumption breakfast noodle intake frequency and the frequency of dinner bread intake and peanuts or almonds consumption) were identified plus eGFR level and the time after participants’ last meal when the blood sample was drawn modelled by spline function using 4-CS as the response were included in the logistic regression model besides sex and age To investigate 4-CS’ effects on the four T2DM-related traits (blood levels of glucose data for non-T2DM individuals were analyzed These four T2DM-related traits were inversed-normal transformed Linear 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Ecol. 94, fiy125. https://doi.org/10.1093/femsec/fiy125 (2018) Download references We would like to thank all the organizing staff and the participants in the Nagahama Study We also thank the Metabolomics Advanced Training and the International Exchange Program (MATRIX) for the financial support is supported by the Kyoto-McGill International Collaborative Program in Genomic Medicine acknowledge financial support from the INSERM Projet de Recherche International DIABETOMARKERS developed the method for LC–MS-derived peak intensity normalization provided statistical and analytical consultation provided medical consultation on metabolic diseases Download citation DOI: https://doi.org/10.1038/s41598-023-40697-2 Uzumaki's premiere episode opened with a stunning use of artistic techniques, utilizing rotoscope and 3D models to bring the pages of Junji Ito's manga to life Episode two is a substantial drop in visual quality for what I can only guess is the result of COVID-19 delays it's hard not to be frustrated by what's on-screen given the multiple pushbacks this show experienced before its premiere there were a lot of behind-the-scenes issues that we don't know about There are unsubstantiated rumors that Nagahama was "kicked off" the project we can look at the credits of this episode and see that something went very I wouldn't associate anything that appears in this episode with Nagahama which is connected to Ogikubo-based Akatsuki studio Phoenix Animation Holdings handled most of the key animation and made up the bulk of the episode's absurd amount of animation directors Everything from the key animation to the coloring was outsourced The disconnected narrative plotting continues at break-neck speed with Kirie seeming even more detached from the increasingly disturbing events happening around her I couldn't bring myself to be shocked or care about most of the many grotesque entries in this episode as characters are barely introduced before disappearing and then transforming or dying in a matter of minutes Kirie and Shuichi will suddenly become emotionally invested in a random star-crossed couple's love affair seemingly accept without much issue as Kirie's hair becomes sentient passably notice classmates turning into snails barely register another classmate get graphically run over by a car and feebly attempt to rescue her brother from being burned to death inside of a lighthouse That's five chapters haphazardly strung together in this episode with the same lack of build-up a moment that could be startlingly grotesque with slimy bits of body horror so it's hard to garner much more of a response while watching Kirie's transforming hair scenes jump all over the place until she's in a sentient follicle face-off with a nameless classmate who only appeared long enough to establish she wants "attention." Any other why and how was left on the cutting room floor in favor of getting to the next spiral-shaped thing Without consistent artistic styling to fall back on the long-awaited Uzumaki series' shortcomings are on full display here Weak characterization and rapid-dash horror beats create a cold entry in what was ripe to be the stuff of nightmares Please view the main text area of the page by skipping the main menu. The page may not be displayed properly if the JavaScript is deactivated on your browser Japanese version Metrics details Although alkaline phosphatase (ALP) activity is relatively low in carriers of recessive type hypophosphatasia (HPP) most are asymptomatic and therefore do not undergo medical evaluations We analyzed the association of ALP-encoding ALPL variants with serum ALP and bone traits in the general Japanese population Study participants (n = 9671) were from the Nagahama Study which was a longitudinal cohort study of an apparently healthy general Japanese population ALPL variants were analyzed by whole-genome sequencing or TaqMan probe assays using DNA extracted from peripheral blood samples The speed of sound in calcaneal bone was assessed by quantitative ultrasound (QUS) and used as surrogate measures of bone mineral density Minor allele frequencies of three variants were higher than expected Variant c.529G > A has been reported as a possible pathogenic variant for adult type HPP Variants c.979C > T and c.1559delT are reported as pathogenic variants for perinatal severe HPP or infantile HPP Serum ALP activity was significantly lower and differed among the three variants (P < 0.001) as well as between individuals with and without any of the three variants (P < 0.001) Serum ALP activity was inversely associated with QUS values although no direct association was observed between the ALPL variants and QUS values An association between serum ALP activity and QUS was confirmed; however we failed to detect an association between ALPL variants and bone traits in the general Japanese population With the recent introduction of effective enzyme replacement therapies genetic analyses are now frequently performed asymptomatic carriers of ALPL variants are sometimes identified the clinical significance of these carriers is unknown It would be desirable if the identification of asymptomatic carriers of ALPL variants could be used to help provide appropriate healthcare to these individuals we analyzed the association of ALPL variants with serum ALP activity and bone traits in the general Japanese population In addition to providing possible insight into the development of healthcare strategies for treating HPP the findings could also serve as a reference for ALPL genetic studies in patients with HPP which was a longitudinal cohort study based on the general population of Nagahama a rural city located in the middle of Japan with ~125,000 inhabitants Apparently healthy community residents aged 30–74 years living independently without any physical impairment or dysfunction were recruited to participate between 2008 and 2010 The current baseline population includes 9,764 participants of which 8289 participated in a follow-up investigation performed 5 years after the baseline survey (2013–2015) By recruiting an additional 1561 participants that met the inclusion criteria 9850 participants comprised the second-visit dataset of the Nagahama Study with the overall total number of participants being 11,325 whole-genome sequencing (WGS) data were available for 1322 individuals of which 17 participated in only the baseline investigation We used a dataset from the follow-up investigation to analyze ALPL variants Exclusion criteria included being pregnant (n = 9) or possibly pregnant (n = 15) severe renal functional decline (estimated glomerular filtration rate [eGFR] < 30 ml/min/1.73 m2; n = 16) incomplete measurement or wide deviation of clinical values used in this study (n = 44) and unsuccessful genotyping of any of the ALPL variants analyzed using the TaqMan assay (n = 89) This resulted in 9671 participants remaining which included 1305 individuals for whom WGS had been completed All study procedures were approved by the Ethics Committee of the Kyoto University Graduate School of Medicine and by the Nagahama Municipal Review Board Written informed consent was obtained from all the participants The sub-sample was chosen to maintain genetic diversity using genome-wide principal component analysis (PCA) of genotype-based data Subsequent downsampling was performed using a greedy algorithm Genomic DNA was extracted from peripheral blood specimens collected during the follow-up investigation phase of the Nagahama Study using a phenol–chloroform method WGS was performed on a HiSeq X sequencer (Illumina Inc. USA) using a DNA sequencing library prepared with a TruSeq Nano DNA Library Prep Kit (350 bp) (Illumina) The three ALPL variants in the total Nagahama Study population identified by WGS were genotyped using a TaqMan probe assay (Thermo Fisher Scientific USA) with commercially available primers and probe sets (NM_000478.5 c.529G > A: C_190624402_10; NM_000478.5 c.979T > C: C_27861030_10) and a custom set (NM_000478.5 c.1559delT: forward primer: 5′-GGCCCCCTGCTGCT-3′ Fluorescence levels of the TaqMan assay products were measured using a QUANTSTUDIO 5 real-time PCR system (Thermo Fisher Scientific) The detectability of each variant was confirmed using a number of Nagahama samples for which the genotype had been determined using WGS Three genotypes of three independent participants that were not determined using the TaqMan assay were displaced by the WGS data These included one in c.979T > C and two in c.1559delT QUS was measured one time in the calcaneal bone of the right leg The reference normal range in JSCC method was 104–338 U/L Menopausal status and medication use were queried using a structured questionnaire Alcohol consumption was calculated by multiplying the amount consumed in a single day and the number of drinking days per week The consumption was described using traditional Japanese units of alcohol (Go) Renal function was assessed using eGFR calculated using the following formula: Frequency values are expressed as mean ± standard deviation Differences in serum ALP activity by the ALPL variants were assessed by analysis of variance (ANOVA) Multiple linear regression analyses were used to identify factors independently associated with serum ALP activity and other clinical traits All statistical analyses were performed using JMP 9.0.2 software (SAS Institute P-values < 0.05 were considered to indicate statistical significance Difference in serum alkaline phosphatase (ALP) activity with three ALPL variants Mean and standard deviation of ALP activity of each variant subgroup (c.529G > A and c.1559delT) individually (a–c) and any of the three variants (d) are shown in the graphs (P < 0.001) Values in parentheses indicate the numbers of study participants Serum ALP activity was inversely associated with the QUS results (Model 2) although no direct association was observed between the ALPL variants and the SOS values from QUS (Model 3) We also evaluated the association between history of fracture and ALPL variants by analyzing the medical records of the study cohort using Fisher’s exact test and logistic regression analysis; we were unable to detect any association (data not shown) analysis between serum ALP activity and phosphate level revealed no direct association (P = 0.529) No significant association was also observed between the ALPL variants and serum calcium level (Model 5) This justifies our choice to use the resource for the basis of our current study the prevalence of individuals homozygous for c.979C > T or c.1559delT were estimated from Hardy-Weinberg equilibrium to be 1/63,000 and 1/513,000 The prevalence of individuals who were compound heterozygotes for c.979C > T and c.1559delT was estimated to be ~1/180,000 These data suggested the existence of many undiagnosed individuals with subclinical or mild HPP phenotypes we were unable to analyze the association of each ALPL variant with the clinical traits For detailed stratified analysis of the association of each variant and ALP level a much larger sample size of subjects with each variant and sampling under uniform conditions will be needed This may have affected the results in the current study and could be a reason for the failed attempt at detecting an association Serum phosphate levels were significantly higher in individuals with ALPL variants, which is consistent with previous reports for most types of HPP [29] serum calcium levels were not associated with ALPL variants The characteristics of ALPL variants may be partially reflected in the biochemistry of non-symptomatic heterozygous carriers of recessive type HPP heterozygous ALPL variants of asymptomatic carriers were significantly associated with the declined serum ALP activity we failed to detect an association with clinically significant bone traits that would contribute the healthcare of asymptomatic carriers This study involved some unavoidable limitations participants in cohort studies are biased because persons in good health tend to be selected This may have limited the detection of effects of ALPL variants on bone traits A molecular-based estimation of the prevalence of hypophosphatasia in the European population Lethal hypophosphatasia successfully treated with enzyme replacement from day 1 after birth The Tissue Nonspecific Alkaline Phosphatase Gene Mutations Database. http://www.sesep.uvsq.fr/03_hypo_mutations.php [Accessed 30 Aug 2019] Clinical and genetic aspects of hypophosphatasia in Japanese patients a common mutation resulting in the perinatal (lethal) form of hypophosphatasia in Japanese and effects of the mutation on heterozygous carriers Parental serum alkaline phosphatase activity as an auxiliary tool for prenatal diagnosis of hypophosphatasia Unexpected high intrafamilial phenotypic variability observed in hypophosphatasia Common mutations F310L and T1559del in the tissue-nonspecific alkaline phosphatase gene are related to distinct phenotypes in Japanese patients with hypophosphatasia Perinatal hypophosphatasia: diagnosis and detection of heterozygote carriers within the family Severe hypophosphatasia: characterization of fifteen novel mutations in the ALPL gene Specific ultrasonographic features of perinatal lethal hypophosphatasia pathology and molecular biology studies in a family harboring a splicing mutation (648+1A) and a novel missense mutation (N400S) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene Three missense variants of metabolic syndrome-related genes are associated with alpha-1 antitrypsin levels CFH and VIPR2 as susceptibility loci in choroidal thickness and pachychoroid disease central serous chorioretinopathy Fast and accurate short read alignment with Burrows-Wheeler transform A framework for variation discovery and genotyping using next-generation DNA sequencing data ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data Attempt at standardization of bone quantitative ultrasound in Japan Quantitative ultrasound for the assessment of bone status Measurement of enzyme activity of control materials containing human enzymes by IFCC reference methods The human alkaline phosphatases: what we know and what we don't know Regional genetic differences among Japanese populations and performance of genotype imputation using whole-genome reference panel of the Tohoku Medical Megabank Project Functional assay of the mutant tissue-nonspecific alkaline phosphatase gene using U2OS osteoblast-like cells Genetic risk factors for atypical femoral fractures (AFFs): a systematic review Rare coding variants in ALPL are associated with low serum alkaline phosphatase and low bone mineral density Review of comparative studies between bone densitometry and quantitative ultrasound of the calcaneus in osteoporosis Identification of novel missense mutations (Phe310Leu and Gly439Arg) in a neonatal case of hypophosphatasia Novel aggregate formation of a frame-shift mutant protein of tissue-nonspecific alkaline phosphatase is ascribed to three cysteine residues in the C-terminal extension Download references We are extremely grateful to the Nagahama City Office and the non-profit organization Zeroji Club for their assistance in analyzing the Nagahama Study The Nagahama Study was supported by a University grant and Grant-in-Aid for Scientific Research (25293141 and 18K18450) from the Ministry of Education and the Research Program for Health Behavior Modification by Utilizing IoT (le0110005) from Japan Agency for Medical Research and Development (AMED); the Takeda Medical Research Foundation; Mitsubishi Foundation; Daiwa Securities Health Foundation; and Sumitomo Foundation This study was also supported by Research on Rare and Intractable Diseases Labor and Welfare Sciences Research Grants [H28-Nanchitou (Nan)-Ippan-017 and 19FC1006] Department of Medical Ethics and Medical Genetics The authors declare that they have no conflict of interest Download citation DOI: https://doi.org/10.1038/s10038-019-0712-3 a junior from Japan majoring in biology and one of Japan Club’s Culture Night committee members said the club’s performance was divided into three parts: modern anime He explained each dance was performed with a different song and costume The first part of the performance was the modern anime dance a junior from Japan studying elementary education Iwano explained people who participated in the modern anime section wore the uniform of anime characters from the anime “Attack on Titan.” She said all characters from this anime wore military uniforms with a jacket and belt on their waist and legs a senior from Japan majoring in hospitality and tourism management is a modern dance from the southern Japanese culture This was performed in the dark with light sticks [We wore a] white shirt and black pants,” said Hyodo He explained performers wore white shirts so the audience can see the performer’s body movements while dancing in the dark Iwano added some of the performers also wore Japanese costumes with a traditional pattern called Ichimatsu Moyou during the Wotagei dance Nagahama said he was responsible for the movements and arrangements of the third dance in the club’s performance a traditional fisherman dance known as Sōran Bushi Nagahama said those who performed this dance wore Japanese headbands with the Happi costume which Iwano explained is typically worn during Japanese festivals He said their Happi for Culture Night was a black and red coat “It’s all about the fishermen in one of the islands of Japan You will see a lot of those powerful moves.” He added the costumes for the last dance will be related to fishermen Nagahama said the headband represents the people’s hardworking labor that causes them to sweat So they wear a headband to prevent the sweat from getting in their eyes Ke Alaka'iCampus News CenterBYU–Hawaii #192055-220 Kulanui Street Bldg 5Aloha Center Room 134(808) 675-3694kealakai@byuh.edu The Blue Steak Wonder hotels offer stunning views and beach access — all from meticulously crafted stylish rooms that harmonize with their surroundings Like their evocative and slightly perplexing moniker captivating charm that sets them apart from everything around them The accommodations are spread through three modern and chic buildings two in scenic Yomitan and one in the lively coastal town of Chatan and each promises a different type of luxurious oceanside experience taking a romantic getaway or in pursuit of a beach party The hotels were constructed by Hiromitsu Hirose who made a name for himself as an architect in Tokyo before moving to Okinawa 20 years ago He worked alongside two of his close friends on the design and decoration and they proudly bill the hotels as the brainchild of three ojisan as well; they came up with the idea one night over steak it stands as a testament to its creators’ resolute originality creativity and independent thinking — values that are apparent in every inch of the rooms they’ve built Each Blue Steak Wonder hotel is designed with intense attention to detail replete with exotic and original flourishes Both Yomitan properties are perched right on the coast allowing for easy beach access and panoramic ocean views a kitchen and a washer-dryer in every room Blue Steak Wonder Nagahama is best suited for groups and families and the centerpiece of every room is a warm 3-meter-long table around which families and friends can gather The Blue Steak Wonder Senaha has a more sleek and minimalist design with black and gray accents accentuating the ocean’s vibrant beauty the view through the floor-to-ceiling windows feels infinite making it ideal for couples or groups looking to relax in a sumptuous setting a bakery and souvenir shop where you can see directly into a factory that makes the region’s famous beni-imo tarts which have six rooms (Nagahama) and three rooms (Senaha) Visitors can opt to stay in smaller — but still exquisite — twin and triple rooms in the deluxe suites or in the building’s crown jewel: a spacious which offers an expansive view of the sea and cityscape each with two double beds and a private bathroom The kitchen and living room boast massive windows looking out on both the shoreline and the cityscape which can also be enjoyed from the room’s large with a reputation for being international and welcoming The Blue Steak Wonder Chatan is only a few minutes by car from American Village and the region’s renowned Sunset Beach guests can partake in the area’s warm beach culture: Around the hotel one of the island’s most popular places to surf dive and snorkel (or just walk along the coast The Blue Steak Wonder hotels don’t resemble typical beachside stays; there’s an air of exoticism about them studied minimalism that recalls an art gallery Every aspect of the experience is carefully considered from the appliances and tableware to the bedding and the wall and ceiling colors The hotels all share a unique trait as well: They all lack common spaces for guests to congregate The first is that it creates a sense of cozy as though you’ve been whisked away to your own (These hotels are great for those looking for a long-term stay.) The second is to encourage visitors to get out and explore Okinawa interacting with the local landscape and community and discovering all that the area has to offer for themselves the hotel also provides a traveling chef service Guests who want a one-of-a-kind in-suite dining experience can choose between two private chefs one expertly trained in Japanese cuisine and one versed in Western-style food seasonal ingredients sourced from the region fresh sashimi and rare fruits that can only be found on the island Though the rooms may not look typically Japanese at first glance there’s something distinctly Japanese about them; they’re imbued with a design philosophy that’s incredibly particular about aesthetics and comfort with gorgeous bathrooms and baths — particularly the penthouse at Chatan which has an outdoor shower and soaking tub on its veranda Despite each location’s close proximity to the shore those staying at a Blue Steak Wonder hotel might find themselves lingering in the room instead of rushing right to the beach sunlit spaces and enjoying the sublimely cozy atmosphere To book a stay at one of the Blue Steak Wonder hotels, visit their website Metrics details High sodium intake is a simple modifiable risk factor for hypertension lower socioeconomic status may be a factor that increases sodium intake We aimed to clarify the association between socioeconomic status and urinary sodium-to-potassium ratio by cross-sectional and longitudinal analyses The study included 9410 community residents Spot urine sodium-to-potassium ratios were measured twice with a 5-year interval Socioeconomic status was investigated using a self-administered questionnaire Cross-sectional analysis revealed that educational attainment was inversely associated with urinary sodium-to-potassium ratio (years of education ≤ 9: 3.0 ± 1.8 whereas no significant association was observed with household income exhibited markedly high sodium-to-potassium ratios (3.6 ± 2.3) and dairy products was also inversely associated with the ratio the associations with educational attainment ( ≤ 9: reference and sex*marital status interaction (β = 0.054 P = 0.001) were independent of these covariates Educational attainment was also inversely associated with differences in the urinary sodium-to-potassium ratio during the follow-up period (odds ratio Lower educational attainment was an independent determinant for urinary sodium-to-potassium ratio may be a factor for reducing salt intake even in high-income countries where equal educational opportunity is assured determining factors that influence sodium intake may be helpful in preventing hypertension We analyzed the second visit dataset (follow-up measurement) describing participants in the Nagahama Study Participants were recruited between 2008 and 2010 from the general population of Nagahama City a rural city inhabited by 125,000 people located in central Japan 14 withdrew consent and 26 were excluded because their genetic analysis demonstrated a different ethnic background Among the remaining baseline population (n = 9764) 8289 participated in the second health survey performed 5 years after the baseline evaluation (2013–2015) By further recruiting 1561 participants meeting the inclusion criteria the second visit dataset of the Nagahama Study comprised 9850 participants Individuals who were excluded from the analysis included women whose urinary Na and K levels were not measured because of menstruation (n = 373) or pregnancy (n = 9) individuals receiving hemodialysis therapy (n = 6) individuals with severe renal functional decline (estimated glomerular filtration rate [eGFR] < 30 ml/min/1.73 m2; n = 16) and individuals with incomplete clinical values or responses to the questionnaire administered (n = 36) 9410 participants were ultimately included in the analysis All study procedures were approved by the ethics committee of the Kyoto University Graduate School of Medicine and the Nagahama Municipal Review Board 7929 participated in the first visit (baseline) measurement between 2008 and 2010 with a 5-year interval between the two measurements Individuals who met the same criteria (n = 7603) were included in the longitudinal analysis BP was measured after few minutes of resting in a sitting position using a standard cuff-oscillometric device (HEM-9000AI BP was measured twice and the mean values were used for the analysis Hypertension was defined as systolic BP ≥ 140 mm Hg Spot urine samples were collected at the first visit (0900–1700 h) and the second visit (0800– 400 h); urinary Na and creatinine (Cr) levels were measured on each day of sampling Time since the last meal was recorded for each participant where 24-h Cr excretion was predicted using the following formula: body weight (kg) × 14.89 + body height (cm) × 16.14−age × 2.04−2444.45 and dairy products was queried using a self-administered questionnaire with the following choices: none and other green and yellow vegetables (e.g. Fruit choices included citrus fruits (e.g. oranges and grapefruit) and other fruits (e.g. Dairy product choices included milk and yogurt and medication history were assessed using a structured self-administered questionnaire Nine education years corresponded to a junior high school graduate whereas 12 education years corresponded to a high school graduate Group differences in numeric variables were assessed using analysis of variance whereas frequency differences were assessed using the chi-squared test Factors independently associated with urinary electrolytes were analyzed using a linear regression or a logistic regression model Statistical analyses were performed using the JMP version 13.1.0 software (SAS Institute P < 0.05 was considered statistically significant Clinical characteristics of the study participants are presented in Table 1 Spot urine Na/K was slightly lower at follow-up (−0.33 ± 2.15) possibly because of a higher frequency of fasting individuals ( ≥ 12 h; follow-up: 79.2% A national trend toward decreasing salt intake as well as increased frequency of participants taking antihypertensive drugs which may enhance consciousness of salt restriction Differences in urinary Na/K at the follow-up measurement based on educational attainment and presence of a live-in spouse Numbers of study participants in each subgroup are indicated in the column Statistical significance was assessed by (a) analysis of variance; (b d) linear regression model adjusted for age and body mass index; and (c) two-way analysis of variance In the separate analysis for Na and K (Table 3) educational attainment exhibited an opposite association with Na/Cr and K/Cr body mass index (BMI) and food consumption also exhibited the opposite association The results of the regression analysis were thus clearer in the analysis for Na/K than for the separate components Mean estimated daily salt intake at the follow-up investigation was 9.3 ± 2.1 g. Regression analysis adjusted for the same covariates listed in Table 3 failed to identify educational attainment as a significant determinant for the estimated daily salt intake ( ≥ 13 years: β = −0.012 diastolic: P = 0.114) were not directly associated with hypertension Odds ratio for the highest quartiles of changes in urinary Na/K between baseline and follow-up values are adjusted odds ratios and 95% confidence intervals fasting time at the follow-up investigation and the following parameters at baseline: age Statistical significance was assessed by the logistic regression model The number of study participants in each subgroup is indicated in parentheses the association between educational attainment and Na/K was independent of age suggesting the importance of health literacy education in addition to general education to maintain satisfactory salt intake the inverse association between education attainment and urinary Na/K was independent of these covariates and was replicated in the analysis using the baseline dataset we also demonstrated an inverse association between educational attainment and 5-year longitudinal changes in Na/K irrespective of the strong confounding of the regression to the mean effect if the Na/K is high upon first measurement it will tend to be closer to the average upon second measurement without any intervention These results indicated that the present findings are not just an epiphenomenon caused by confounding of other relevant clinical factors and that the findings may represent the persistent effect of educational attainment on salt intake The inverse association between education attainment and urinary Na/K was also independent of brachial BP and antihypertensive medication As several antihypertensive drugs such as diuretics and blockers of renin–angiotensin system might influence urinary Na/K we further performed a separate analysis and found the inverse association only in individuals not taking antihypertensive drugs this result should be carefully considered because the treated individuals were older and thus more likely to have fewer years of education The results of the regression analysis in the treated individuals might be therefore somewhat underestimated Another reason for the possible underestimation might be insufficient statistical power due to the relatively small number of participants taking antihypertensive drugs Further studies in hypertensive patients are needed to clarify this issue A clear association was not observed between educational attainment and estimated daily salt intake As years of education was inversely associated with Na/Cr and positively associated with K/Cr Na/K might be a more susceptible marker of salt loading in relation to the educational attainment Inaccuracy in estimation of salt intake might be another reason consumption of these foods was also associated with educational attainment independent of the major covariates Educational attainment may be associated with urinary Na/K by directly influencing sodium intake and indirectly modulating dietary habits further investigations considering these cofounding factors will help clarify reasons for the differences in urinary Na/K based on sex and marital status and provide a hint for reducing salt intake in men A possible reason may be the difference in study settings the present study is based on individuals who live in a specific geographic area A large study including various populations may identify an inequality of urinary Na/K based on household income We therefore adjusted the fasting time in the regression analyses we investigated socioeconomic factors using a questionnaire which may contain potential misclassification any misreporting occurs independently of the urinary Na/K and thus will not cause serious bias we did not consider changes in SES during the follow-up period in the longitudinal analysis although there might be some changes in the household income and family members changes in educational attainment are unlikely There may be confounding of potential changes in SES particularly changes in the family members in the results of the longitudinal analysis we clarified that lower educational attainment was independently associated with spot urine Na/K The present results support the importance of health literacy education even in high-income countries where educational opportunity is assured Intersalt: an international study of electrolyte excretion and blood pressure Results for 24 h urinary sodium and potassium excretion Descriptive epidemiology of spot urine sodium-to-potassium ratio clarified close relationship with blood pressure level: the Nagahama study Relationships between urinary electrolytes excretion and central hemodynamics and arterial stiffness in hypertensive patients Association of urinary sodium and potassium excretion with blood pressure Effects on blood pressure of reduced dietary sodium and the dietary approaches to stop hypertension (DASH) diet Effect of longer term modest salt reduction on blood pressure: cochrane systematic review and meta-analysis of randomized trials Urinary sodium and potassium excretion and risk of cardiovascular events Socioeconomic determinants of sodium intake in adult populations of high-income countries: a systematic review and meta-analysis Factors associated with high sodium intake based on estimated 24-hour urinary sodium excretion: the 2009–11 Korea national health and nutrition examination survey Urinary sodium and potassium excretion and risk of hypertension in Chinese: report from a community-based cohort study in Taiwan Socioeconomic status is significantly associated with dietary salt intakes and blood pressure in Japanese workers (J-HOPE Study) Within-country variation of salt intake assessed via urinary excretion in Japan: a multilevel analysis in all 47 prefectures Salt intakes around the world: implications for public health Socioeconomic inequality in salt intake in Britain 10 years after a national salt reduction programme Normotensive salt sensitivity: effects of race and dietary potassium Sodium and potassium in the pathogenesis of hypertension A simple method for estimating 24 h urinary sodium and potassium excretion from second morning voiding urine specimen in adults A simple method to estimate populational 24-h urinary sodium and potassium excretion using a casual urine specimen Revised equations for estimated GFR from serum creatinine in Japan DASH-style diet and 24-hour urine composition Geographic and socioeconomic variation of sodium and potassium intake in Italy: results from the MINISAL-GIRCSI programme Spatial variation of salt intake in Britain and association with socioeconomic status Combined effects of eating alone and living alone on unhealthy dietary behaviors obesity and underweight in older Japanese adults: results of the JAGES Socioeconomic indicators are independently associated with nutrient intake in French adults: a DEDIPAC study Diurnal variation of urinary sodium-to-potassium ratio in free-living Japanese individuals Download references We are extremely grateful to the Nagahama City Office and the nonprofit organization Zeroji Club for their support in performing the Nagahama Study. The authors would like to thank Enago (www.enago.jp) for the English language review the Practical Research Project for Rare/Intractable Diseases (ek0109070 the Comprehensive Research on Aging and Health Science Research Grants for Dementia R&D (dk0207006) the Program for an Integrated Database of Clinical and Genomic Information (kk0205008) from Japan Agency for Medical Research and Development (AMED) and the Takeda Medical Research Foundation Download citation DOI: https://doi.org/10.1038/s41440-018-0101-x Share your travel photos with us by hashtagging your images with #visitjapanjp The glorious Edo period of Japan birthed numerous cultural marvels but perhaps none as grand as the Nagahama Hikiyama Festival where dozens of hikiyama (an elaborate wooden float with a kabuki theatre stage) are slowly paraded through the streets of Nagahama in Shiga Prefecture Held between the 13th and 16th of April every year this ‘moving theatre’ is one of Japan’s three great float festivals and has a history stretching back to the middle of the Edo period (late 17th century) The festival is all about children’s kabuki performed by boys aged 5 to 12 – playing both male and female roles in full makeup and costume – on the hikiyama Each of the individually-designed hikiyama has a name and divided into three groups of four floats; only one group is paraded each year There is also a “guardian” float – which has no stage – named Naginata-yama that appears every year The floats centre around the Nagahama Hachimangu Shrine where legend says a former lord of Nagahama Castle – Hideyoshi Toyotomi – spread his wealth among the townspeople in honour of his first son Part of that treasure went into building 12 hikiyama to be celebrated at the shrine annually float teams developed a healthy rivalry that encouraged increasingly beautiful and intricate designs some housing 400-year-old Belgian tapestries depicting domestic and battle scenes from ancient Japan These marvels of construction have two storeys – the first housing a kabuki stage and dressing room with a pavillion on the second floor capped by storied gabled roofs which is quite a feat considering many of the floats are hundreds of years old Outside of the festival season you can see them at the Nagahama Hikiyama Museum you can watch the boys practise their kabuki performance (three times daily) at each of their float’s neighbourhood practice halls you can also see scantily-clad young men (wakashu) from the four floats create a frenzy by splashing themselves with cold water and running from the Nagahama Hachimangu Shrine to the Hokoku Shrine across town where they splash in a well again This is done to wish for a successful festival While the main festival happens on April 15th (called honbi) the hikiyama procession and kabuki performances start from April 14th when each float travels from their respective neighbourhoods to Nagahama Hachimangu Shrine pulled by the wakashu as they shout ‘Yoisa The honbi starts from morning when the hikiyama are paraded from Hachimangu Shrine to Hokoku Shrine with kabuki performances taking place successively on each float until night falls You can catch the festival at any time during the day especially along the Otemon-dori shopping arcade Nagahama is an Edo-era port city that once had the ancient Hokkoku Kaido highway (which connected both coasts of Japan) running through its heart its history can be relived by strolling through historic Kurokabe Square everybody in town salivates for the Mackerel Somen This warm bowl of goodness is Nagahama’s most iconic dish: tender slow-cooked mackerel on a bed of soupy noodles The dish was born out of necessity – many women married into farming communities and made this relatively simple dish to save time since their strong hands were needed in the fields during harvest time The mackerel is boiled for two days seasoned soy sauce Japanese sake and sugar before it is grilled and then served on top of somen noodles in dashi (fish broth) Yokarou is the most famous establishment serving Yakisaba Somen – this 200-year old restaurant is run out of an old wooden house along the ancient Hokkoku Kaido highway There’s always a crowd – but the reward is a bowl of Nagahama’s finest noodles in an authentic Another popular dish is Noppei Udon – a bowl of udon noodles in thick, starchy soup garnished with fried tofu and fishcake. Nagahama’s most famous place to try this is Momijiya Noppei Udon whose udon is served with momiji (maple leaf) tofu and a giant shiitake mushroom you can head to Nagahama Roman Brewery – a local craft beer bar that’s known not only for its ale but also for its local pub fare like Ohmi beef and funazushi (fermented fish) that’s unique to Shiga prefecture The Nagahama Hachimangu Shrine is a 15-minute walk from JR Nagahama Station The terminus of the hikiyama festival procession is at Hokoku Shrine which is about 10-minute walk away and just a 5-minute walk from Nagahama Station The Nagahama Hikiyama Museum is also a 15-minute walk from JR Nagahama Station Browse the JNTO site in one of multiple languages The top floor of the Nagahama Castle Historical Museum is an observatory from which the cherry blossoms when the petals glow under yozakura illuminations while the sun sets over Lake Biwa Sakura 100: Japan’s Best Blossoms Banner photo © Nagahama Tourism Association.) Metrics details Abnormalities in circadian blood pressure (BP) variation have been suggested to be associated with cardiovascular diseases and mortality Factors affecting this variability need to be clarified to precisely evaluate the risk of circadian BP abnormalities Given the seasonal differences in casual BP it was hypothesized that nocturnal BP may also differ by season we aimed to clarify the seasonality of circadian BP variation as well as the factors associated with this seasonality in a large-scale general population (n = 4780) This is a cross-sectional study based on multiday BP values measured in the evening Measurements were taken at home using an automatic cuff-oscillometric device The sleeping period was objectively defined by actigraphy The nocturnal systolic BP fall was significantly less in individuals whose BP was measured during the summer season (summer resulting in higher frequencies of riser (summer 37.0%) patterns in the summer season (p < 0.001) The results of linear regression analysis identified the middle (β = 0.154 p < 0.001) and summer season (β = 0.261 p < 0.001) as strong positive determinants for decreasing the nocturnal SBP fall No seasonality was observed in day-to-day variability of the dipping pattern (Kendall’s coefficient: winter The nocturnal BP fall was largely different by season with a higher frequency of riser and non-dipper patterns in the summer The seasonality might not be due to the seasonal difference in day-to-day variability of nocturnal BP changes which might represent excessive body fluid retention that increases sleep BP to facilitate sodium excretion and diuresis given a low frequency of individuals showing high BNP levels in a general population additional factors need to be clarified to further understand the mechanisms underlying circadian BP variations and the reproducibility of nocturnal BP measurement was not considered We therefore further investigated the association between day-to-day nocturnal BP variability and seasonality by analyzing multiday BP values measured during the night Seasonality in nocturnal BP fall might be an important factor in epidemiological studies particularly in studies aiming to evaluate the prognostic and diagnostic significance of circadian BP abnormalities This is a cross-sectional study using a dataset describing participants in the Nagahama Prospective Cohort for Comprehensive Human Bioscience (the Nagahama Study) Participants in this community-based prospective cohort study were recruited between 2008 and 2010 from the general population of Nagahama City a rural city of 125,000 inhabitants located in central Japan and without physical impairment or dysfunction were eligible and 26 were excluded based on genetic analysis demonstrating a differing ethnic background the total number of cohort participants was 9764 Participants in the Nagahama cohort were invited to a follow-up assessment conducted 5 years after baseline evaluations (2013–2015) and 8289 of the original 9764 cohort members participated After excluding 137 individuals who died and 279 who had moved away from Nagahama City Among the 8289 participants in the follow-up investigation individuals who met the following criteria were excluded from the analysis: pregnant women (n = 24) obstructive sleep apnea therapy by continuous positive airway pressure (n = 36) or oral appliance (n = 9) severe renal functional decline (estimated glomerular filtration rate [eGFR] <45 ml/min/1.73 m2 or urinary albumin ≥300 mg/day incomplete or wide deviation of clinical values required for the present study (n = 16) Participants who were considered shift workers (n = 15) according to home BP monitoring time were also excluded All study procedures were approved by the ethics committee of Kyoto University Graduate School of Medicine and by the Nagahama Municipal Review Board BP monitoring at home was provided as an optional examination upon request An automatic cuff-oscillometric device (HEM-7080IC Japan) was provided to participants who intended to undergo home BP monitoring Participants were required to measure home BP (morning and evening BP) for 7 days and sleep BP for the last 5 nights (day 3 to day 7) according to the following procedures: [home BP]: measure BP by themselves in a sitting position within 1 h after awakening (morning BP) or just before going to bed (evening BP) before taking antihypertensive drugs (morning BP measurement) and after a few minutes of rest in a sitting position; [sleep BP]: sleep while wearing a cuff on the upper arm The BP monitor was programmed to automatically measure BP at midnight All BP and heart rate (HR) values were recorded in the built-in memory of the device The daily sleeping period was defined using an actigraphy device (Actiwatch 2 This device can measure physical activity and illuminance using a built-in three-dimensional accelerometer and silicon photodiode Well-trained technicians defined the individual’s daily sleeping period using computed actigraphy (Actiware Philips Respironics) and a self-reported sleep diary BP values measured during the sleeping period and within 1 h before sleeping were considered as sleep If there were multiple readings in each slot the mean value was calculated as a representative value and morning BP values for a given day were available (n = 4780) were included in the final analysis Home BP monitoring was performed from June to February The daily nocturnal BP dipping level was calculated as a percent change of sleep BP to awakening BP (average of morning and evening BPs); [(sleep BP–awake BP)/awake BP] × 100 The nocturnal dipping pattern was defined by the mean of daily nocturnal SBP change as follows: extreme-dipper increase in sleep SBP compared with awakening SBP Day-to-day variability of BP values (mmHg) and nocturnal BP dipping (%) were assessed using the coefficient of variation (CV; standard deviation/mean) The CV was calculated for individuals whose home BP readings were available for more than 3 days (n = 3475) Other clinical parameters used in this study were obtained from a personal record of measurements taken at the follow-up investigation Details regarding alcohol consumption and medical treatment including antihypertensive drug use and sleep apnea therapy were obtained using a structured self-reporting questionnaire Alcohol consumption was calculated by multiplying the amount consumed in a single day and the number of drinking days per week and was described in Japanese traditional units of alcohol (Go) and mean temperatures in Nagahama city were obtained from a database of the Japan Meteorological Agency and frequency differences were assessed using the chi-squared test Multiple linear regression was used to identify factors that were independently associated with nocturnal SBP dipping Multinomial logistic regression analysis with extreme-dipper as a reference was used to identify factors for dipper Reproducibility of that nocturnal BP dipping pattern was assessed using κ statistics while the intra-individual concordance ratio of the dipping pattern during the latest three nights was assessed using Kendall’s coefficient of concordance Statistical analyses were performed using statistical software (JMP ver Kendall’s coefficient of concordance was calculated using R software and the Kendall command packaged in the irr library A p-value of <0.05 was considered to be statistically significant The clinical characteristics of the study subjects are summarized in Table 1 Sleep BP values were slightly lower than evening and morning BP values and mean systolic and diastolic BP differences between sleeping and awakening were −10.8 ± 10.5 and −7.5 ± 7.3 mmHg Home BP monitoring was performed for 1–7 days by the participants The frequencies of extreme-dipper, dipper, non-dipper, and riser patterns were 6.5, 34.7, 45.2, and 13.6%, respectively. Differences in clinical parameters according to dipping pattern are summarized in Table 2 serum BNP levels were significantly different by dipping pattern Although there was an inverse association between BNP levels and eGFR (log-normalized BNP; r = −0.175 differences in BNP levels by dipping pattern were independent of eGFR (analysis of covariance for log-normalized BNP; dipping pattern: p = 10.0 Seasonal effects on nocturnal BP changes BP monitoring at home was performed from June to February The dotted lines are quadratic regression lines (morning SBP b The percentage decline in sleep SBP [(sleep SBP−awake SBP) × 100/awake SBP] and mean temperature at Nagahama city during investigation (2013–2015) obtained from a database of the Japan Meteorological Agency are shown The number of subjects in each subgroup is shown in columns c Frequency differences in nocturnal dipping patterns; extreme-dipper increase in sleeping SBP compared with awakening SBP A similar relationship was observed in the analysis for DBP (middle: coefficient = 1.775 the effect of season on nocturnal SBP dipping (coefficient; ≥65 years: middle = 2.006 summer = 4.319; < 65 years: middle = 2.834 summer = 4.421) and DBP dipping (coefficient; ≥65 years: middle = 1.029 summer = 3.261; <65 years: middle = 2.135 summer = 4.298) were slightly stronger in the younger subgroup Although serum BNP levels were also significantly different by season the seasonal variation in nocturnal BP changes was independent of BNP level When sleep duration (Supplementary Table 1) or midpoint of sleep (Supplementary Table 2) was further included in the regression models Seasonal differences in day-to-day BP variability The closed circle and square indicate the mean day-to-day coefficient of variation (CV) of SBP and DBP The dotted-line indicates a quadratic regression line (evening BP: SBP The day-to-day CV was calculated in individuals whose home BP was available for more than 3 days (n = 3475) The seasonal effect was assessed by a multiple linear regression analysis using the winter season as a reference The adjusted factors in this model were age cross-sectional study involving multiday measured sleep BP we clarified that there was a marked seasonal variation in nocturnal BP dipping level and consequently higher frequencies of non-dipper and riser patterns in the summer season The seasonal variation might not be due to seasonal differences in the day-to-day variation in nocturnal BP dipping levels because the day-to-day variability of the nocturnal BP level did not differ by season the seasonality might not be due to an increase in the individual’s daily BP variation As the summer season was associated with both lower awakening BP and higher nighttime BP the increase in the prevalence of the non-dipping pattern in the summer might not simply be a result of awakening BP decline its effect on nocturnal BP levels might not be strong enough to raise it above awakening BP levels as well as the presently observed insignificant association of sleep duration and sleeping period with seasonality in nocturnal BP change sleep parameters might not be a primary reason for the seasonal variation in nocturnal BP fall Involvement of the remaining physiological factors such as insufficient deactivation of sympathetic nervous activity needs to be investigated to shed light on the mechanism causing seasonality involvement in nocturnal BP fall Reproducibility of the nocturnal BP dipping pattern was modest Because we used a multiday measured sleep BP in the seasonal variation analysis biases of poor reproducibility in the present findings might be kept to a minimum A lack of seasonal differences in the day-to-day concordance of the nocturnal BP dipping pattern (Kendall’s coefficient) also supports the robustness of the present findings the poor reproducibility of the nocturnal dipping pattern in general should be interpreted with caution when ambulatory monitored BP was used in epidemiological studies Multiday measurement may be the easiest method to certainly evaluate circadian BP variation we did not measure intra-individual seasonal variation in nocturnal BP which remains a possibility of confounding population differences across the measurement seasons We used actigraphy to determine the sleeping period In contrast to the studies that determined sleeping period by a self-reported sleep diary our study has the strength of accurate measurement of sleep BP we found large seasonal variations in nocturnal BP fall and its dipping pattern in a large general population Careful attention should be given to seasonality in epidemiological studies regarding circadian BP variation The poor reproducibility of the nocturnal BP dipping pattern should also be cautiously considered Prognostic effect of the nocturnal blood pressure fall in hypertensive patients: the Ambulatory Blood Pressure Collaboration in patients with hypertension (ABC-H) meta-analysis Increased nighttime blood pressure or nondipping profile for prediction of cardiovascular outcomes Chronotherapy with conventional blood pressure medications improves management of hypertension and reduces cardiovascular and stroke risks Isolated nocturnal hypertension and subclinical target organ damage: a systematic review of the literature Associations of systolic and diastolic blood pressure night-to-day ratios with atherosclerotic cardiovascular diseases Retinal vessel caliber and its relationship with nocturnal blood pressure dipping status: the SABPA study Prognostic significance of the nocturnal decline in blood pressure in individuals with and without high 24-h blood pressure: the Ohasama study Predictors of all-cause mortality in clinical ambulatory monitoring: unique aspects of blood pressure during sleep Non-dipping pattern of hypertension and obstructive sleep apnea syndrome B-type natriuretic peptide is a determinant of the nocturnal increase in blood pressure independently of arterial hypertrophy and hypoxia Seasonal variations in home and ambulatory blood pressure in the PAMELA population Hanazawa T, Asayama K, Watabe D, Hosaka M, Satoh M, Yasui D, Obara T, Inoue R, Metoki H, Kikuya M, Imai Y, Ohkubo T. Seasonal variation in self-measured home blood pressure among patients on antihypertensive medications: HOMED-BP study. Hypertens Res. 2016; https://doi.org/10.1038/hr.2016.133 Weather-related changes in 24-hour blood pressure profile: effects of age and implications for hypertension management Summer does not always mean lower: seasonality of 24 h home and 24 h ambulatory blood pressure in patients with essential hypertension Seasonal variation in meteorological parameters and office ambulatory and home blood pressure: predicting factors and clinical implications Seasonal differences in diurnal blood pressure of hypertensive patients living in a stable environmental temperature Seasonal variation in cause-specific mortality: are there high-risk groups 25-year follow-up of civil servants from the first Whitehall study Seasonal variation in stroke incidence in Hisayama High sodium sensitivity implicates nocturnal hypertension in essential hypertension Sodium restriction shifts circadian rhythm of blood pressure from nondipper to dipper in essential hypertension Diuretics shift circadian rhythm of blood pressure from nondipper to dipper in essential hypertension Circadian rhythm of natriuresis is disturbed in nondipper type of essential hypertension Northern Iwate Heart Disease Registry Consortium A community based epidemiological and clinical study of hospitalization of patients with congestive heart failure in Northern Iwate Bedtime administration of long-acting antihypertensive drugs restores normal nocturnal blood pressure fall in nondippers with essential hypertension Changing the timing of antihypertensive therapy to reduce nocturnal blood pressure in CKD: an 8-week uncontrolled trial Effects of nighttime single-dose administration of vasodilating vs sympatholytic antihypertensive agents on sleep blood pressure in hypertensive patients with sleep apnea syndrome Spanish Society of Hypertension Ambulatory Blood Pressure Monitoring Registry Investigators Prevalence and factors associated with circadian blood pressure patterns in hypertensive patients Effects of habitual alcohol intake on ambulatory blood pressure Influence of alcohol intake on circadian blood pressure variation in Japanese men: the Ohasama study The causal effects of alcohol on lipoprotein subfraction and triglyceride levels using a Mendelian randomization analysis: The Nagahama study SESSA Research Group.; J-SHIPP Study Group Mendelian randomization analysis in three Japanese populations supports a causal role of alcohol consumption in lowering low-density lipid cholesterol levels and particle numbers Association of night-time home blood pressure with night-time ambulatory blood pressure and target-organ damage: a systematic review and meta-analysis Download references We are extremely grateful to the Nagahama City Office and non-profit organization Zeroji Club for their help in performing the Nagahama study for their help in the preparation of this manuscript The present study was supported by a university grant the Practical Research Project for Rare/Intractable Diseases the Comprehensive Research on Aging and Health Science Research Grants for Dementia R&D from the Japan Agency for Medical Research and Development (AMED) and a research grant from the Takeda Science Foundation and Fukuda Lifetec-Keiji to Kyoto University Graduate School of Medicine Kyoto University The Nagahama study group executive committee is composed of the following individuals: Yasuharu Tabara Kyoto University Graduate School of Medicine (Ya T the Department of Health Informatics (Yo T the Department of Medical Ethics and Medical Genetics (S K) and Kyoto University School of Public Health Download citation DOI: https://doi.org/10.1038/s41440-017-0003-3 If you were to ask Hiroshi Nagahama how he cultivated such an extensive resume he might just say it was a little bit of luck and his habit to say “yes” to just about anything another work with quite an experimental style It all started when Nagahama watched Wicked City when he was in high school. “As I was watching, I didn't think of it as anime,” Nagahama said. “I was just surprised that I was watching it like a movie. It left a strong impression of what animation is capable of,” adding that it was the first time he watched the end credits of a movie. Seeing that it was a Madhouse production Nagahama made it his goal to join the studio Nagahama started his career working on Yawara! A Fashionable Judo Girl and Record of Lodoss War even working between the two at the same time Nagahama said he gained a reputation for being dedicated to his work “At that time, I got 160 yen for one Yawara cel and 210 yen for a Lodoss cel,” Nagahama said. “For that 210 yen, one cel I worked on was a large dragon. I worked on [the dragon's] scales for days.” But because of his hard work on Lodoss War, he says the character designers Yutaka Izubuchi and Nobuteru Yūki still take care of him to this day After building his key animation skills working on Battle Angel, Nagahama decided to leave Madhouse. It was then Shinya Hasegawa, Nagahama's former animation school classmate, reached out and asked him to be an animation director for a new project with another up-and-coming director named Kunihiko Ikuhara Nagahama's first assignment was to make some image boards so he drew "The Forest of Duels," Anthy's greenhouse and he's sitting back on a sofa,” Nagahama said says ‘I'll be right back’ and I heard him make a phone call He came back and said 'You're in charge of the art design.'” Shocked by Ikuhara's proposal Ikuhara then told Nagahama he was also the animation director and in charge of the conceptual design “I guess what I created just fit perfectly with the image Ikuhara had in his head,” Nagahama said After finishing Utena, Nagahama would meet the director Akitarō Daichi while working on Sexy Commando Gaiden: Sugoi yo!! Masaru-san. Daichi later recruited Nagahama to work on the first anime adaptation of Fruits Basket, telling him that he had two days to work on the storyboards for the opening animation of “For Fruits Basket” by Ritsuko Okazaki but Nagahama said her influence still stays with him every day “It doesn't feel like a traditional opening,” Nagahama said “She believed if you put everything you have She kept telling me that all those feelings will reach the viewer.” Nagahama would officially start his directorial career with Mushi-Shi (a title he always intended to be his debut), go onto direct Detroit Metal City (which he claims Cowboy Bebop director Shinichirō Watanabe directly helped him get in the job) and then move on to one of his more contemporary titles Flowers of Evil (but not without a little negotiation) Nagahama said a producer from King Records reached out and asked him to make an anime adaptation of Flowers of Evil but Nagahama replied: “what this manga conveys to the viewer could not be conveyed in animation.” After a month or so of trying to convince Nagahama The producer asked once again what it would take to make Flowers of Evil an anime but there's no way King Records will allow it to happen,'” Nagahama said And it might get a very negative reaction from the viewers.” “Just tell me what you want!” said the producer the producer said it sounded great and approved his idea “I still don't know how we made it happen or how I made [Flowers of Evil],” Nagahama said “I have partial fragments of a memory of making it I only have images that have nothing to do with animation All the live-action footage we used to rotoscope When asked about the future of any Flowers of Evil adaptations Nagahama said the ending was purposefully left open-ended for future work King Records will let me make more,” he added If you saw Nagahama at any point over the weekend you might have also seen him wearing either a Spider-Man or The Reflection t-shirt Nagahama said he grew up reading American comics as a kid even now preferring American comics to manga Nagahama emphasized how much it meant to him not only working with Stan Lee but also having a show where they were both credited at the top “My first decision was to make it look like printed paper," Nagahama said “The concept was that you could take what's on the screen It was very difficult for the animators.” Nagahama also took the chance during a panel to praise Spider-Man: Into the Spider-Verse not only because of his lifelong passion for Spider-Man but because of how the style carried itself throughout the movie “Seeing that made me think we could make The Reflection a different way." Nagahama added they still have a lot of materials they can work with for future The Reflection stories “We're talking with Lee's company to create more Anime News Network later had an opportunity to sit down with Nagahama for an interview at the convention Nagahama: I was episode director for Episode 10 of Rinshi!! Ekoda-chan There were 12 episodes and for each one there is a different director The audience thought they were looking at monsters That was our objective and I wanted to create something unique and special I went to your panel about American comics and was very impressed What was your first experience with an American comic When did you realize that it was different than Japanese comics Nagahama: When I was 10-years-old, I bought the fourth volume of Spider-Man. Iceman from X-Men was a guest in the issue and I noticed the skull texture and muscles looked realistic. I was moved by seeing that people could make art like that. In Japanese anime and comics, like Kamen Rider and robot anime there's usually one villain per episode and they will always blow up and die Sometimes the villain will remake their suit and that drama continues Los Angeles or places that we know in real life so it's as if the characters are here in our world That was the main difference I noticed compared to American comics I know you're a fan of American comics, but in America, My Hero Academia regularly is at the top of sales lists and outsells Marvel and DC. Why do you think Americans are reading My Hero Academia more than Marvel or DC Comics Especially because My Hero Academia is influenced by Marvel and DC Nagahama: To be honest, I don't really know. For Dragon Ball, One Piece and Naruto Japanese people didn't anticipate that those titles would be big overseas It's a sign that Japanese manga is accepted in foreign countries I could say the opposite is true too: American comics didn't click with Japanese people at first more people in Japan who recognize Spider-Man and Batman So after Japanese people started to accept American comics and American people also started to like manga Americans might think things like My Hero Academia are interesting because it feels like an American comic you said that your next project will premiere in North America first Nagahama: An American company actually offered that job to me [Note: It was later confirmed at Crunchyroll Expo Nagahama will work on the adaptation of Junji Ito's Uzumaki horror manga for Adult Swim] You and three other people (Kiyotaka Waki, Yoshiaki Kyogoku and Shōichi Hotta) at Otakon have talked about the influence of Spider-Man: Into the Spider-Verse I'm surprised because that's four industry people in the same weekend saying how much they like this movie Do you think Spider-Verse will have future influence on anime My overall thoughts may be different than the other three but I've read Spider-Man since I was 10 years old I realized how much of a direct and deep understanding I had of the series but it was also a new and revolutionary approach I just want to make sure first it is ok I ask this next question: May I ask about Kyoto Animation What can the anime industry do to recover from this Nagahama: I was so shocked when it happened The lives that were lost were in the same position I was 30 years ago: You go into the studio but you don't really have an official position then I wouldn't be here today talking with everyone in Washington everyone had that same feeling of “that could have been me 30 years ago.” It transcended sadness or anger After thinking about their families and what their futures could have been but the people who lost their lives won't come back We can't do anything to replace the family's anger and sadness The last thing I'll say is I came to this event because the incident happened I came here as a mission to be there for everyone To see and hear that in person and then go back to Japan is what I should do now So I want to thank you for asking that question Our thanks to Hiroshi Nagahama and Otakon for this opportunity HIGHLAND PARK - Police dashboard camera videos were recently released showing an altercation between the Highland Park Police Department and an Edison man who died later that day died in June 2016 following an altercation with the Highland Park police the Middlesex County Prosecutor's Office said that Nagahama died at Robert Wood Johnson University Hospital in New Brunswick "hours after he struggled with police who revived him when they found him lying on a street in Highland Park" and that the results of an autopsy were not immediately available READ: Judge splits decision in OPRA case involving Edison man's death READ: Judge to rule on portion of OPRA lawsuit involving Edison man's death The release said that "Nagahama became belligerent and struggled with police" and was "not placed under arrest but was taken to the hospital by rescue workers." The videos show a more complete story as the first police officer arrives to South Fifth Avenue Nagahama can be seen laying on his back in the street near an intersection The officer called into headquarters through his police radio and said that he was at the scene of a hit-and-run of a vehicle and a pedestrian.  Nagahama and the officer are not in view of the dashboard camera the two can be seen standing in the intersection and more police officers arrive The responding officer moves his car closer and four police officers can be seen speaking to Nagahama Nagahama can be seen talking to the officers while wearing a blue button-down shirt and glasses Words!" Nagahama yelled when approached by one of the officers another officer can be heard on the radio calling for first aid but added that there's an "intoxicated individual." Nagahama then gives an identification card to another officer and continues to talk while waving his arms.  The situation changes quickly when Nagahama crosses his hands in front of him and steps up close to one of the officers He moves his arms to the small of his back, makes a loud noise The officer grabs Nagahama and pulls him over to the hood of a police car by his arm "You are hurting me," Nagahama said to the officers An officer tells Nagahama to face the hood of the car or else he's going to "have a seat in a cell." He also told Nagahama that he's "going to go to jail" if he doesn't cooperate Nagahama moves his hands away from his back and a struggle ensues All four officers are seen trying to subdue Nagahama One of the officers puts his hands on Nagahama's face Nagahama attempts to push the officers away at one point putting his hand on the back of an officer's head "You're going to get sprayed!" an officer said The officers bend Nagahama backward against the police car's hood with his arms fully spread An officer pulls out what appears to be pepper spray and holds it above Nagahama's face The struggle moves off screen but can still be heard Nagahama continues to yell and then screams: "He hit me!" before making guttural cries for nearly a minute An officer demands that Nagahama stop moving his hands appear to be handcuffed behind his back The officers place a surgical mask on his face covering his mouth They roll Nagahama away and place him in the ambulance He would be pronounced dead three hours later the use-of-force reports filed in connection with the Highland Park police officers' interactions with Nagahama were not released by authorities The Libertarians for Transparent Government filed a lawsuit against the Middlesex County Prosecutor's Office after it declined to release the records and a judge in November ordered the release of the use-of-force reports chairman of the New Jersey Libertarian Party's Open Government Advocacy Project said that the release of the documents was a positive move in shedding more light on Nagahama's case but there are still questions to be answered "We shouldn't be having all this mystery," Paff said This is a guy who had a life and we shouldn't have to guess at these things — some of these blanks should be filled in The Highland Park officers who filled out the use-of-force reports include Sgt Patrolman Brian O'Mara and Patrolman Christopher DeCosta They noted that Nagahama was under the influence in their reports All of the reports said that Nagahama resisted police officer control and all officers said they used compliance holds as well as their hands and fists against Nagahama O'Mara noted that he also used a chemical or natural agent against Nagahama Staff Writer Nick Muscavage: 908-243-6615; ngmuscavage@gannettnj.com Metrics details The sodium-to-potassium ratio (Na/K) of a urine sample is a simple index of salt loading we aimed to determine whether the Na/K value affects blood pressure (BP) at any age We analyzed a dataset of the general population (the Nagahama study) including baseline and second-visit measurements performed 5 years after the baseline Spot urine samples were used for Na/K assessments A total of 18,505 observations were analyzed using a linear mixed model including the measurement term as a random effect Urinary Na/K values showed a positive association with BP When the highest quartile of Na/K was further divided by the urinary Na/creatinine (Cre) and K/Cre levels the high-Na/Cre (3.58) and high-K/Cre (0.75) (Na/K = 4.80) groups as well as the low Na/Cre (1.23) and low-K/Cre (0.26) (Na/K = 4.87) groups exhibited similar effects on systolic BP (6.82 mmHg [95% CI: 5.72–7.92] and 6.63 mmHg [95% CI: 5.35–7.91] A similar association was observed in other Na/K quartiles The positive association of Na/K and Na/Cre with BP was steeper in the older groups while the inverse association of K/Cre was predominant in the younger population The results of the multivariate analysis identified interaction terms between age and Na/K Na/Cre and K/Cre as significant determinants for SBP The positive association of urinary Na/K with BP was independent of the urinary Na and K levels The association between Na/K and BP may not be uniform across ages by decade because Na/K is a ratio and not an absolute value it is unclear whether the same Na/K values have a similar influence on BP irrespective of the Na and K levels we proposed to discern whether the same Na/K values calculated as a high Na-to-high K ratio and a low Na-to-low K ratio have similar influences on BP To support the practical use of Na/K as an index of salt loading we analyzed a dataset of the Nagahama study a large-scale general population-based study in Japan Because urinary Na/K and BP values involve random measurement errors multiple measurements are preferable for their association analysis We also investigated age-dependency in the relationship between urinary Na/K and BP Participants were recruited from the general population of Nagahama a rural city located in central Japan inhabited by ~125,000 people A baseline investigation of the Nagahama study was performed between 2008 and 2010 Community residents aged 30–74 years living independently without any physical impairment or dysfunction were eligible a total of 9154 participants were included in the analysis after excluding individuals who met the following criteria: pregnancy (n = 42) unavailability of urinary Na and K values due to menstruation (n = 438) severe renal functional decline (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2 or urinary albumin ≥ 300 mg/g creatinine [Cre]; n = 82) incomplete clinical values or responses to the questionnaire administered (n = 31) receipt of hemodialysis therapy (n = 2) at the second health survey and wide deviation of urinary Na and K values (Mahalanobis distance > 7 8289 individuals participated in the second health survey performed 5 years after the baseline evaluation (2013–2016) the second-visit dataset of the Nagahama Study comprised 9850 participants A total of 9351 participants were included in the analysis after excluding 499 individuals who met the same exclusion criteria as described above This study was approved by the Ethics Committee of the Kyoto University Graduate School of Medicine and by the Nagahama Municipal Review Board Written informed consent was obtained from all study participants Spot urine samples were collected at the baseline measurement (0900–1700 h) and the second-visit measurement (0800–1400 h) and Cre levels were measured on each day of sampling The time since the last meal was recorded for each participant were calculated within the baseline and the second-visit datasets and then combined to avoid potential stratification Brachial BP was measured after a 5-min rest in the sitting position using a cuff-oscillometric device (HEM-9000AI; Omron Healthcare and the mean value was used in the analysis Hypertension was defined as a participant meeting any or all of the following criteria: SBP ≥ 140 mmHg Alcohol consumption was obtained by a self-administered questionnaire using Japanese traditional units of alcohol (Go) The use of antihypertensive drugs was also assessed by using a questionnaire Values are presented as the mean ± standard deviation or frequency Group differences in numeric variables were assessed by analysis of variance Linear mixed model analysis using a total of 18,505 observations (baseline observations: 9154; second-visit observations: 9351) was applied to identify independent determinants for SBP The linear mixed model included the measurement term (baseline or second-visit measurements) as a random effect while the following factors were included as fixed effects: age Covariate-adjusted group differences in SBP were also calculated by the linear mixed model Statistical analyses were performed using JMP version 14.3.0 software (SAS Institute A P value of less than 0.05 was considered statistically significant The clinical characteristics of the study participants are summarized in Table 1 7493 individuals participated in both the baseline and second-visit measurements participated in either the baseline or second-visit measurement Lower panel: crude mean SBP calculated by the linear regression model included measurement term as a random effect In this cross-sectional analysis of a large general population with twice-measured clinical values we clarified that the positive association of urinary Na/K and BP was independent of the ratio composition the same Na/K values calculated as high Na-to-high K ratio and low Na-to-low K ratio had similar influences on BP Na/K is therefore a simple risk marker for hypertension that does not require consideration of the Na and K excretion levels The association between Na/K and BP may not be uniform across age by decade particularly when the association of Na and K is analyzed separately Age-dependent nutritional intervention may be a better approach to decrease Na/K and dairy product consumption with urinary K excretion levels whereas a lower education level was associated with smaller amounts of K excretion considering the large differences in the absolute levels of Na/Cre and K/Cre among the Na/K quartiles it might be difficult to maintain Na/K sufficiently enough to lower the BP levels via only K supplementation as this study had a cross-sectional setting the longitudinal effect of the compensatory action of K must be clarified salt restriction in older persons and K supplementation in younger individuals may be a better approach to decrease Na/K with an aim to reduce the BP The strong inverse association of urinary K with BP in younger populations may compensate for the weak association of Na in this age group and account for the positive association of Na/K with BP across all age groups Additional studies in other populations are warranted to generalize the present findings our study emphasizes the usefulness of urinary Na/K as a risk factor for hypertension irrespective of excretion levels of Na and K such as salt restriction in older populations and K supplementation in younger populations may decrease the urinary Na/K and thereby prevent hypertension Effects of oral potassium on blood pressure Meta-analysis of randomized controlled clinical trials The effect of a dietary supplement of potassium chloride or potassium citrate on blood pressure in predominantly normotensive volunteers The effect of low-dose potassium supplementation on blood pressure in apparently healthy volunteers Download references The authors thank the Nagahama City Office and the nonprofit organization Zeroji Club for their assistance in performing the Nagahama study and Technology of Japan: the Practical Research Project for Rare/Intractable Diseases (ek0109070 and the Practical Research Project for Lifestyle-related Diseases including Cardiovascular Diseases and Diabetes Mellitus (ek0210066 from the Japan Agency for Medical Research and Development (AMED); the Takeda Medical Research Foundation; the Mitsubishi Foundation; Daiwa Securities Health Foundation 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/s41440-019-0276-9 Metrics details Circulating levels of inflammatory proteins have to be prognostic markers of all-cause mortality α1-Antitrypsin (AAT) is a major inflammatory plasma protein but its association with all-cause mortality is unclear We aimed to evaluate the prognostic significance of AAT levels for all-cause mortality Study participants comprised 9682 community residents (53.5 ± 13.3 years old) The mortality rate increased linearly with AAT quintiles (Q1 There were significant correlations between AAT and high-sensitivity C-reactive protein (hsCRP) levels (correlation coefficient when adjusted for possible covariates including hsCRP identified the fifth AAT quintile as a risk factor for all-cause death (hazard ratio An analysis of participants older than 50 years (hazard ratio The hazard ratio increased proportionately in combination with high AAT and high hsCRP levels and the highest hazard ratio reached 4.51 (95% confidence interval High AAT levels were determined to be an independent risk factor for mortality in the general population Although these studies were based on the same male population the results indicated that circulating AAT levels can serve as an inflammatory marker of the potential risk associated with future cardiovascular events and mortality we investigated associations between circulating AAT levels as well as its combination with high-sensitivity CRP (hsCRP) and all-cause mortality in a large-scale general population with a follow-up period of approximately 10 years Penalized cubic splines of the association between baseline AAT and hsCRP levels and the hazard ratio for all-cause mortality Lines indicate the hazard ratio and 95% confidence interval (CI) of baseline (A) α1-Antitrypsin (AAT) and (B) log-transformed high-sensitive C-reactive protein (hsCRP) for all-cause mortality Bar graph indicates number of study participants Survival curve of all-cause mortality by the quintiles of baseline α1-antitrypsin (AAT) and high-sensitivity C-reactive protein (hsCRP) levels The hazard ratio for all-cause mortality in participants aged ≥ 50 years (N = 5972) High AAT and high CRP were ≥ 145 mg/dL (5th quintile) and ≥ 0.21 μg/mL (3rd to 5th quintiles) (A) Crude hazard ratio (HR) and 95% confidence interval (CI) In this longitudinal study of a large-scale general population we identified elevated AAT levels as an independent determinant of all-cause mortality Because this association was independent of hsCRP the combination of AAT and hsCRP showed a stronger association with all-cause mortality than that of either AAT or hsCRP alone there was no clear relationship between AAT quintiles and the same clinical risk factors Although the reasons for the lack of an association between AAT and any of the known risk factors remain uncertain the independency from other risk factors might be a reason for its more evident association with all-cause mortality than that of hsCRP but the association between AAT with all-cause mortality was also unrelated to cancer history our longitudinal analysis results did not change substantially when the participants who died within 1 year after baseline investigations were excluded from the analysis nor did the sensitivity analysis when potential cases of AAT deficiency were excluded the association between AAT and all-cause death might not be due to reverse causation bias due to including participants with serious clinical complications at baseline Although we do not have data on other inflammatory markers the independent association of AAT and hsCRP supports the possibility that in combination with other inflammatory markers each would show a stronger association with all-cause mortality It should be clarified whether GlycA signals a composite measure of acute-phase reactant proteins or a specific combination of inflammatory markers show stronger associations with all-cause mortality we could not investigate the association between AAT and cardiovascular events due to an insufficient number of event cases we could not investigate the potential association with cause-specific death Further long-term follow-up is needed to elucidate these unknowns high AAT was an independent risk factor for all-cause mortality in the general Japanese population Our results indicate the importance of evaluating AAT levels as a risk factor for adverse outcomes which is an ongoing longitudinal study based on the clinical data of community residents of Nagahama city The study participants were recruited between 2008 and 2010 from community residents aged 30–74 years old who were living independently without physical impairment or dysfunction 9682 participants were included in the study after the exclusion of individuals who met the following exclusion criteria: widely deviating clinical values of gamma-glutamyltransferase (γGTP) (≥ 500 IU/L and incomplete data on the clinical values required for this study (N = 59) All study procedures were performed in accordance with relevant regulations and guidelines including the Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan and the declaration of Helsinki The baseline clinical characteristics of the study participants were obtained at the time of recruitment Serum levels of AAT and hsCRP were measured using a blood sample drawn at the baseline investigations in a for-profit laboratory (SRL Inc. Japan) using the N-antiserum to Human Alpha-1-Antitrypsin Kit or N-Latex CRP II Kit (Siemens Healthcare Diagnostics Other blood markers were measured using the same sera in another commercial laboratory (Medic Inc. The following measurement kits were used for the assessment: albumin Albumin II-HA test Wako (Fujifilm Wako Co. Determiner L HbA1c (Hitachi Chemical Diagnostics Systems Co. Japan); high-density lipoprotein cholesterol Determiner L HDL-C (Hitachi Chemical); low-density lipoprotein cholesterol Metaboread LDL-C (Hitachi Chemical); creatinine L-type Wako ALT-J2 (Fujifilm Wako); gamma-glutamyl transferase Clinical histories and smoking and drinking habits were queried using a structured Heavy drinking was defined as ≥ 2 (men) or ≥ 1 (women) Go drink per sitting which is a Japanese traditional liquor unit Brachial blood pressure (BP) was measured twice using a cuff-oscillometric device (HEM-9000AI; Omron Healthcare which was performed a few minutes after the test participant had rested in the sitting position The mean of the two readings was used as the representative value The primary outcome was all-cause mortality We followed cases involving relocation out of Nagahama city and those of all-cause death by reviewing residential registry records managed by the Nagahama City Office We calculated the follow-up period as the duration between baseline investigations and the date of relocation or death or the current end of the follow-up period (March 31 Because the first case of SARS-CoV-2 infection in Nagahama city was reported on April 3 which was a few days after the last day of the follow-up period (March 31 excessive mortality attributable to SARS-CoV-2 was unlikely to have impacted the data used for this study A P-value less than 0.05 was considered to be statistically significant The datasets analyzed during the current study are not publicly available due to ethical reasons but are available from the corresponding author upon reasonable request Ridker, P. 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R Foundation for Statistical Computing. https://www.R-project.org/ (2021) Download references We would like to thank all members of the Nagahama study group for their assistance in conducting the Nagahama study We are very grateful to the Nagahama City Office and non-profit organization Zeroji Club for their assistance in the Nagahama study This work was supported by a university grant Science and Technology of Japan; Practical Research Project for Rare/Intractable Diseases (ek0109070 Research and Development Grants for Dementia (dk0207006 Program for an Integrated Database of Clinical and Genomic Information (kk0205008) Research Program for Health Behavior Modification by Utilizing IoT (le0110005 Practical Research Project for Lifestyle-related Diseases including Cardiovascular Diseases and Diabetes Mellitus (ek0210066 and Research and Development Grants for Longevity Science (dk0110040) from the Japan Agency for Medical Research and Development; Takeda Medical Research Foundation Each author participated sufficiently in this work; Y.T.: conceptualization of this study funding acquisition; K.S.: data acquisition data curation; S.K.: cohort study design; T.N.: cohort study design Download citation DOI: https://doi.org/10.1038/s41598-021-96833-3 Sorry, a shareable link is not currently available for this article. 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Volume 6 - 2015 | https://doi.org/10.3389/fmicb.2015.01554 Previous studies of microbial communities in deep-sea hydrothermal ferric deposits have demonstrated that members of Zetaproteobacteria play significant ecological roles in biogeochemical iron-cycling the ecophysiological characteristics and interaction between other microbial members in the habitat still remain largely unknown we investigated microbial communities in a core sample obtained from shallow hydrothermal iron-oxyhydroxide deposits at Nagahama Bay of Satsuma Iwo-Jima Scanning electron microscopic observation showed numerous helical stalk structures suggesting the occurrence of iron-oxidizing bacteria Analysis of 16S rRNA gene sequences indicated the co-occurrence of iron-oxidizing Zetaproteobacteria and iron-reducing bacteria such as the genera Deferrisoma and Desulfobulbus with strong correlations on the sequence abundance CARD-FISH indicated that the numbers of Zetaproteobacteria were not always consistent to the frequency of stalk structures In the stalk-abundant layers with relatively small numbers of Zetaproteobacteria cells accumulation of polyphosphate was observed inside Zetaproteobacteria cells whereas no polyphosphate grains were observed in the topmost layers with fewer stalks and abundant Zetaproteobacteria cells These results suggest that Zetaproteobacteria store intracellular polyphosphates during active iron oxidation that contributes to the mineralogical growth and biogeochemical iron cycling These observations strongly suggest that microbial communities involving Zetaproteobacteria play significant ecological roles in biogeochemical iron and other elemental cycles ecophysiology and growth/survival strategy of Zetaproteobacteria correlated with other members in the iron-oxidizing microbial ecosystem are still largely unknown Light microscopic observation of these deposits showed twisted stalk structures suggesting the occurrence of iron-oxidizing microbial communities that mediate the formation process of iron-oxyhydroxide deposits Regional (A) and local (B) maps of Satsuma Iwo-Jima The seawater is brownish-red due to the presence of iron oxyhydroxides The yellow star indicates the sampling point in this study we investigated microbial communities in the shallow hydrothermal iron-oxyhydroxide deposits (water depth: ~3 m) in the Nagahama Bay To understand the distribution and ecophysiological characteristics of Zetaproteobacteria cells in this iron-rich habitat we obtained a 50 cm-long core sample and studied microbial communities using scanning electron microscopy (SEM) and catalyzed reporter deposition-fluorescence in situ hybridization (CARD-FISH) techniques as well as diversity and correlation analyses of 16S rRNA gene-tagged sequences A 50-cm-long sediment core was collected from an iron-rich hydrothermal mound in the Nagahama Bay in May 2013 by scuba divers using a clear acrylic tube (Figure 2). For DNA and SEM analyses, 10 cm3 subsamples were collected from the split core and stored at −20°C until further processing. There are hard and soft layers inside the core and the subsamples were only taken from relatively soft and undisturbed layers in this study (Figure 2B) For microscopic analyses such as cell count and fluorescence in situ hybridization (FISH) 10 cm3 of sediments were fixed with 4% paraformaldehyde (A) The shallow hydrothermal iron-oxyhydroxide deposits off Satsuma Iwo-Jima (B) A 50 cm-long core sample examined in this study with the right side representing the seafloor Sample preparation and observation by a SEM was conducted as previously described (Kiyokawa and Ueshiba, 2015) The frozen iron-oxyhydroxide sample was dried in a freeze dryer (IWAKI and then subsequently fixed on a microscope slide using conductive tapes The slide was coated with a 30-nm platinum film using an ion-sputtering device (JEOL The coated samples were analyzed by a field emission-SEM (JEOL with analysis of acquired images using MetaMorph software (Molecular Devices illumina sequencing was performed using a MiSeq platform with MiSeq Reagent Kit v2 500 cycles (Illumina ARB software was used for designing an oligonucleotide probe specific for Zetaproteobacteria The sequence data have been submitted to the DDBJ/EMBL/GenBank databases under accession number LC074716 to LC074722 and DRA004034 Scanning electron micrograph of iron oxyhydroxides (A) Overview of iron-oxyhydroxide morphology Helical stalk-like structures and particulate deposits on the surface were observed Fine particulate minerals adhere to the stalks Figure 4. Left: Microbial community structures based on phylum-level classification using 16S rRNA gene-tagged sequences. Phyla comprising higher than 10% of the total sequence reads are shown in yellow. Middle: Relative abundance of stalks observed by light microscopy. Right: Cell concentrations estimated by SYBR Green I staining (red bars) and the relative abundance of Zetaproteobacteria detected by CARD-FISH (blue circles; also see Figure 5) Fluorescent image-based cell count showed that the number of microbial cells was highest in the topmost CH1_7 at 4.23 × 108 cells cm−3 and declined sharply in CH1_6 to 7.26 × 107 cells cm−3 (Figure 4 Cell concentrations in iron-oxyhydroxide deposits below CH1_6 were relatively constant at around 6 to 7 × 107 cell cm−3 down to the sample CH1_2 and then decreased again to 1.65 × 107 cells cm−3 in the deepest sample CH1_bottom Illumina sequencing provided around 100,000 16 S rRNA sequences per sample after removing chimeras and low-quality sequences. Taxonomic analysis of the 16S rRNA sequences indicated that members within the phylum Chloroflexi are the most predominant microbial component throughout the 50 cm-core column, representing 35–40% of the total sequence reads in each sample (Figure 4) accounting for 5–15% of the total sequence reads in all depth horizons Sequences related to Zetaproteobacteria were prominent only in the topmost layer The proportion of Zetaproteobacteria sequences decreased down to ~1% or less in the middle and bottom layers In the middle layers from CH1_2 to CH1_6 where the stalk structures were frequently observed, Deferribacteres represented 3–4% of the total sequence reads. Almost all of the Deferribacteres sequences were closely related to the genus Caldithrix, which are known as thermophilic nitrate-reducing bacteria (Miroshnichenko et al., 2003) Gemmatimonadetes and the candidate division OP8 were also prevalent only in the middle layer representing 3–5% and 7–9% of the total sequence reads members of the candidate division KB1 represent 11% of the total sequence reads but its metabolic and physiological characteristics are not predictable because of no representative isolates in this group In the bottom layer of CH1_bottom and CH1_1 the Zetaproteobacteria abundance was as low as 1% where only a few stalk-structures were observed (A,C) Zetaproteobacteria detected by CARD-FISH using a Zeta709 probe (B,D) High-concentration DAPI staining showed polyphosphate that emits yellowish fluorescence; blue indicates DNA inside cells White arrows indicate Zetaproteobacteria cells detected by CARD-FISH Since the reported genome of M. ferroxydans PV-1 has genes related to polyphosphate metabolism (Singer et al., 2011), we tried to stain cells with a high concentration of DAPI, revealing that Zetaproteobacteria accumulate polyphosphate grains within the cells at the middle layer (Figure 5B) no polyphosphate grains were observed in Zetaproteobacteria cells at the top and bottom layers suggesting that there are at least 3 types of ecological niches in the cored 50 cm-long iron-oxyhydroxyide deposit Bray-Curtis dissimilarity matrix of microbial communities based on 16S rRNA gene-tagged sequences at the genus-level classification More red color indicates higher similarity Three distinct clusters correspond to the top and bottom layers of the examined 50 cm-long core sample colored by blue Other sequences such as CH1_BAC4 were closely related to sequences of Mariprofundus ferrooxydans and its relatives Molecular phylogenetic analysis of Zetaproteobacteria using the maximum-likelihood method with the Jukes-Cantor model The V1-V4 region of 16 S rRNA sequences was used Sequences marked in red indicate Zetaproteobacteria obtained in this study and in blue indicate pure cultures We performed the community network analysis based on Spearman's rank correlation coefficient data at the genus-level classification of the sequences. Interestingly, the frequencies of iron-oxidizing Zetaproteobacteria strongly correlated with anaerobic or microaerophilic bacteria, such as the members of iron-reducing Deferisoma and sulfate-reducing Desulfobulbus (Figure 8) which contains iron-oxidizing bacteria that can also reduce iron under reductive conditions were also positively correlated with Zetaproteobacteria The only exception was the members of Marinicella which are aerobic heterotrophs positively correlated with the other microbial members Negative correlation was observed with the candidate division NPL-UPA2 which sequences have been widely detected in both marine and terrestrial environments and their metabolic and physiological characteristics are still unknown Community networks based on Spearman's correlation analyses Only nodes representing first and second neighbors of Zetaproteobacteria (i.e. Mariprofundus sp.) and only strong correlations (rho values greater than 0.9) are shown Green and blue lines indicate positive and negative correlations Lines connected to Mariprofundus are drawn in bold which may create the patchily heterologous redox states that biogeochemical iron and other elemental cycles preferentially occur we did not observed any stalk- or sheath-like structures in the topmost and bottom layers implying that abiotic iron oxidation is dominant or other biotic oxidation process occurs without formation of the unique structures Although it still remains unknown if these members primarily utilize ferric iron for the anaerobic energy respiration instead of sulfur compounds or even both flexible to the in situ redox state the strong correlations between iron oxidizers and reducers indicate the occurrence of iron cycling in this environment we interpret that Zeteproteobacteria in the middle layer oxidize ferrous iron and store polyphosphate grains inside the cell they may be different metabolic and/or physiological state(s) gaining energy from iron-oxidation and/or heterotrophy without forming stalk-like structures This might be an adaption mechanism of iron-oxidizing Zetaproteobacteria; however mechanisms for their redox-sensing and energetic response to the environmental change still remain largely elusive we show that Zetaproteobacteria play significant ecological roles in iron cycling with other iron reducers and construct a unique microbial ecosystem in shallow hydrothermal iron-oxyhydroxide deposits we first demonstrated that Zetaproteobacteira in the natural ecosystem store polyphosphate grains inside cells for energy storage and a phophate source with iron-oxidation and stalk formation We also observed that Zetaproteobacteria without pholyphosphate grains with fewer stalk formations have largest population indicating a possibility that Zetaproteobacteria changed their metabolism depending on the environments These results provide some new insights into ecophysiology of iron-oxidizing Zetaproteobacteria and the microbial ecosystem in marine hydrothermal environments and SK sampled and pretreated a core sample YM and TMH performed the molecular works as DNA extraction and sequencing of 16S rRNA TTH and YM carried out microscopic works including cell count and FISH and FI designed of the work and drafted the manuscript which was critically riveted by all authors The final manuscript was approved by all authors 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 authors are grateful for the technical assistance of S This work is supported in part by the JSPS Grants-in-Aid for Science Research (no The Supplementary Material for this article can be found online at: http://journal.frontiersin.org/article/10.3389/fmicb.2015.01554 Phylogenetic identification and in situ detection of individual microbial cells without cultivation Global patterns of 16S rRNA diversity at a depth of millions of sequences per sample Lithotrophic iron-oxidizing bacteria produce organic stalks to control mineral growth: implications for biosignature formation Competitive-exclusion of sulfate reduction by Fe(Iii)-reducing bacteria - 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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) or licensor 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: Tatsuhiko Hoshino, aG9zaGlub3RAamFtc3RlYy5nby5qcA== 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 Metrics details Our current understanding of the Universe comes In particle physics an almost perfect symmetry between matter and antimatter exists a striking matter/antimatter imbalance is observed This contradiction inspires comparisons of the fundamental properties of particles and antiparticles with high precision Here we report on a measurement of the g-factor of the antiproton with a fractional precision of 0.8 parts per million at 95% confidence level Our value /2=2.7928465(23) outperforms the previous best measurement by a factor of 6 The result is consistent with our proton g-factor measurement gp/2=2.792847350(9) and therefore agrees with the fundamental charge time (CPT) invariance of the Standard Model of particle physics our result improves coefficients of the standard model extension which discusses the sensitivity of experiments with respect to CPT violation by up to a factor of 20 we report an improved measurement of the magnetic moment of the antiproton to resolve single antiproton spin transitions an ultra-strong magnetic bottle is needed (a) Schematic of the Penning trap set-up used in the BASE experiment A cloud of antiprotons is stored in the RT which supplies single particles to the CT and the AT when required The CT is used for continuous magnetic field measurements The AT is the trap with the strong superimposed magnetic bottle which is used to measure the cyclotron frequency and the Larmor frequency All traps are equipped with radio-frequency excitation electronics and highly sensitive superconducting detection systems (b) Cyclotron and (c) Larmor resonance curves The error bars in (b,c) represent the standard deviations of the individual measurements This unique trap enables us to conduct antiproton experiments even during AD machine-shutdowns The CT has the same geometry as the RT and is located 50 mm away from the AT Single particle cyclotron frequency measurements at ν+,CT≈29.6 MHz allow for continuous sampling of the trap’s magnetic field with an absolute resolution of a few nanotesla The AT has the strong superimposed magnetic bottle B2 and the central ring electrode is made out of ferromagnetic Co/Fe material This distorts the magnetic field in the centre of the trap such that ν+,AT≈18.727 MHz and νL,AT≈52.337 MHz The strong B2 couples the spin magnetic moment as well as the angular magnetic moment of the radial modes to its axial frequency νz,AT (n+ The resolution which will eventually be achieved in the determination of the g-factor is consequently limited by the ability to resolve these two frequencies we scan the resonance lines only in a close range around the cut-frequencies continuously changes the magnetron radius ρ−(t) the magnetic field experienced by the particle This softens the slope of the resonance lines close to ν+,cut and νL,cut then we determine the cyclotron energy by an axial frequency measurement This sequence is repeated until E+/kB<1.1 K For particles at such low cyclotron energies and axial frequency averaging times >90 s we achieve axial frequency fluctuations Ξz,back<0.120 Hz we tune the particle to the centre of the magnetic bottle by adjusting offset voltages on the trap electrodes This is crucial to suppress systematic shifts in the frequency measurements (a) We first centre the particle in the trap by cooling the magnetron motion to E−/kB<4 mK Then we measure the modified cyclotron frequency ν+,AT,1 Subsequently we scan the Larmor resonance νL,AT and then measure the modified cyclotron frequency again ν+,AT,2 Afterwards we re-cool the magnetron motion For a more detailed explanation of the experiment sequence we refer to the text (b) Sequence of axial frequency measurements of 30 s averaging time while a radial dipolar drive at νrf,k is applied The drive frequency is adjusted after each 10 measurements Once the drive excites cyclotron transitions νrf,k≈ν+,cut (c) Projection of axial frequency data to axial frequency fluctuation Ξz(νrf) The error bars represent the standard deviations of the individual measurements The red and green vertical lines indicate the determined mean value ν+,cut and its 95% confidence level uncertainties the blue solid line is a fit based on the the data-analysis described in the text The measured distribution of points Ξz(νrf,k) constrains the random walk ξ−(t) in the magnetron mode which has taken place during the frequency scan Each individual measurement can be associated to a gaussian sub-distribution wk(ν (a) Cumulative measured axial frequency fluctuation Ξz(νrf) for a background measurement and two different spin-flip drive frequencies at νrf,1=52,336,800 Hz and νrf,2=52,336,900 Hz The blue data points reflect the background measurement the green and the red points display Ξz(νrf,1) and Ξz(νrf,2) The solid lines indicate the 68% confidence intervals of the measurements (b) Statistical significance (Ξz(νrf)−Ξz,back)/(σ(ΔΞz(νrf) ΔΞz,back) for three different background fluctuations Ξz,back and as a function of the number of accumulated measurements For all frequency determinations which contribute to the g-factor evaluation the experiment was operated under the conditions highlighted by the yellow background νL,AT and νc,2 the g-factor is evaluated by calculating g/2=νL,AT/<νc> This accounts for linear drifts in the magnetic field experienced by the particle during the scan of the Larmor frequency The error bars of the individual measurements are based on the uncertainties of the individual frequency measurements which are dominated by the random walk in the magnetron mode The first number in brackets represents the 95% confidence interval of the measured mean the second number in brackets represents the scatter of the error according to t-test statistics Systematic errors come from non-linear drifts of the field of the superconducting magnet drifts of the voltage source which is used to define the trapping potential and the random walk ξ+(t) in the modified cyclotron mode From measurements with the co-magnetometer particle we estimate Δg/g|B0≈0.015 p.p.m Continuous voltage measurements constrain Δg/g|V<0.001 p.p.m. while we obtain for the random walk in the cyclotron mode Δg/g|+≈0.020 p.p.m The non-linear contribution of the magnetron walk ξ−(t) to a systematic shift of the g-factor is implicitly considered in the primary data-evaluation of the measured resonance lines We add these errors by standard error propagation and obtain Implementation of this method to further improve the precision in antiproton magnetic moment measurements to the p.p.b level will be targeted in our future research The data sets for the current study are available from the corresponding authors on reasonable request Sixfold improved single particle measurement of the magnetic moment of the antiproton New high-precision comparison of electron and positron g factors Precision mass spectroscopy of the antiproton and proton using simultaneously trapped particles Two photon laser spectroscopy of antiprotonic helium and the antiproton to electron mass ratio An improved limit on the charge of antihydrogen from stochastic acceleration High-precision comparison of the antiproton-to-proton charge-to-mass ratio Precision spectroscopy of a charged particle in an imperfect Penning trap Continuous Stern-Gerlach effect: principle and idealized apparatus One-particle measurement of the antiproton magnetic moment The CERN antiproton decelerator (AD) in 2002: status Open-endcap Penning traps for high precision experiments A cryogenic detection system at 28.9 MHz for the non-destructive observation of a single proton at low particle energy Laser-noise-induced heating in far-off resonance optical traps Resolution of single spin flips of a single proton Observation of spin flips with a single trapped proton Mode coupling in a Penning trap: π pulses and a classical avoided crossing High-precision measurement of the magnetic moment of the proton Lorentz-violating spinor electrodynamics and Penning traps Download references We acknowledge technical support by the Antiproton Decelerator group and all other CERN groups which provide support to Antiproton Decelerator experiments We acknowledge financial support by RIKEN Initiative Research Unit Program the Grant-in-Aid for Specially Promoted Research (no GSI-Helmholtzzentrum für Schwerionenforschung GmbH The experimental apparatus was developed and constructed by S.U. and S.S.; The experiment was commissioned by H.N. developed the software system and experiment control participated in the 2015 antiproton run and contributed to the data-taking performed the systematic studies and wrote the manuscript which was then discussed and approved by all authors The authors declare no competing financial interests supplementary discussion and supplementary references Download citation International Journal of Theoretical Physics (2020) Metrics details Although various risk factors have been identified for the development of age-related macular degeneration (AMD) risk factors of early AMD have been relatively under studied We aimed to investigate AMD risk factors by evaluating multiple factors in association with large drusen In a community-based cross-sectional survey in Japan 971 large drusen cases and 3,209 controls were compared for 65 variables The association and the effect size of each factor were evaluated with logistic regression analysis using a backward-elimination approach Multivariate analyses identified a significant association in serum calcium level (odds ratio [OR] = 0.932 ARMS2 A69S (rs10490924) genotype (OR = 1.046 Hypocalcemia was observed in 7.2% of large drusen cases and in 5.5% of controls (P = 0.0490) pneumoniae infections was more frequent in large drusen cases (56.4%) than in conrols (51.7% pneumonia infection and age are significant factors in the development of the early stages of AMD studying and preventing disease progression during the early stages of AMD are of increasing importance The pathophysiology of AMD is still poorly understood and considered to be a constellation of diseases of varying etiologies using a relatively large number of Japanese adults The distributions of predominant characteristics according to 971 large drusen cases and 3,209 controls are shown in Table 1 Study cases were significantly older than controls (65.1 ± 5.9 and 61.7 ± 6.5 years a significant association was found between ARMS2 A69S (rs10490924) and drusen; the frequency of the minor allele T which is known as a risk allele for developing advanced AMD was significantly higher in cases than in controls (P < 0.001) CFH Y402H (rs1061170) and CFH I62V (rs800292) did not show a significant association with drusen (P > 0.05) The relative strength of the significant factors for large drusen that showed a significant association in the final multivariate analysis Serum calcium level had the strongest effect on the development of large drusen; the other factors were ARMS2 A69S (rs10490924) genotype High-density lipoprotein (HDL) cholesterol α1-antitrypsin and high-sensitivity C-reactive protein (hs-CRP) had limited effect on disease development with odds ratio between 1.000 and 1.001 A diamond represents the point estimate of odds ratio for each factor with a horizontal line of the 95% confidence interval (CI) Serum calcium levels in drusen cases were significantly lower than controls (9.05 and 9.11 mg/dL, respectively; P < 0.001). When applying the normal range of serum calcium (8.6–10.3 mg/dL), hypocalcemia (calcium level <8.6 mg/dL) was more frequent in the large drusen cases than in controls; 7.2% in drusen cases and 5.5% in controls, respectively (P = 0.0490; Table 3) similar disease processes may affect calcification of the subretinal space leading to the development of drusen and a central nervous system with poor calcium control although α1-antitrypsin showed a potential association for drusen the effect of this factor on disease development was limited (OR = 1.001) which showed a significant relationship between C would indicate the significant role of the complement pathway in the inflammatory process with the disease development we did not find strong associations between CFH genotypes and drusen our result would suggest that the activation of the alternative complement pathway by C pneumoniae might be more important than that by CFH gene variation in the early stages of AMD in Asians there might be subretinal deposits without calcification that are currently called “drusen” by fundoscopy it remains unknown if low calcium intake can be the risk of the development of drusen Following basic and clinical research investigating the role of calcium in AMD is therefore needed by simultaneous evaluation of multiple factors including systemic we found a strong association between serum calcium level pneumonia infection and the development of drusen Our findings suggest a significant role for these factors during the early course of AMD The Nagahama Study is a community-based prospective cohort study designed to determine the prevalence and risk factors of various diseases in a community a total of 6,118 residents of Nagahama City aged ≥50 years participated in the Nagahama Study All protocols and informed consent procedures were approved by the Kyoto University Graduate School and Faculty of Medicine Ethics Committee the Ad Hoc Review Board of the Nagahama Cohort Project and the Nagahama Municipal Review Board of Personal Information Protection This study was carried out in accordance with the approved guidelines 3,209 individuals lacking any sign of AMD (drusen or advanced AMD) in both eyes were selected Twenty-nine cases with advanced AMD and a total of 1,386 individuals including 276 with pigment epithelial abnormalities only and 1,110 with drusen less than 125 µm in diameter or reticular pseudodrusen calculated as the daily number of cigarettes × years of smoking were genotyped using TaqMan single nucleotide polymorphism assay with the PRISM 7700 system (Applied Biosystems USA) and Human610-Quad BeadChips and HumanOmni2.5 BeadChips (Illumina Descriptive statistics are presented and estimates of center and dispersion are described as mean and standard deviation (SD) analysis of variance (ANOVA) or the χ2 test were used P values < 0.05 were considered statistically significant The list of authors in the Nagahama Study Group: T.N. Visual function and dysfunction in early and late age-related maculopathy A simplified severity scale for age-related macular degeneration: AREDS Report No Medicare costs for neovascular age-related macular degeneration Prevalence and characteristics of age-related macular degeneration in the Japanese population: the nagahama study A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration Significance of C2/CFB Variants in Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy in a Japanese Population cardiovascular disease and age-related macular degeneration Age-Related Macular Degeneration Risk Factors Study Group Progression of age-related macular degeneration: association with body mass index Cardiovascular risk factors and the long-term incidence of age-related macular degeneration: the Blue Mountains Eye Study C-reactive protein level and risk of aging macula disorder: The Rotterdam Study Early age-related maculopathy in the cardiovascular health study Risk factors for incident age-related macular degeneration: pooled findings from 3 continents Risk factors for age-related maculopathy in a 14-year follow-up study: the Copenhagen City Eye Study Distribution of allele frequencies and effect sizes and their interrelationships for common genetic susceptibility variants The five-year incidence and progression of age-related maculopathy: the Beaver Dam Eye Study Susceptibility genes for age-related maculopathy on chromosome 10q26 CFH and ARMS2 variations in age-related macular degeneration polypoidal choroidal vasculopathy and retinal angiomatous proliferation Serological association between Chlamydia pneumoniae infection and age-related macular degeneration Is Chlamydia pneumoniae infection a risk factor for age related macular degeneration Exposure to Chlamydia pneumoniae infection and progression of age-related macular degeneration Scanning electron microscopy of human drusen Correlations in distribution and concentration of calcium copper and iron with zinc in isolated extracellular deposits associated with age-related macular degeneration Prevalence and progression of basal ganglia calcification and its pathogenic mechanism in patients with idiopathic hypoparathyroidism Identification of Chlamydia pneumoniae within human choroidal neovascular membranes secondary to age-related macular degeneration Exposure to Chlamydia pneumoniae infection and age-related macular degeneration: the Blue Mountains Eye Study The association of prior cytomegalovirus infection with neovascular age-related macular degeneration Complement factor H gene polymorphisms and Chlamydia pneumoniae infection in age-related macular degeneration endothelial dysfunction and age-related maculopathy complement activators and risk of age-related macular degeneration A role for local inflammation in the formation of drusen in the aging eye No association of age-related maculopathy susceptibility protein 2/HtrA serine peptidase 1 or complement factor H polymorphisms with early age-related maculopathy in a Chinese cohort Insights into the genetic architecture of early stage age-related macular degeneration: a genome-wide association study meta-analysis Prevalence of age related maculopathy in a representative Japanese population: the Hisayama study Nine-year incidence and risk factors for age-related macular degeneration in a defined Japanese population the Hisayama study Download references We thank the participants of the Nagahama Study Nagahama City Office and the nonprofit organization Zero-ji Club for Health Promotion The following investigators are core members of the Nagahama Study Group: Takeo Nakayama (Department of Health Informatics Akihiro Sekine (Department of Genome Informatics Shinji Kosugi (Department of Medical Ethics Yasuharu Tabara (Center for Genomic Medicine Kyoto University) and Michiaki Mishima (Department of Respiratory Medicine This study was partly supported by grants-in-aid from the following organizations: the Ministry of Education Science and Technology of Japan (2006–2012); the Japan Society for the Promotion of Science (Nos 22791706 and 22791653); the Japanese National Society for the Prevention of Blindness; and the Takeda Science Foundation (2008–2012) Akitaka Tsujikawa & Nagahisa Yoshimura Download citation Graefe's Archive for Clinical and Experimental Ophthalmology (2018)