This website is using a security service to protect itself from online attacks The action you just performed triggered the security solution There are several actions that could trigger this block including submitting a certain word or phrase You can email the site owner to let them know you were blocked Please include what you were doing when this page came up and the Cloudflare Ray ID found at the bottom of this page Contact: David Yoshitomi, Arts and Culture Manager, david.yoshitomi@ventura.org Ventura County Community Foundation (VCCF) and the Ventura County Arts Council (VCAC) are excited to announce the Arts and Culture Investment Fund grant recipients investing $700,000 in funding to support the arts and culture community in the county The grants support 36 Ventura County-based nonprofit arts and culture organizations and 62 independent artists who were selected through a highly competitive grant application process Nearly 300 applications across the two groups were received during the application window Grant awards range from $5,000 to $150,000 for the nonprofit organizations The Arts and Culture Investment Fund grant program was approved by the County of Ventura Board of Supervisors to provide services and resources for the arts and culture community as it continues to recover from the impact of the COVID-19 pandemic The nonprofit grant process is administered by VCCF while the artist grant process is managed by VCAC “The County of Ventura is proud to support this diverse group of nonprofit arts and culture organizations and artists from across Ventura County,” said David Yoshitomi the County of Ventura’s Arts and Culture Manager “This initiative provides essential resources to help the arts and culture sector recover from the pandemic and continue their work I’m grateful to the Board of Supervisors for recognizing the importance of supporting both organizations and artists through providing the funding for this monumental grant program.” grant recipients will participate in a series of technical assistance workshops led by the Economic Development Collaborative that will cover best practices in areas such as capital management The combination of funding and training is intended to support the resilience and sustainability of the grant recipients strengthening the cultural and creative sectors in the county The full impact of the grant program will be shared in a final report due next year The Arts and Culture Investment Fund is the County’s first dedicated arts and culture grant program and the largest such funding opportunity ever offered by local government in Ventura County The funding allocation was approved as part of the County’s 2023 Recovery Plan to support ongoing recovery from the pandemic A total of $800,000 in grant funding is available through the program with $700,000 distributed through this grant application process and $100,000 through a separate matching grant contingency fund For more information on the grant programs and a full list of the grant recipients, please visit ventura.org/arts Guest speaker David Yoshitomi shares his paternal family’s history as guest speaker during the 2025 Ventura County JACL installation luncheon at the Ronald Reagan Presidential Library & Museum If the surname of the guest speaker — David Yoshitomi — for the Ventura County JACL chapter’s 45th chapter installation rings familiar to the Los Angeles County Japanese American community served as executive director of the Japanese American Cultural and Community Center in 1981 you might say that Los Angeles-born-and-raised David Yoshitomi inherited his father’s commitment to culture Just as his old man was the JACCC’s first executive director and would become known for not only presenting more performances and exhibitions by Japanese artists than any other theatre/gallery outside of Japan he also saw to it that the JACCC made available spaces at the Doizaki Gallery and the Aratani Theatre for such non-Japanese/non-Japanese American artists as El Teatro Campesino Lula Washington Dance Theatre and the Los Angeles Philharmonic David Yoshitomi recalled seeing “productions that would range from kabuki to [Chicano comedy and performance troupe] Culture Clash which is a Spanish-language group — it really opened my eyes to the breadth of the arts in general.” It’s little wonder that he was selected in 2022 by the County of Ventura’s Executive Office as its first arts and culture manager As the guest speaker for the installation luncheon 26 at the Ronald Reagan Presidential Library & Museum in Simi Valley Yoshitomi told of a saga that many in attendance could relate to namely his paternal family’s journey from Japan to the United States including evacuation and incarceration during World War II who describes himself as a “fourth-generation Yonsei Hapa Japanese American,” the speaking engagement was a family affair with his parents Cindy Yoshitomi — a pastor with the Santa Barbara-based St Anthony’s Catholic Community — and Gerald Yoshitomi in attendance assistant principal at Ventura High School Why is the county interested in arts and culture?’ I think the first reason is a $3.1 billion industry in Ventura County and that’s without any attention being paid to it by local government Yoshitomi noted that the monetary figure was slightly larger than agriculture in Ventura County we know what an important role the agriculture community plays here “I think the more important reason is the social impact of arts and culture here in Ventura County.” The board was installed by Pacific Southwest Gov Reprising their roles as co-presidents were Lily Anne Welty Tamai and Megan Gately with Jessica Wan and Janice McCormick as co-vice presidents Anne Chilcott as secretary and Ken Nakano as treasurer Sharing cemetery restoration coordinator duties were Nakano and Chilcott with Betty Katsura serving as book club moderator Ventura County JACL Co-President Megan Gately (center) holds a tablet connected to PSW Gov who administered the oath of office to the chapter’s new board remotely Board members were presented certificates of recognition from Ventura County Board of Supervisors member Janice Parvin California State Assembly member Steve Bennett (D-Ventura) and Rep The chapter also presented David Yoshitomi with a certificate of appreciation for serving as the guest speaker Leaf KYOTO Store Locations Made in Kyoto / The famous Kyoto sweets named after dragons will celebrate its 100th anniversary in the year of the dragon in 2024 there are wagashi related to temples and shrines as well as sweets associated with seasonal and annual events This section introduces the charm and background of these sweet treats which you can taste and feel the present time (the season) of Kyoto this long-established Kyoto sweets shop is trusted by those involved in the tea ceremony and temples ［There are three directly managed stores in the area near the Kyoto Gyoen: the main store has a museum where you can learn about the history of Kyoto sweets and a tea room where you can taste Unryu with powdered green tea making it an attractive place to relax and enjoy the world of Kyoto sweets In addition to the standard Unryu and the mildly finished Shiro Unryu made with white azuki beans the store also sells a reprinted version of Unryu using luxurious Tanba dainagon available only at the directly-managed store Unryu is a moist muraume-an paste with large pieces of ogura-an (sweet red bean paste) rolled into it The man who created this simple yet profound hit product was Tomejiro Ishihara he rebuilt his store and was impressed by a painting of a dragon by Kano Doshun at Shokokuji Temple He decided to create a confectionary that looked like a brave dragon which was different from the elegant atmosphere he had previously created The name "Unryu" was also given to the confectionery by Master Taiko Yamazaki of Shokokuji Temple whom Rujiro Ishihara looked up to as his teacher holds permanent exhibitions on the history of Japanese confectionery and seasonal special exhibitions Admission tickets from 700 yen (varies depending on the exhibition) include matcha green tea and unryu which can be served at the Shounken tea house The brand "Toiro by Tawaraya Yoshitomi" was launched in 2018 with the concept of "Japanese sweets to deliver ten different feelings Hana no Iro" series of colorful amber and kompeito sugar assortments for 830 yen The "Toiro (都色) - Kyo-Daruma (京ダるま)," a strawberry-flavored ramune-like confection using a wooden mold for dried confections and "Hana no Iro (華の色) - Momiji (モミジ)," which expresses the four seasons using tangerine- and grape-flavored amber sugar are fresh with a fruitiness that is rare in Japanese confectionery The 10th generation of the brand's founder's will to carry on the tradition coexists with a sensibility that fits the needs of today's people Raspberry black tea (half-necked) from the "Color of Fruits" series A sweet and sour adult taste that would go well with a warm winter drink the 100th anniversary of the birth of Unryu I used to think of the 100th anniversary as a goal I feel that it is a passing point on the way to the next 100 years We will continue to ask how we can preserve Kyoto sweets a culture and industry that Kyoto should protect and continue to offer Unryu that is in tune with the times," said Ishihara which is made in the shape of a lucky animal that is said to turn things around for the better Representative: Yoshikiyo Ishihara / Born in 1964 Ishihara is the ninth generation of the family head of the confectionery business He is also the president of the Kyoto Confectionery Cooperative Association and the head of the congregation of Shokokuji Temple CA – The County of Ventura’s Executive Office has selected David Yoshitomi as the new Arts and Culture Manager to lead countywide arts “Arts and culture are a fundamental thread of our community’s fabric and contribute greatly to our economic vibrancy and quality of life,” said Chair of the Board of Supervisors Matt LaVere “We are thrilled that David will help lead the County in this area Our Board created this new position in May this year and I deeply appreciate Supervisor Carmen Ramirez’s dedication to building support for arts and cultural efforts in Ventura County making it possible to create this position.” “We are grateful to welcome David Yoshitomi to the County as his 15-year track record of cultivating community connections around arts and culture will contribute greatly to preserving and promoting the rich culture and community bonds that bring our local economy to life,” said County Executive Officer Dr David Yoshitomi came to the County of Ventura from the City of Simi Valley where he was responsible for the development and implementation of the 5-year strategic plan for their Cultural Arts Center he launched the City of Simi Valley’s first municipal arts grant program and spearheaded much of the Cultural Arts Center’s cultural programming including its first Multicultural festival Yoshitomi also served as Interim Executive Director and Board Chair of Bell Arts Factory in Ventura he is credited with improving the financial performance of the organization and implementing new programs to better serve the residents in the Ventura Avenue community David holds a Bachelor’s Degree in Sociology from the University of California San Diego and a Master’s Degree in Public Administration from California State University San Bernardino he received the Arts Leader award from the Ventura County Arts Council “Ventura County is home to so many cultural traditions and a rich creative heritage,” said Yoshitomi “I’m grateful for the opportunity to work with the artists and other community members and organizations in developing a shared vision for the creative economy in the County From painting and music to design and architecture arts and culture have such a great impact on our daily lives and I look forward to helping the businesses and professionals in these fields grow and prosper.” Yoshitomi will support strategic planning and coordination with local agencies and organizations to plan and develop an arts and culture strategy for the County of Ventura Yoshitomi started the new role at the County on Monday To learn about the County of Ventura’s Economic Vitality efforts, visit https://www.vcevsp.org/ Metrics details The interactions of CD4+ T cells and B cells are fundamental for the generation of protective antibody responses as well as for the development of harmful autoimmune diseases Recent studies of human tissues and blood samples have established a new subset of CD4+ B helper T cells named peripheral helper T (Tph) cells which interact with B cells within lymphoid organs Tph cells provide help to B cells within inflamed tissues Tph cells share many B helper-associated functions with Tfh cells and induce B cell differentiation toward antibody-producing cells The differentiation mechanism is also partly shared between Tph and Tfh cells in humans and both Tfh and Tph cells can be found within the same tissues Tph cells display features distinct from those of Tfh cells such as the expression of chemokine receptors associated with Tph cell localization within inflamed tissues and a low Bcl-6/Blimp1 ratio current evidence shows that the target of Tph cells is limited to memory B cells we first summarize recent findings on human Tph cells and discuss how Tph and Tfh cells play shared and distinct roles in human diseases we first briefly summarize the phenotype and function of the Tph cells present in inflamed human tissues and discuss how Tph and Tfh cells play redundant and distinct roles in various human diseases Tph cells are defined as CD4+ T cells that provide help to B cells in inflamed tissues in autoimmune diseases Tph cells are often defined solely by their phenotype as PD-1hi CXCR5−CD4+ T cells Further studies on more refined markers of Tph cells for a deeper understanding of their biology are warranted particularly in association with inflamed tissues will increase our understanding of their association with disease pathogenesis Differentiation of Tfh and Tph cells in humans Smad2 and Smad3 activation by TGF−β and Activin A is vital for the differentiation of naïve CD4+ T cells into Tfh and Tph cells Environmental IL-2 inhibits the differentiation of both subsets Activated Stat3 and Stat4 induced by IL-12 and IL-23 stimulation promotes the development of CXCR5+ Tfh precursors that migrate toward B cell follicles and eventually differentiate into Bcl-6hi mature Tfh cells CXCR5− non-Tfh cells exit the secondary lymphoid organs and migrate into peripheral inflamed tissues under the direction of chemokine receptors (CCR2 TGF−β stimulation contributes to the production of CXCL13 by Tph-like cells via Sox4 and to the formation of tertiary lymphoid structures (TLSs) in inflamed tissues Both Bcl-6 and Sox4 likely contribute to CXCL13 expression by Tfh cells Tph-like cells might gain Th1 and Tfh-like features in inflamed tissues in response to environmental cytokines Tfh and Tph cells might coevolve in inflamed lymphoid organs in response to Tfh-promoting cytokines and Tph precursors differentiate into mature Tph cells in the periphery Tph cells can localize outside lymphoid follicles (extrafollicles) and provide help to memory B cells CXCR5− atypical memory B cells might also be a target of Tph cells The transcription factor Maf is integral for IL-21 expression in both Tph and Tfh cells the target of Tph cells seems to be limited to memory B cells Tph cells might promote the differentiation of CD11c+CD21−CXCR5− B cells into autoantibody-producing cells outside TLSs and lymphoid aggregates The features of Tph cells likely differ among diseases by the adoption of signals from microenvironmental factors within the inflamed tissues It will be important and valuable to assess the features of Tph cells that are specific for each inflammatory disease and tissue and to elucidate their precise functions in inflamed tissues together with their location and interactions with other cells Such studies will provide novel insights into disease pathogenesis and novel therapeutic targets TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus Constitutively altered frequencies of circulating follicullar helper T cell counterparts and their subsets in rheumatoid arthritis Role of the frequency of blood CD4+ CXCR5+ CCR6+ T cells in autoimmunity in patients with Sjögren’s syndrome Systemic inflammation in progressive multiple sclerosis involves follicular T-Helper Th17- and activated B-cells and correlates with progression Association of circulating follicular helper T cells with disease course of NMO spectrum disorders Number of circulating follicular helper 2 T cells correlates with IgG4 and interleukin-4 levels and plasmablast numbers in IgG4-related disease Altered circulating T follicular helper cell subsets in patients with psoriasis vulgaris Inhibition of increased circulating Tfh cell by anti-CD20 monoclonal antibody in patients with type 1 diabetes Possible involvement of chemokine C-C receptor 7- programmed cell death-1+ follicular helper T-cell subset in the pathogenesis of autoimmune hepatitis CXCR5+ CD4+ T follicular helper cells participate in the pathogenesis of primary biliary cirrhosis A higher frequency of CD4+CXCR5+ T follicular helper cells in patients with newly diagnosed IgA nephropathy Ectopic lymphoid-like structures in infection Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis Mature antigen-experienced T helper cells synthesize and secrete the B cell chemoattractant CXCL13 in the inflammatory environment of the rheumatoid joint A distinct human CD4+ T cell subset that secretes CXCL13 in rheumatoid synovium A BAFF/APRIL-dependent TLR3-stimulated pathway enhances the capacity of rheumatoid synovial fibroblasts to induce AID expression and Ig class-switching in B cells Two populations of circulating PD-1hiCD4 T cells with distinct B cell helping capacity are elevated in early rheumatoid arthritis Mass cytometry reveals systemic and local immune signatures that distinguish inflammatory bowel diseases Human tonsil B-cell lymphoma 6 (BCL6)-expressing CD4+ T-cell subset specialized for B-cell help outside germinal centers Involvement of inducible costimulator in the exaggerated memory B cell and plasma cell generation in systemic lupus erythematosus CD4(+) follicular helper T cell infiltration predicts breast cancer survival CXCL13-producing TFH cells link immune suppression and adaptive memory in human breast cancer Cell distance mapping identifies functional T follicular helper cells in inflamed human renal tissue Phenotype and functions of memory Tfh cells in human blood PD-1+CXCR5−CD4+T cells are correlated with the severity of systemic lupus erythematosus Expanded circulating peripheral helper T cells in systemic lupus erythematosus: association with disease activity and B cell differentiation PD-1hiCXCR5– T peripheral helper cells promote B cell responses in lupus via MAF and IL-21 A CD4(+) T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate Pathophysiology of T follicular helper cells in humans and mice Attenuation of follicular helper T cell-dependent B cell hyperactivity by abatacept treatment in primary Sjögren’s syndrome Circulating PD-1(+)CXCR5(−)CD4(+) T cells underlying the immunological mechanisms of IgG4-related disease Cytotoxic Tph-like cells are involved in persistent tissue damage in IgG4-related disease Distinct phenotype of CD4(+) T cells driving celiac disease identified in multiple autoimmune conditions Increased frequency of PD-1(hi)CXCR5(−) T cells and B cells in patients with newly diagnosed IgA nephropathy Circulating CXCR5-PD-1hi peripheral T helper cells are associated with progression to type 1 diabetes Human Sox4 facilitates the development of CXCL13-producing helper T cells in inflammatory environments The cytokine TGF-beta co-opts signaling via STAT3-STAT4 to promote the differentiation of human TFH cells Activin A programs the differentiation of human TFH cells TGF-beta induces the differentiation of human CXCL13-producing CD4(+) T cells Transforming growth factor-beta production by synovial tissues from rheumatoid patients and streptococcal cell wall arthritic rats Studies on secretion by synovial fibroblast-like cells and immunohistologic localization Cytokines in chronic inflammatory arthritis Failure to detect T cell lymphokines (interleukin 2 and interleukin 3) and presence of macrophage colony-stimulating factor (CSF-1) and a novel mast cell growth factor in rheumatoid synovitis T follicular helper cell biology: a decade of discovery and diseases Distinct effector B cells induced by unregulated toll-like receptor 7 contribute to pathogenic responses in systemic lupus erythematosus Extrafollicular responses in humans and SLE The immune cell landscape in kidneys of patients with lupus nephritis The IL-12-STAT4 axis in the pathogenesis of human systemic lupus erythematosus B cells and tertiary lymphoid structures promote immunotherapy response B cells are associated with survival and immunotherapy response in sarcoma Tertiary lymphoid structures improve immunotherapy and survival in melanoma and selection of B lymphocytes infiltrating human ductal breast carcinomas Novel ganglioside antigen identified by b cells in human medullary breast carcinomas: the proof of principle concerning the tumor-infiltrating B lymphocytes Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer Download references This work was supported by the Advanced Research and Development Programs for Medical Innovation (AMED-CREST) from the Japan Agency for Medical Research and Development (AMED; to HU) and Grants-in-Aid for Scientific Research from the Ministry of Education Institute for the Advanced Study of Human Biology Global Health and Emerging Pathogens Institute Download citation DOI: https://doi.org/10.1038/s41423-020-00529-z Anyone you share the following link with will be able to read this content: a shareable link is not currently available for this article Northwest Asian Weekly April 6, 2015 By Former Executive Director Karen Yoshitomi was recognized for her years of service to the organization Karen Yoshitomi was the Japanese American Citizens League (JACL) PNW Regional Office Director (National Staff) for over 22 years Karen resigned to be Executive Director for the Japanese Cultural and Community Center of Washington The Seattle JACL used the Banquet as an occasion to give Karen a surprise (unannounced) “Tomodachi” award for her years of service and friendship for the Seattle JACL Union Bank and Tim Otani were recognized for years of support to the Seattle JACL and the community Other award winners included Union Bank and Tim Otani The were recognized for years of support to the Seattle JACL and the community Ngoc Dinh presented the Sam Shoji Unsung Hero Award to Stan Shikuma Seattle JACL’s incoming president Sarah Baker presented the Community Service Award to Wing Luke Board Co-president Ellen Ferguson Police in Japan said Tuesday they have referred to prosecutors ramen noodle chain Ichiran, its president and six officials for allegedly making foreign students work illegally at its Osaka stores in violation of the immigration law. Manabu Yoshitomi, 53, president of the Fukuoka-based chain serving thin noodles and pork-bone soup, and the six officials are suspected to have made Vietnamese and other foreign students work over the permitted limit of 28 hours a week at two of its stores in Osaka from September through November. They have admitted to the charge, with Yoshitomi quoted by police as saying, "Although I was aware of the illegal practice, I had left the matter to the head office's labor management department. I am responsible for not thoroughly complying" with the law. The managers of the two stores were among the six officials. One of the managers said the illegal practice was "necessary to continue the service." The popular ramen chain, which was known among foreign students to offer high wages, had many foreign workers at the stores in the busy Dotonbori shopping district in Osaka. In November, the police arrested a Vietnamese worker at one of the stores for immigration law violation and searched the head office. More foreign workers at Ichiran were subsequently arrested on the same charge. Ichiran, founded in 1993, is best known for partitions surrounding each seat at counter tables so individual customers can "concentrate on the ramen flavor." It currently runs about 70 stores in Japan and abroad, including the United States, Hong Kong and Taiwan, according to the company website. To have the latest news and stories delivered to your inbox, subscribe here. Simply enter your email address below and an email will be sent through which to complete your subscription. Please check your inbox for a confirmation email. If you wish to change your message, press 'Cancel' to go back and edit. Thank you for reaching out to us.We will get back to you as soon as possible. Volume 10 - 2019 | https://doi.org/10.3389/fimmu.2019.01395 This article is part of the Research TopicRegulation of Immunity by Non-Immune CellsView all 12 articles Synovial tissue is a membranous non-immune organ lining joint cavities where it supports local immune responses and functions directly and indirectly in joint destruction due to chronic inflammatory diseases such as rheumatoid arthritis (RA) the dominant non-immune cells of synovial tissues mainly contribute to joint destruction via multiple mechanisms FLS respond to endogenous ligands of pattern recognition receptors (PRRs) and inflammatory cytokines as non-immune cells FLS aid in the activation of immune responses by interacting with immune cells and by supporting ectopic lymphoid-like structure (ELS) formation in synovial tissues FLS directly cause the pathogenicity of RA i.e. we describe new findings and review the mechanisms underlying the regulation of immune reactions by non-immune FLS and their roles in inflammatory diseases such as RA cellular communication between FLS and hematopoietic immune cells may play a large role in the RA pathogenesis including local autoantibody production in the RA synovium The synovium is a membranous organ lining the joint cavity. In normal physiological conditions within the joint cavity, the synovium supplies nutrients and the extracellular matrix (ECM) components of cartilage (3) FLS also strongly participate in the pathogenesis of RA FLS support the development of the hyperplastic RA synovium as tertiary lymphoid organs (TLOs) by interacting with immune cells and organizing ectopic (tertiary) lymphoid-like structures (ELSs) which lead to joint deformity through osteoclastogenesis and the production of extracellular protease enzymes we describe new findings and examine the role of FLS in the RA pathogenesis FLS recognize both pathogens and endogenous ligands through the PRRs and these interactions lead to the pathogenesis of RA communication between FLS—a type of stromal cell—and immune cells may lead to the signature RA phenotype we review the interactions of FLS with each cell type Schematic outline of interactions between FLS and immune cells The clinical relevance of autoantibodies in RA supports the important roles of B cells in the RA pathogenesis. Indeed, administration of the B-cell-depleting anti-CD20 antibody, rituximab, produces good clinical results for RA (49). Autoantibodies develop initially in the synovium rather than in peripheral blood and are class-switched during the development of RA (13) which indicates that the local synovial environment is a main contributor to the development and maturation of autoantibody-producing B cells Schematic outline of FLS contribution to TLO formation These findings suggest a connection between autoantibodies and organ-specific antigens depending its structure and components As a consequence of activated immune responses hyperplastic synovial tissues of RA (pannus) aggressively invade adjacent cartilage leading to the destruction of multiple joints Clinical studies demonstrated that the vasculature of the RA synovium reflects joint inflammation and correlates with future joint deformities we discuss FLS effector functions and their regulation in addition to integrin α9β1 and cadherin 11 FLS may play a role in the formation of the synovial lining These adhesion molecules also have effector functions in RA RA FLS cultured in a three-dimensional manner secrete greater amounts of effector factors it remains to be investigated whether gp38 is also involved in hypertrophy of the RA synovium Treatments targeting integrins or other adhesion molecules may be candidate alternatives for patients with refractory synovial hyperplasia which is consistent with the correlation between inflammation and cartilage degradation Further investigation of the interactions between FLS and immune cells will improve our understanding of human immunology and aid in the development of new RA treatments The author confirms being the sole contributor of this work and has approved it for publication This review is supported by JSPS KAKENHI Grant Number JP19H03780 The author declares 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 diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide doi: 10.1002/1529-0131(200001)43:1<155::AID-ANR20>3.0.CO;2-3 Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis Overexpression of toll-like receptors 3 and 4 in synovial tissue from patients with early rheumatoid arthritis: toll-like receptor expression in early and longstanding arthritis RNA released from necrotic synovial fluid cells activates rheumatoid arthritis synovial fibroblasts via Toll-like receptor 3 Hyaluronan is not a ligand but a regulator of toll-like receptor signaling in mesangial cells: role of extracellular matrix in innate immunity Citrullination enhances the pro-inflammatory response to fibrin in rheumatoid arthritis synovial fibroblasts Local Joint inflammation and histone citrullination in a murine model of the transition from preclinical autoimmunity to inflammatory arthritis A specific anti-citrullinated protein antibody profile identifies a group of rheumatoid arthritis patients with a toll-like receptor 4-mediated disease Bacterial peptidoglycans but not CpG oligodeoxynucleotides activate synovial fibroblasts by toll-like receptor signaling Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis Ectopic lymphoid neogenesis in rheumatic autoimmune diseases Rheumatoid arthritis synovial tissue harbours dominant B-cell and plasma-cell clones associated with autoreactivity Synovial fibroblasts self-direct multicellular lining architecture and synthetic function in three-dimensional organ culture Granulocyte/macrophage colony-stimulating factor-mediated induction of class II MHC antigen on human monocytes: a possible role in rheumatoid arthritis Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis doi: 10.1002/1529-0131(199809)41:9<1552::AID-ART5>3.0.CO;2-W Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin-6 receptor monoclonal antibody in rheumatoid arthritis: a randomized PubMed Abstract | CrossRef Full Text | Google Scholar placebo-controlled study evaluating the efficacy and safety of MDX-1100 a fully human anti-CXCL10 monoclonal antibody in combination with methotrexate in patients with rheumatoid arthritis A randomised phase IIb study of mavrilimumab a novel GM-CSF receptor alpha monoclonal antibody TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation Denosumab treatment effects on structural damage and bone turnover in rheumatoid arthritis: a twelve-month Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls CrossRef Full Text | Google Scholar Head-to-head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: findings of a phase IIIb T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17(+) Th cells that cause autoimmune arthritis T follicular helper (TFH) cells in normal and dysregulated immune responses doi: 10.1146/annurev.immunol.26.021607.090344 T cells that help B cells in chronically inflamed tissues Interleukin 17 contributes to the chronicity of inflammatory diseases such as rheumatoid arthritis Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II Efficacy and safety of secukinumab in the treatment of moderate-to-severe plaque psoriasis: a randomized placebo-controlled phase II dose-ranging study doi: 10.1146/annurev-immunol-031210-101400 CrossRef Full Text | Google Scholar Mature antigen-experienced T helper cells synthesize and secrete the B cell chemoattractant CXCL13 in the Inflammatory environment of the rheumatoid joint A distinct human CD4+T cell subset that secretes CXCL13 in rheumatoid synovium TGF-beta induces the differentiation of human CXCL13-producing CD4(+) T cells TGF-beta requires CTLA-4 early after T cell activation to induce FoxP3 and generate adaptive CD4+CD25+ regulatory cells The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat Synergistic induction of CXCL9 and CXCL11 by toll-like receptor ligands and interferon-gamma in fibroblasts correlates with elevated levels of CXCR3 ligands in septic arthritis synovial fluids The production of CXCR3-agonistic chemokines by synovial fibroblasts from patients with rheumatoid arthritis CCL20 produced in the cytokine network of rheumatoid arthritis recruits CCR6(+) mononuclear cells and enhances the production of IL-6 Migration of CX3CR1-positive T cells producing type 1 cytokines and cytotoxic molecules into the synovium of patients with rheumatoid arthritis in a first-in-patient phase 1/2 study on rheumatoid arthritis Rheumatoid arthritis progression mediated by activated synovial fibroblasts CD2-mediated adhesion facilitates T lymphocyte antigen recognition function Cell-contact-dependent activation of CD4(+) T cells by adhesion molecules on synovial fibroblasts Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis CXCR5 expressing human central memory CD4 T cells and their relevance for humoral immune responses Efficacy and safety of belimumab in patients with rheumatoid arthritis: a phase II IL-6 as a keystone cytokine in health and disease The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells CD4(+) follicular helper T cell infiltration predicts breast cancer survival Persistence and responsiveness of immunologic memory in the absence of secondary lymphoid organs Clinical significance of synovial lymphoid neogenesis and its reversal after anti-tumour necrosis factor alpha therapy in rheumatoid arthritis Lymphotoxin beta-mediated stimulation of synoviocytes in rheumatoid arthritis Rheumatoid fibroblast-like synoviocytes overexpress the chemokine stromal cell-derived factor 1 (CXCL12) which supports distinct patterns and rates of CD4+ and CD8+ T cell migration within synovial tissue Characterization of CCL19 and CCL21 in rheumatoid arthritis The tumour-associated glycoprotein podoplanin is expressed in fibroblast-like synoviocytes of the hyperplastic synovial lining layer in rheumatoid arthritis RANKL expressed on synovial fibroblasts is primarily responsible for bone erosions during joint inflammation Production of interleukin-7 and interleukin-15 by fibroblast-like synoviocytes from patients with rheumatoid arthritis doi: 10.1002/1529-0131(199907)42:7<1508::AID-ANR26>3.0.CO;2-L The ability of synoviocytes to support terminal differentiation of activated B cells may explain plasma cell accumulation in rheumatoid synovium Mediation of the proinflammatory cytokine response in rheumatoid arthritis and spondylarthritis by interactions between fibroblast-like synoviocytes and natural killer cells Human CD4+CD3- innate-like T cells provide a source of TNF and lymphotoxin-alphabeta and are elevated in rheumatoid arthritis Single cell cloning and recombinant monoclonal antibodies generation from RA synovial B cells reveal frequent targeting of citrullinated histones of NETs NETosis as source of autoantigens in rheumatoid arthritis Characterization of a synovial B cell-derived recombinant monoclonal antibody targeting stromal calreticulin in the rheumatoid joints Citrullinated aggrecan epitopes as targets of auto-reactive CD4+ T cells in patients with rheumatoid arthritis regulation and consequences of protein SUMOylation Increased extracellular survivin in the synovial fluid of rheumatoid arthritis patients: fibroblast-like synoviocytes as a potential source of extracellular survivin A critical role of Cyr61 in interleukin-17-dependent proliferation of fibroblast-like synoviocytes in rheumatoid arthritis PI3 kinase delta is a key regulator of synoviocyte function in rheumatoid arthritis and TGF beta synergistically induce synovial lining hyperplasia via inducible PI3K delta Cadherin-11 in synovial lining formation and pathology in arthritis Constitutive activation of integrin alpha9 augments self-directed hyperplastic and proinflammatory properties of fibroblast-like synoviocytes of rheumatoid arthritis The CLEC-2–podoplanin axis controls fibroblastic reticular cell contractility and lymph node microarchitecture Clinicopathological correlations of podoplanin (gp38) expression in rheumatoid synovium and its potential contribution to fibroblast platelet crosstalk Targeting synovial neoangiogenesis in rheumatoid arthritis Longitudinal power Doppler ultrasonographic assessment of joint inflammatory activity in early rheumatoid arthritis: predictive value in disease activity and radiologic progression The role of hypoxia and HIF-dependent signalling events in rheumatoid arthritis Human inflammatory synovial fibroblasts induce enhanced myeloid cell recruitment and angiogenesis through a hypoxia-inducible transcription factor 1alpha/vascular endothelial growth factor-mediated pathway in immunodeficient mice The pathogenic role of angiogenesis in rheumatoid arthritis Hypoxia-inducible factor-2alpha is an essential catabolic regulator of inflammatory rheumatoid arthritis Angiopoietins: a link between angiogenesis and inflammation Local synovial engagement of angiogenic TIE-2 is associated with the development of persistent erosive rheumatoid arthritis in patients with early arthritis The transcriptional response of normal and rheumatoid arthritis synovial fibroblasts to hypoxia Hypoxia-inducible factor-1 as regulator of angiogenesis in rheumatoid arthritis - therapeutic implications Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice Proteinases in the joint: clinical relevance of proteinases in joint destruction Increased expression of integrins on fibroblast-like synoviocytes from rheumatoid arthritis in vitro correlates with enhanced binding to extracellular matrix proteins Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis Keywords: fibroblast-like synoviocytes (FLSs) Citation: Yoshitomi H (2019) Regulation of Immune Responses and Chronic Inflammation by Fibroblast-Like Synoviocytes Received: 07 January 2019; Accepted: 03 June 2019; Published: 19 June 2019 Copyright © 2019 Yoshitomi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) distribution or reproduction in other forums is permitted provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited in accordance with accepted academic practice distribution or reproduction is permitted which does not comply with these terms *Correspondence: Hiroyuki Yoshitomi, eW9zaXRvbWlAa3VocC5reW90by11LmFjLmpw 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 Russia’s invasion of Ukraine has taught Taiwan many lessons about preparing for a possible Chinese invasion Japan should also take this opportunity to learn What more can Japan’s Self-Defense Forces do to prepare given their inevitable participation in any potential conflict over Taiwan The former consists of about 200 islands and is about 650 nautical miles (1,200 kilometers) long The latter consists of about 35 islands and is about 135 nautical miles (250 kilometers) long Both areas are only 270 to 430 nautical miles (500 to 800 kilometers) away from China’s mainland and would likely be exposed to fierce PLA attack to secure air and naval passages No one knows when China intends to invade Taiwan but given China’s rapidly growing military capabilities and increasingly aggressive actions preparing for this scenario is an urgent issue for Japan Beijing will rely on the PLA’s anti-access/area denial capability to disturb any military intervention by the United States and other countries countermeasures against these will be essential to deter and for the United States to conduct effective countermeasures alone Close cooperation between the United States and allies in this region including the sharing of roles in countermeasures What follows in this article is first a brief discussion of current United States and Japanese thinking and actions on the subject the article transitions to providing recommendations for what the Japan Self-Defense Forces should do next to maximize their ability to help deter such a Chinese invasion in the first place and — should Beijing choose to attack regardless — to help ensure the attack fails Japan Needs Expeditionary Advanced Base Operations Expeditionary advanced bases are established as temporary bases ashore or inshore within a contested or potentially contested maritime area to conduct sea denial An expeditionary advanced base consists of assets for information Expeditionary advanced base operations are expected to be a countermeasure against the PLA’s anti-access/area denial threat in the first island chain Japan’s Southwest Islands and the Luzon Strait critical maritime terrain facing China and next to Taiwan would be suitable for expeditionary advanced base operations The U.S. Marine Corps has a plan to establish three littoral regiments in the Indo-Pacific theater These regiments will be the core unit of expeditionary advanced base operations and will include a headquarters A littoral combat team will have three infantry companies and an anti-ship missile battery considering the length of the first island chain three such regiments will not be sufficient to ensure robust sea denial in all areas To prevent a sea-denial gap in the first island chain it is essential that the United States’ allies Japanese and Philippine Defense Posture in the First Island Chain The Air Self-Defense Force has doubled the number of fighter aircraft on the airbase on Okinawa Island And the Maritime Self-Defense Forces around the Southwest Islands seem to be activated recently too little is being done to enhance the defense posture of the Luzon Strait Challenge for the Japan Self-Defense Forces Marine Corps focuses primarily on the Luzon Strait Japan’s forces will likely have to conduct sea-denial operations against the PLA mostly if not exclusively on their own What changes should they make to ensure they are properly prepared for such a situation In the initial phase of a potential Chinese invasion of Taiwan the PLA will likely attack military assets and facilities in and around Japan to prevent the Japan Self-Defense Forces from cooperating with U.S and conducted in a sophisticated manner by air it would be difficult for Japan to prevent this attack and keep air and maritime superiority around the Southwest Islands its forces need to find ways to conduct sea denial in this situation considering the PLA’s likely air and maritime superiority around the Southwest Islands in time of war including a long voyage and flight from Japan’s mainland would be very dangerous and likely lead to thousands of casualties This is a serious challenge for the Japan Self-Defense Forces How the Japan Self-Defense Forces Should Deal with This Challenge the Japanese forces should revise their current strategy to a more feasible one with a much higher probability for success and sea denial would be carried out by units located in the Southwest Islands This will require significantly enhancing the limited capabilities of the forces forward-deployed on the islands not from forward positions within the islands Considering that large vessels such as these carriers are increasingly vulnerable to PLA air and maritime capabilities it is time to re-envision how Japan will employ its F-35Bs it will also be necessary to build many dispersed bunkers for F-35Bs in the Southwest Islands and providing maintenance while avoiding attacks by the PLA fixed-radar sites in the Southwest Islands will likely be destroyed by the PLA in the initial phase of the conflict The air branch therefore needs to deploy more survivable and sustainable measures for air awareness including unmanned aerial vehicles and mobile radar systems The Ground Self-Defense Force is scheduled to deploy three anti-ship missile batteries in the Southwest Islands by 2023 but this is too few considering the damage expected from the opening salvos of PLA attack it needs to deploy more intelligence units to the Southwest Islands and a stockpile of ammunitions and supplies for sustainable and robust activities given the limited number and size of training areas for the ground force in the Southwest Islands rotating well-trained units from Japan’s mainland would be an effective way to keep high operational readiness the Ground Self-Defense Force needs to pre-position some detachments of the Amphibious Rapid Deployment Brigade in the Southwest Islands in order to avoid serious danger during the long voyage and flight from Japan’s mainland These detachments can conduct more agile amphibious operations to other islands nearby The mission of these detachments will not only involve retaking islands but also establishing temporary bases in other islands for sea denial with anti-ship missile batteries and other units This will confuse the PLA’s intelligence activities and targeting and provide opportunities of robust sea denial This is a new type of operation for the brigade Marines’ expeditionary advanced base operations concept would go a long way toward addressing current littoral mobility deficiencies some 30 Caimen-90s should be deployed in the Southwest Islands They can carry a package of units to establish a temporary base for sea denial in other islands Those units would comprise an infantry company of the amphibious brigade the ground force should deploy more than 10 CH-47 heavy cargo helicopters in the Southwest Islands for swift island-hopping transportation Combined with the above recommended changes all three branches should change their current posture and primary large-signature operating constructs as these are increasingly vulnerable to surprise attacks and lacking in sufficient force protection the Japan Self-Defense Forces should prioritize distributing forces If the Japanese forces want to focus their efforts on combat missions thorough preparation for the protection of civilians in cooperation with local governments and other responsible organizations will be needed Change Is Both Possible and Urgently Needed Now If the Japan Self-Defense Forces and the U.S. Marine Corps establish sea-denial zones on the north and south sides of Taiwan, the U.S. Navy would then be able to focus on conducting operations for broader sea control in the East China Sea and the northern part of the South China Sea. At the same time, U.S. Air Force aircraft can fly there, and the U.S. Army’s Multi-Domain Task Forces with medium- and long-range missiles can deploy there This posture will have strong impacts on China’s intention and capability to invade Taiwan By the end of 2022, Tokyo will revise Japan’s central guiding documents for national security and defense. These documents, the National Security Strategy and National Defense Program Guidelines especially in PLA capabilities and increasingly assertive and coercive behavior major revisions to both documents are essential Ukraine’s lessons for Japan should be also considered How to carry out robust sea denial around the Southwest Islands needs to be one of the main focuses Nozomu Yoshitomi is a retired major general of the Japan Ground Self-Defense Force he has been a professor at the College of Risk Management Image: U.S. Navy (Photo by Mass Communication Spc. 2nd Class Aaron T. Smith) Signing up for this newsletter means you agree to our data policy This adversarial model of labor-management relations doesn’t have to be the default a commissioner for the Federal Mediation and Conciliation Services (FCMS) a neutral federal agency that provides free services to both labor and management is to prepare both employees and organized labor “to engage and have a really good foundation for the relationship,” one marked by communication and trust rather than opacity and conflict labor can even be a partner to leadership in making culture change within an organization who often works with labor management committees—groups of representatives from both sides that meet regularly to address shared concerns and projects—about what that culture-focused collaboration can look like and what tactics from these groups can teach leaders about building trust between labor and management more broadly Here’s an excerpt of our conversation How can nonprofits serve as a model for labor-management partnerships you’re not going to have as much willingness for organizations to talk about employee input into hiring or how the organization actually functions What I found in the nonprofit world is they’re willing to talk about these items—DEI issues Nonprofits are more willing to talk about these more progressive issues—not just as policy or ‘Yeah we’re going to have this,’ but to actually put it into their collective bargaining contract They’re willing to sit down with the union and say ‘We need to negotiate about what our culture looks like.’ Some in the private sector would not be willing necessarily to go down that road We’re starting to see that break through a little bit Are there examples you can share of labor and management partnering to change culture There’s one project with a union and an employer where they’re trying to make a cultural change around sexual harassment and it’s developed into this really great partnership where they’re able to implement cultural change together There’s another one we’re working on where there’s a lot of absenteeism and labor and management are working together to figure out That’s not within the collective bargaining realm but really great things can happen outside of a collective bargaining agreement to help an organization improve their efficiency by labor and management being able to collaborate with each other You really value my opinion and what we have to say,’ you’re going to find a happier they’re willing to go out of their way a little bit more that really breaks everything down and the company has a hard time moving forward or progressing with the times When leaders have that union with them to be able to help them move along When you encounter workplaces with conflict or mistrust between labor and management what tactics do you recommend for building trust between those two parties Are my actions going to align with what I said I was going to do Will I go a little bit out of my way to go over and say ‘hi’ versus just walking by somebody one thing I encourage is to bring food back and forth When you have your labor management committees This interview was conducted as part of a joint project between Charter and the Aspen Institute’s Business Roundtable on Organized Labor look out for our upcoming playbook on new approaches to labor-management relationships Metrics details PD-1hiCXCR5−CD4+ T cells are involved in the formation of ectopic lymphoid-like structures (ELSs) by the secretion of chemokine CXCL13 but how the transcription of CXCL13 is regulated in CD4+ T cells is still unclear Here we show that Sox4 is a key transcription factor for CXCL13 production in human CD4+ T cells under inflammatory conditions IL-2-neutralizing culture conditions give rise to PD-1hiCXCR5−CD4+ T cells that preferentially express CXCL13 and transcriptome analysis and lentiviral overexpression indicate Sox4 association with the CXCL13 transcription Sox4 is significantly upregulated in synovial CD4+ T cells from patients with rheumatoid arthritis (RA) and further correlates with ELS formation in RA synovium our studies suggest that Sox4 contributes to CXCL13 production and ELS formation at inflammatory sites in humans the transcriptional regulation that mediates CXCL13 production by PD-1hiCXCR5−CD4+ T cells at the inflammatory sites remains to be explained These findings collectively imply that local inflammatory conditions could be involved in the development of CXCL13-producing PD-1hiCXCR5−CD4+ T cells likely by regulating the expression of transcription factors we explore transcription factors related to CXCL13-producing CD4+ T cells at local inflammatory sites we differentiate CXCL13-producing PD-1hiCXCR5−CD4+ T cells under inflammatory conditions in vitro and conduct transcriptome analysis Sox4 is the only transcription factor that fulfills the screening criteria; in RA in a TGF-β-positive and IL-2-limiting condition and in CD4+ T cells in local inflammatory sites compared with blood CD4+ T cells lentiviral transduction of the Sox4 gene in human naive CD4+ T cells induces an intense production of CXCL13 and Sox4 expression in RA synovium is significantly associated with ELS formation These data collectively indicate that Sox4 expression in human CD4+ T cells contributes to the mechanisms of chronic inflammation via CXCL13-dependent ELS formation at local inflammatory sites IL-2-limiting conditions give rise to CXCL13-producing PD-1hiCXCR5-CD4+ T cells in vitro a–c Healthy human naive CD4+ T cells were differentiated with TCR stimulation and the indicated cytokines in the presence or absence of neutralizing anti-IL-2 antibody for 5 days Representative dot plots of PD-1 and intracellular CXCL13 (a) Transcriptome analysis identified Sox4 as a transcription factor relating to CXCL13-producing CD4+ T cells a Human blood CD4+ T cells labeled with CellTrace™ Violet were differentiated in the presence of the indicated cytokines and neutralizing anti-IL-2 antibody for 5 days Quadrants define CXCL13-positive/negative cells and cells with 0–1 divisions and cells with ≥ 2 divisions b Outline for the screening of candidate transcription factors d Sox4 expression in human naive CD4+ T cells unstimulated or stimulated with anti-CD3/CD28 antibodies for 24 h in the presence of TGF-β was assessed by quantitative PCR (c) or immunoblotting (d) f Human naive CD4+ T cells were cultured with TCR stimulation in the presence of the indicated cytokines (e) or TGF-β plus a TGF signal inhibitor Relative SOX4 expression was measured by quantitative PCR h Relative mRNA expression of CXCL13 (g) and Sox4 (h) assessed by quantitative PCR in naive human CD4+ T cells differentiated with TCR stimulation and the indicated cytokines in the presence (solid) or absence (open) of neutralizing anti-IL-2 antibody for 3 days Cumulative data (n = 6 from two experiments in c–e h) are presented as corresponding dots and the mean ± SEM and r and P-values by Pearson’s correlation analysis Numbers in flow cytometry plots indicate the percentage of cells in the indicated region these findings indicate that TGF-β-positive IL-2-limiting inflammatory conditions contribute to Sox4 expression in human CD4+ T cells Sox4 is functionally involved in CXCL13 production by CD4+ T cells b Human naive CD4+ T cells were transduced with mock or Sox4 by YFP-expressing lentivirus and differentiated with 2 ng/ml TGF-β a Representative dot plots of YFP and intracellular CXCL13 representative histograms of CXCL13 in YFP+ gated cells transduced with mock (black) or Sox4 (red) and graphical summary for the relative induction of CXCL13-positive cells in YFP+ cells compared with YFP− cells are shown b Relative expression of CXCL13 in sorted mock- or Sox4-transduced naive CD4+ T cells determined by quantitative PCR d Sox4-transduced human naive CD4+ T cells were cultured with TCR stimulation in the presence of TGF-β at 0 (gray) or in the presence (red) or absence (black) of neutralizing anti-IL-2 antibody (d) Representative histograms and a graphical summaries are shown Cumulative data (n = 6 from two experiments) are presented as corresponding dots and the mean ± SEM collectively indicate that the function of Sox4 could be affected by the status of the intracellular signals and that TGF-β stimulation and low IL-2 levels promote both Sox4 expression and the subsequent CXCL13 production Conserved domains HMG and TAD are functionally crucial for CXCL13 induction in human CD4+ T cells b Wild-type Sox4 or Sox4 truncated at the indicated domain (left) were transduced into human naive CD4+ T cells Relative induction of CXCL13-positive cells in YFP+ cells compared with YFP− cells is shown (right) c Relative CXCL13 induction in differentiated human naive CD4+ T cells transduced with human and mouse Sox4 d Relative expression of mSox4 and mCxcl13 in mouse spleen tissue (defined as 1.0) in mouse CD4+ T cells cultured for 5 days with TCR stimulation and TGF-β and in Sox4-transduced mouse CD4+ T cells differentiated for 5 days f Mock- or Sox4-transduced human naive CD4+ T cells were differentiated under Th2-polarizing (e) or Th1-polarizing (f) conditions Representative dot plots of YFP+ gated cells and relative IL-4 (e) or IFN-γ (f) induction in YFP+ cells compared with YFP− cells are shown Cumulative data (n = 6) are presented as corresponding dots and the mean ± SEM **P < 0.01 and ***P < 0.001 by one-way ANOVA These findings imply a possible contribution of Sox4 on Th1 activity and CXCL13-dependent ELS formation in Th1-dominant inflammatory conditions They further indicate that human Sox4 slightly promotes Th1 differentiation but does not have an obvious effect on Th2 differentiation these results imply that inflammatory conditions regulate the expression of Sox4 and that the ELS formation regulated by CXCL13 expression depends on upregulated Sox4 expression in human CD4+ T cells Sox4 is involved in CXCL13 production by PD-1hiCXCR5−CD4+ T cells at inflammatory sites and also possibly in the resulting ELS formation both TGF-β signaling and the suppressed IL-2 promote Sox4 expression and its promotion of CXCL13 production CXCL13 production by human CD4+ T cells might be finely regulated by the Sox4 expression and the surrounding environment CXCL13 production by Sox4-expressing CD4+ T cells not only in TGF-β-positive IL-2-limiting conditions but also in Th1-polarizing conditions might imply the possible involvement of Sox4 in ELS formation via CXCL13 in Th1-dominant conditions in addition to the locally inflamed sites of RA In vitro culture showed that the expression of these transcription factors is regulated by inflammatory conditions but in a manner different from that of Sox4 implying that the expression of transcription factors and the phenotypes of CD4+ T cells might be regulated by the surrounding inflammatory environment Sox4 (upregulated by IL-2-limiting) intensively induced CXCL13 production whereas MAF (downregulated by IL-2-limiting) was involved in the expression of genes related to B-helper activity These effects imply a division of roles in their regulation of human CD4+ T cells: Sox4 contributes to PD1hiCXCR5−CD4+ T cells in ELS formation via CXCL13 production The transcription repressor Blimp1 also intensively modulates the expression of signature genes of PD1hiCXCR5−CD4+ T cells Although Blimp1 expression did not change significantly in our clinical samples regulation of this transcription repressor might be important for the pathogenesis of some inflammatory diseases the upregulation of Sox4 failed to induce CXCL13 in mouse CD4+ T cells despite the abundant expression of Sox4 protein These findings indicate that in vitro and in vivo analysis of the Sox4/CXCL13 axis using mouse models may be misleading Further understanding the role of Sox4 and other transcription factors relating to human CD4+ T cells may expand our knowledge of human immune responses at inflammatory sites and provide new insights into human immunology and inflammatory diseases Ethical approval for this study was granted by the ethics committee of Kyoto University Graduate School and Faculty of Medicine Written informed consent was obtained from all study participants Peripheral blood mononuclear cells (PBMCs) from healthy volunteer were collected using Lymphocyte Separation Solution 1.077 (Nacalai Tesque) Blood CD4+ T cells were isolated with CD4 T Cell isolation kit (Miltenyi Biotec) Naive blood CD4+ T cells were purified with naive CD4 T Cell isolation kit II (Miltenyi Biotec) through the magnetic column twice as a fraction negative for CD8 The purity of CD3+CD4+CD45RA+ cells in the sorted cells was more than 98% Synovial tissues were minced and digested with 2.5 mg/ml collagenase (Roche) at 37 °C for 1.5 h and then analyzed Blood samples were collected together with clinical blood tests PBMCs or synovial mononuclear cells were collected using Lymphocyte Separation Solution 1.077 (Nacalai Tesque) CD4+ T cells were sorted with Aria II (BD Biosciences) as a population of CD3+CD4+ T cells Mouse CD4+ T cells were isolated with CD4 microbeads (L3T4 Miltenyi Biotec) from pooled splenocytes and lymph node cells of 6–8 weeks old female BALB/cCrSlc (Japan SLC All mice were maintained in a specific pathogen-free condition and all animal studies were conducted in accordance with the principles of the Kyoto University Committee of Animal Resources which are based on the International Guiding Principles for Biomedical Research Involving Animals Human T cells were differentiated for 5 days in a humidified 5% CO2 incubator at 37 °C with IMDM (Thermo Fisher) supplemented with 10% fetal bovine serum (Thermo Fisher) 100 units/ml penicillin and streptomycin (Thermo Fisher) under stimulation with plate-bound 5 μg/ml anti-CD3 (OKT3 Thermo Fisher) antibodies in the presence of 2 ng/ml TGF-β1 (Cell Signaling Technology) unless otherwise described cells were stimulated with 5 μg/ml anti-CD3 and 5 μg/ml neutralizing anti-IL-4 antibodies (BioLegend) and 10 ng/ml IL-12 (Peprotech); for Th2 differentiation and 5 μg/ml neutralizing anti-IFN-γ antibodies (BioLegend) and 20 ng/ml IL-4 (Peprotech) cells were cultured for 5 h with 4 μM monensin Recombinant tumor necrosis factor and IL-1β were obtained from Miltenyi For the analysis of Sox4 expression 24 h after stimulation human naive CD4+ T cells were stimulated with anti-CD3/CD28 antibodies in serum-free X-VIVO™ 15 medium (LONZA) in the presence of the indicated cytokines (each 10 ng/ml) and signal inhibitors (SB431542 (Stemgen) or SIS3 (Cayman)) Mouse CD4+ T cells were differentiated for 5 days under stimulation with plate-bound 1 μg/ml anti-CD3 (145−2C11 BioLegend) in complete RPMI-1640 (Nacalai Tesque) supplemented with 10% fetal bovine serum penicillin and streptomycin (Thermo Fisher) Genes upregulated in Fraction II more than fourfold compared with Fraction VI were excluded from the candidates as Treg-related genes The complementary DNAs encoding human SOX4 (NM_003107.2) or mouse Sox4 (NM_009238.2) were cloned by PCR and inserted into the multi-cloning sites of CSII-EF-MCS-IRES2-Venus (provided by Dr Truncation of the N-terminus domain (2aa–56aa) or TAD (423aa–474aa) of human Sox4 was performed with KOD-Plus-Mutagenesis KIT (TOYOBO) For the short hairpin RNA (shRNA) lentivirus synthesized oligonucleotides were inserted into pENTR/U6 vector and subsequently transferred to the lentiviral destination vector CS-RfA-EG (provided by Dr which expresses green fluorescent protein (GFP) with a Gateway destination cassette by performing an LR clonase reaction (Life Sciences) The inserted sequences for shRNA were as follows: for human Sox4 5′-GGA GGA ACT CCT GCC ATT ATT CTC GAG AAT AAT GGC AGG AGT TCC TCC TTT TTT-3′; and negative control 5′-ATC CGC GCG ATA GTA CGT ATT CTC GAG AAT ACG TAC TAT CGC GCG GAT TTT TTT-3′ HEK293T cells were transiently transfected with the expression vector and an envelope plasmid pMD2.G (gifts from Didier Trono; Addgene plasmid #12259 and # 12260) Lentiviral supernatants were collected 72 h after transfection concentrated by ultracentrifugation at 36,000 × g for 2 h washed with Hankʼs Balanced Salt Solution (Wako) and ultracentrifuged again to prevent the carryover of culture medium Human naive CD4+ T cells were stimulated with anti-CD3/28 antibodies for 24 h without cytokines transduced with lentiviral supernatant at a multiplicity of infection of 10–50 by 90 min centrifugation at 3200 × g and 32 °C TGF-β1 at 2 ng/ml was added just after the transduction Mouse CD4+ T cells were stimulated with anti-CD3/28 antibodies for 48 h transduced with lentiviral supernatant at a multiplicity of infection of 10–50 in the presence of 6 μg/ml polybrene without spin infection moved to a new culture plate with fresh complete RPMI medium 24 h after transduction mRNA was extracted using RNAeasy mini or micro kit (Qiagen) cDNA synthesis was performed using SuperPrep® RT Kit for qPCR (TOYOBO) qRT-PCR was performed using THUNDERBIRD™ SYBR® qPCR Mix (TOYOBO) on StepOne Plus (Thermo Fisher) with the following primers: hCXCL13 (5′-TCTCTGCTTCTCATGCTGCT-3′ and 5′-TCAAGCTTGTGTAATAGACCTCCA-3′) h18srRNA (5′-AACTTTCGATGGTAGTCGCCG-3′ and 5′-CCTTGGATGTGGTAGCCGTTT-3′) hSOX4 (5′-AAGATCATGGAGCAGTCGCC-3′ and 5′-CGCCTCTCGAATGAAAGGGA-3′) hPDCD1 (5′- CTCCAGGCATGCAGATCC-3′ and 5′-GGCCTGTCTGGGGAGTCTA-3′) hSH2D1A (5′-AGGCGTGTACTGCCTATGTG-3′ and 5′-GTACCCCAGGTGCTGTCTCA-3′) hCXCR5 (5′-GCCATGAACTACCCGCTAAC-3′ and 5′-TCTGTCCAGTTCCCAGAACA-3′) hIL21 (5′-AGGAAACCACCTTCCACAAA-3′ and 5′-GAATCACATGAAGGGCATGTT-3′)3 hIFNG (5′-GCATCGTTTTGGGTTCTCTTG-3′ and 5′-AGTTCCATTATCCGCTACATCTG-3′)3 hBATF (5′-ACACAGAAGGCCGACACC-3′ and 5′-CTTGATCTCCTTGCGTAGAGC-3′) hICOS (5′-GGATGCATACTTATTTGTTGGCTTA-3′ and 5′-TGTATTCACCGTTAGGGTCGT-3′) hTIGIT (5′-GCTGGTGTCTCCTCCTGATCT-3′ and 5′-TGTGCCTGTCATCATTCCTG-3′) hCTSB (5′-GGCTATGTGGTACCTTCCTGG-3′ and 5′-GCTTCAGGTCCTCGGTAAACA-3′) hCD200 (5′-AGGATGGAGAGGCTGGTGA-3′ and 5′-ACCACTGCTGCCATGACC-3′) hSLAMF6 (5′-TCCAATCGCTCCTGTTTGTCT-3′ and 5′-AAGAGTTACTGACTCCCCCAGA-3′) hTOX (5′-CCTGCCTGGACCCCTACTAT-3′ and 5′-CTGGCTGGCACATAGTCCTG-3′) hBCL6 (5′-GTTTCCGGCACCTTCAGACT-3′ and 5′-CTGGCTTTTGTGACGGAAAT-3′)3 hBlimp1 (5′-AACTTCTTGTGTGGTATTGTCGG-3′ and 5′-TCTCAGTGCTCGGTTGCTTT-3′)3 hMAF (5′-CACCCTGCTCGAGTTTGTG-3′ and 5′-CATGAGCCAGACACCCATT-3′) mSox4 (5′-ACAGCGACAAGATTCCGTTC-3′ and 5′-GTCAGCCATGTGCTTGAGG-3′) mCxcl13 (5′-CATAGATCGGATTCAAGTTACGCC-3′ and 5′-TCTTGGTCCAGATCACAACTTCA -3′) mGapdh (5′-GTGTTCCTACCCCCAATGTGT-3′ and 5′-ATTGTCATACCAGGAAATGAGCTT-3′) The expressions of human and mouse mRNA were normalized by that of h18srRNA and mGapdh the membrane was probed with anti-human/mouse Sox4 rabbit polyclonal antibody (AB5803 Merc Milipore; 1:200) followed by incubation with horseradish protein (HRP)-conjugated anti-rabbit IgG antibody (7074 or the membrane was probed with HRP-conjugated anti-human/mouse β-actin antibody (AC-15 The membrane was visualized using ECL Prime Western Blotting Detection Reagent (GE Healthcare) cells were cultured for 5 h with 4 μM monensin (Sigma-Aldrich) and stained with eBioscience™ Intracellular Fixation & Permeabilization Buffer (Thermo Fisher) and antibodies for intracellular molecules Cells transfected with YFP- or GFP-expressing lentiviral particles were fixed with 4% paraformaldehyde (Nacalai Tesque) instead of eBioscience™ Intracellular Fixation & Permeabilization Buffer to avoid the bleaching of YFP or GFP Data were acquired with a FACS Canto II flow cytometer (BD Biosciences) and were analyzed with FlowJo 10.0.8 (Tree Star) Fixable Viability Dye eFluor 780 or eFluor 506 (Thermo Fisher) was used to exclude dead cells The border between positive and negative populations was determined according to the staining with isotype controls and BV421-conjugated anti-CD3 (UCHT1) were obtained from Biolegend Fluorescein isothiocyanate (FITC)-conjugated control mouse IgG1 and eFluor660-conjugated anti-cMAF (sym1F1) were obtained from Thermo Fisher APC-conjugated or PE-conjugated anti-CXCL13 (53610) and control mouse IgG1 were obtained from R&D Systems FITC-conjugated anti-IFN-γ (B27) and FITC-conjugated anti-HLA-DP and DR (CR3/43) were obtained from BD Bioscience and DAKO Paraffin-embedded synovial tissues of RA were sectioned, deparaffinized, and antigen-retrieved with 0.01 M citric acid of pH 6.0. The clinical background of the patients is shown in Supplementary Table 3 Immunohistochemistry was performed with Sox4 antibody (HPA029901 1:100) and detected with EnVisionTM Detection System (DAKO) ELS formation (Score E) and the presence of Sox4-positive cells within the infiltrating cell population without ELSs (Score SN) or with ELSs (Score SE) were assessed by a semi-quantitative four-point scale (none The total Sox4 expression score corresponds with the sum of the SN and SE scores Triple immunofluorescence staining was performed with CXCL13 antibody (BCA1 1:50) and detected with TSA Plus Fluorescence Kit (PerkinElmer Fluorescence imaging analysis was performed using the FSX100 Fluorescence Microscope (Olympus) Statistical significance was determined using a two-tailed Student’s t-test one-way analysis of variance with Tukey’s multiple comparison test or Spearman’s rank correlation as appropriate with JMP Pro 13 (JMP) P-values of < 0.05 were considered statistically significant No pre-specified effect size was calculated and no statistical method was used to predetermine sample size The affymetrix data have been deposited in the GEO database under the accession number GSE117139 The data supporting the findings of this study are available upon reasonable request to the authors A distinct human CD4 + T cell subset that secretes CXCL13 in rheumatoid synovium T follicular helper cells in human autoimmunity Lymphoid neogenesis in rheumatoid synovitis directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen ICOS deficiency is associated with a severe reduction of CXCR5( + ) CD4 germinal center Th cells Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular Follicular B helper T cell activity is confined to CXCR5(hi)ICOS(hi) CD4 T cells and is independent of CD57 expression Unique gene expression program of human germinal center T helper cells TGF-β induces the differentiation of human CXCL13-producing CD4( + ) T cells Immune homeostasis enforced by co-localized effector and regulatory T cells EBI2 augments Tfh cell fate by promoting interaction with IL-2-quenching dendritic cells TGF-beta requires CTLA-4 early after T cell activation to induce FoxP3 and generate adaptive CD4 + CD25 + regulatory cells Functional delineation and differentiation dynamics of human CD4 + T cells expressing the FoxP3 transcription factor Sox-4 facilitates thymocyte differentiation Defects in cardiac outflow tract formation and pro-B-lymphocyte expansion in mice lacking Sox-4 The transcription factor Sox4 is a downstream target of signaling by the cytokine TGF-beta and suppresses T(H)2 differentiation TGF-beta-activated SMAD3/4 complex transcriptionally upregulates N-cadherin expression in non-small cell lung cancer is a transcriptional activator in lymphocytes Bcl6 and Maf cooperate to instruct human follicular helper CD4 T cell differentiation and regulation of T follicular helper cells TOX is required for development of the CD4 T cell lineage gene program Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells Conversion of peripheral CD4 + CD25- naive T cells to CD4 + CD25 + regulatory T cells by TGF-beta induction of transcription factor Foxp3 Homeostatic maintenance of natural Foxp3( + ) CD25( + ) CD4( + ) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization FoxP3 + regulatory T cells promote influenza-specific Tfh responses by controlling IL-2 availability Lymphoid chemokine B cell-attracting chemokine-1 (CXCL13) is expressed in germinal center of ectopic lymphoid follicles within the synovium of chronic arthritis patients CXCL13 and B-cell activating factor as putative biomarkers in systemic sclerosis C-X-C motif chemokine 13 (CXCL13) is a prognostic biomarker of idiopathic pulmonary fibrosis Ectopic lymphoid structures support ongoing production of class-switched The American Rheumatism Association 1987 revised criteria for the classification 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative the oncogenic fusion protein in synovial sarcoma is a cellular context-dependent epigenetic modifier Download references Narumiya for technical support and constructive discussion This work was supported by the Special Coordination Funds for Promoting Science and Technology from Ministry of Education Science and Technology and Astellas Pharma and by JSPS KAKENHI Grant Number JP16K15663 Department of Regeneration Science and Engineering Institute for Frontier Life and Medical Sciences Department of Cell Growth and Differentiation Center for iPS Cell Research and Application Aya Miyagawa-Hayashino & Hironori Haga Kyoto University Graduate School of Medicine Department of Advanced Medicine for Rheumatic Diseases contributed to cellular and molecular experiments contributed to the patient recruitment and sample acquisition Astellas Pharma had no role in the study design or in the collection or the decision to submit the manuscript for publication Publication of this article was approved by an intellectual property committee composed of representatives from Kyoto University and Astellas Pharma declare the following competing interests that they received research funding from Astellas The remaining authors declare no competing interests Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Download citation DOI: https://doi.org/10.1038/s41467-018-06187-0 Sign up for the Nature Briefing newsletter — what matters in science Media Contact: David Yoshitomi, Arts & Culture Manager, County of VenturaDavid.Yoshitomi@ventura.org — TOArts and County of Ventura Arts and Culture proudly announce the inaugural ReFrame Ventura County (ReFrame VC) Arts Summit 2024; a first in the county event that centers arts and culture as creative and economic drivers for our region and empower attendees from across the creative and cultural arts Taking place at Studio Channel Islands Art Center in Camarillo ReFrame VC will kick off with keynote presentation from Evan Meyer Technology Entrepreneur and newly appointed District Chief for Senator Henry Stern Meyer will share insights on leveraging arts Tailored breakout groups and workshops designed for independent artists and the nonprofit sector are led by artist Allison Wyper “Can I Make a Living Doing This?” focusing on financial management for artists while Marcy Heim’s “From Surviving to Thriving” provides powerful strategies on how to ask for anything artfully These sessions will be followed by focus groups enabling participants to shape Ventura County’s strategic plan for arts The afternoon sessions will inspire attendees to “reframe” discussions on arts and culture Tracy Hudak of CA for the Arts will stress the importance of advocacy in the field and The CreArtive Freedom Family will take participants through three dance and movement segments highlighting the diversity in our relationships The summit will wrap up with a “Marketplace of Ideas” networking session offering attendees the chance to connect over wine and small bites “We’re thrilled to co-present the ReFrame VC Arts Summit 2024 with County of Ventura Arts and Culture and are grateful for the leadership of the steering committee without whom planning this event would not have been possible,” shared Niki Richardson “ReFrame VC is a platform designed to celebrate the transformative power of arts and culture in Ventura County and employees of arts and culture organizations and advocate for the vibrant arts community in our region.” Registration is $25.00 per person, or $50.00 for three people (from the same organization) and includes a welcome coffee and resource fair, lunch, and the Marketplace of Ideas wine reception. Tickets are available at https://bit.ly/ReFRAMEVC and collaboration to provide community support in and around the Bank of America Performing Arts Center The County of Ventura’s Arts & Culture Division is responsible for leading Countywide strategic planning for arts and residents to develop collaborative strategies that intersect Metrics details Folic acid and folate receptors (FOLRs) play an important role in the downregulation of homocysteine (Hcy) While several studies have reported that FOLR1 and FOLR2 import folic acid into cells we evaluated the impact of FOLR3 on the metabolism of Hcy alongside its protective effect against homocysteine-induced neurotoxicity we constructed FOLR3-overexpressed HEK293 cells (FOLR3+ cells) and evaluated cell growth folic acid intake and Hcy-induced neurotoxicity Subjects with a high expression of FOLR3 exhibited low levels of plasma homocysteine The ectopic expression of FOLR3 enhanced cell growth and the enhanced effect was neutralised by folic acid-deficient media The Western blot analysis revealed that FOLR3 is secreted into cell supernatant The folic acid intake of FOLR3+ cells was higher than that of wild-type cells Supernatant from FOLR3+ cells showed a protective effect on Hcy-induced cytotoxicity FOLR3 expression in plasma is negatively correlated with plasma homocysteine Our study emphasizes the role of FOLR3 in the intake of folic acid into cells on the one hand and its protective role in Hcy-induced cytotoxicity on the other practical approaches to normalise Hcy levels are strongly recommended for persons who prone to developing hyperhomocysteinemia FOLR3 expresses in humans rather than mice and rats Several studies have investigated the role of FOLR1 and FOLR2 This study aims to explore the relationship between FOLR3 and Hcy in our body; it also intends to investigate the impact of FOLR3 on folic acid metabolism A flowchart of subjects included in this study. Plasma homocysteine concentration is negatively correlated with the expression levels of FOLR3 in plasma (A) ELISA analysis of plasma homocysteine in subjects with the high or low expression levels of FOLR3; low expression level (n = 34) and high expression level (n = 36) (B) Spearman rank correlation analysis between plasma homocysteine and FOLR3 signal intensity FOLR3 expression enhances folic acid uptake. Quantification of folic acid into cell with/without FOLR3. Unpaired t-test was used for statistical analysis and all data presented mean ± S.E. (n = 3). *p < 0.05, **p < 0.01 n.s.; not significant. Involvement of FOLR3 and folic acid in cell growth of HEK293 cells (A) The effect of FOLR3 expression on cell growth of HEK293 cells (B) Cell growth of FOLR3-expressed HEK293 cells with/without folic acid Two-way ANOVA with Sidak’s test for multiple comparisons was used for statistical analysis and all data presented mean ± S.E FOLR3 secretes into cell supernatant and reduces homocysteine induced-neurotoxicity (A) The FOLR3 expression in the empty vector or FOLR3+ cells culture supernatant (B) The effect of supetnatant of FOLR3-overexpressed HEK293 cell on homocysteine-induced toxicity in SH-SY%Y Two-way ANOVA with SIdak’s test for multiple comparisons was used for statistical analysis and all data presented mean ± S.E Our study alludes to the potential effects of FOLR3 on Hcy-relating diseases Some secretory proteins communicate with the organs and have several effects on our body FOLR3 ameliorates Hcy cytotoxicity and is captured in SH-SY5Y cells These results suggest that secreted FOLR3 may cause Hcy to have a minimal effect on the terminal tissue and reduce the Hcy level in plasma and the risk of Hcy-related diseases The upregulation of FOLR3 and supplementation of folic acid can be advantageous treatment strategies for hyperhomocysteinemia patients and for the prevention of Hcy-related diseases Our study showed that FOLR3 upregulated folic acid concentration in the cells These data indicate that secreted FOLR3 could induce p53 methylation by efficient folic acid uptake and affect the cell viability of SH-SY5Y cells Endocytosis involves the process of transporting molecules into the cell by engulfing it with its membrane Folic acid internalises GPI-anchored FOLR1 and FOLR2 via endocytosis and exerts its functions in the cell secreted FOLR3 is migrated to terminal tissues and may interact with endocytosis-related protein to induce endocytosis for the internalisation of folic acid Enhancing FOLR3 expression may promote folic acid functions production of nucleic acid and creation of red blood cells Further research is necessary to investigate the correlation between FOLR3 and innate or adaptive response Plasma Hcy levels in our study is lower compared with those pervious study This discrepancy may be due to the different measure approach and the storage time from the day the plasma was collected until the plasma homocysteine was measured we explained this research to the participants before distributing the research questionnaires plasma homocysteine concentration was measured using an Axis Homocysteine EIA Kit (Axis-Shield Diagnostics Ltd. the absorbance was measured at 405 nm using an EnVision 2104 Multimode Plate Reader (PerkinElmer USA) was used to extract total RNA from the cells The RNA quality was estimated using the Agilent RNA 6000 Nano Kit (Agilent The RNA integrity number for all the samples was higher than 6.5 (on a 0–10 scale) MessageAm II aRNA Amplification Kit (Ambion USA) was used to synthesise antisense RNA (aRNA) from 1 mg of total RNA 5 mg of aRNA was fragmented and hybridised in the prototype Food-Sensitivity-Evaluation DNA Chip The hybridised aRNA was labelled Cy5 (GE Healthcare Japan and fluorescence was assessed using a detector system (Yokogawa Electronic Co. All gene expressions were normalised by the 8 reference genes [actin beta; ATP synthase subunit b mitochondrial; glyceraldehyde-3-phosphate dehydrogenase; General Transcription Factor IIB; phospholipase A2 group V; ribosomal protein S5; Tubulin Alpha 1b and ribosomal protein Human embryonic kidney cell line HEK293 cells were cultured in 10% fetal bovine serum (FBS) with Dulbecco’s Modified Eagle’s Medium (DMEM) at 37 °C in a humidified atmosphere with 5% CO2 FOLR3 expression vector (pcDNA3.1+ /C-(K)-DYK [OriGene Technologies Human neuroblastoma SH-SY5Y cells were cultured in 10% FBS with a 1:1 mixture of Eagle’s Minimum Essential Medium and Ham’s F-12 Nutrient Mix at 37 °C in a humidified atmosphere with 5% CO2 To assess the role of FOLR3 in cell growth HEK293 cells (containing empty vector) and FOLR3+ cells were pre-treated with 10% FBS-containing DMEM for 24 h and then the media were exchanged with 10% FBS-containing DMEM To estimate the involvement of folic acid on cell growth of FOLR3+ cells HEK293 cells (containing empty vector) and FOLR3+ cells were pre-treated with 10% FBS-containing DMEM for 24 h and then the media were exchanged with DMEM or folic acid-depleted DMEM (containing 10% FBS) cultured cells were washed and calculated the same method as above To test if secreted FOLR3 affects Hcy-induced toxicity supernatant of HEK293 cells (containing empty vector) or FOLR3+ cells incubated with serum-free DMEM for 48 h were filtered by 0.2 μm filter SH-SY5Y cells were pre-treated with 10% FBS-containing DMEM for 24 h and then the media were exchanged with 2.5 mM Hcy and the supernatant of HEK293 cells (containing empty vector) or FOLR3+ cells Western blot analysis performed as described previously33 cells were harvested in a cell lysis buffer Approximately 50 mg of protein was diluted in a sample buffer The samples were boiled and electrophoresed in SDS-polyacrylamide gels and the gels were blotted to Trans-Blot nitrocellulose membranes (Bio-Rad Laboratories The membranes were blocked with 2.5% BSA-TBST for 1 h followed by overnight incubation with the following primary Abs diluted in 2.5% BSA-TBST: anti-Flag Ab and b-actin Ab Membranes were rinsed three times with TBST and treated with an HRP-conjugated secondary Ab (anti-mouse or anti-rabbit IgG) The labelled membranes were rinsed with TBST and bands were detected using TMA-6 chemiluminescence agents (Lumigen Cultured HEK293 cells were washed with ice-cold PBS added 1000 μL of 5% ammonia and homogenised the cells with Handy Sonic model UR-20P (TOMY SEIKO Cell lysates were vacuum dried using Speed Vac SC110A (Savant Farmingdale The residue was resuspended with 1: 1 acetonitrile: water (500 μL) and 20 μL of 100 μM MTX (solvent: acetonitrile: water = 1: 1 solution) was added as an internal standard The cell lysate was vortexed for 20 seconds and then centrifuged at 12,000 xg for 10 minutes and the supernatant was collected and dried using Speed Vac SC110A The residue was reconstituted with 1: 1 acetonitrile: water (140 μL) and 100 μL of the supernatant was collected as the sample Samples (3 µL) were injected into 150 × 2.1 mm CAPCELL CORE C18 column (2.7 µm) (Osaka Soda Japan) performing LC-MS-8050 (Shimadzu Co. The mobile phase flow was 0.15 mL/min and operated at 40 °C The mobile phase contained (A) 0.05% formic acid in H2O and (B) 0.05% formic acid in acetonitrile using a gradient elution of A–B (85:15) in 0–1 min A–B (0:100) → A–B (85:15) in 11–11.5 min and A–B (85:15) in 11.5–15 min The selected ion monitoring was used to operate the ESI in the positive ion mode The folic acid (pteroylglutamic acid) concentration was normalised to the total protein concentration measured using the BCA method USA) was used to extract total RNA from cells and tissues USA) was used to assess the RNA concentrations based on absorbance at 260 and 280 nm The quantitative real-time PCR-based analysis was conducted based on the relative standard curve method to quantify the expression of indicated genes 1.4 μL of cDNA was applied as the template for quantitative real-time PCR-based analysis based on the CFX manager according to the manual The sequences for the primers using quantitative real-time PCR-based analysis were as follows: human actin beta (ACTB): forward; 5′-GGCACCCAGCACAATGAA-3′ FOLR3: forward; 5′-GACGGACCTGCTCAATGTCT-3′ The mRNA expression was calculated based on the cycle times of each gene The cycle threshold of ACTB was performed for normalisation All the statistical analyses included the unpaired t-test two-way ANOVA with Sidak’s post hoc test or Spearman’s correlation tests using GraphPad Prism On the mechanism of homocysteine pathophysiology and pathogenesis: a unifying hypothesis Journal of the American Society of Echocardiography 90 Homocysteine and neuropsychiatric disorders Homocysteine Levels and the Risk of Osteoporotic Fracture Serum total homocysteine concentrations and risk of mortality from stroke and coronary heart disease in Japanese: The JACC study Relationship between increase of serum homocysteine caused by smoking and oxidative damage in elderly patients with cardiovascular disease Effect of advanced age on plasma homocysteine levels and its association with ischemic stroke in non-valvular atrial fibrillation Prevalence of anemia in persons 65 years and older in the United States: Evidence for a high rate of unexplained anemia Control of growth of mammalian cells in culture with folic acid Serum high concentrations of homocysteine and low levels of folic acid and vitamin B12 are significantly correlated with the categories of coronary artery diseases Homocysteine and methylmalonic acid as indicators of folate and vitamin B12 deficiency in pregnancy Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: Implications for cancer and neuronal damage Structural basis for molecular recognition of folic acid by folate receptors functionality and gene regulation of folate receptor isoforms: Implications in targeted therapy and Receptor Type β in Hematopoietic Cells: cDNA Cloning Folate Receptor Type γ Is Primarily a Secretory Protein Due to Lack of an Efficient Signal for Glycosylphosphatidylinositol Modification: Protein Characterization and Cell Type Specificity Evaluation of the Neurotoxic/Neuroprotective Role of Organoselenides Using Differentiated Human Neuroblastoma SH-SY5Y Cell Line Challenged with 6-Hydroxydopamine Acrylamide affects proliferation and differentiation of the neural progenitor cell line C17.2 and the neuroblastoma cell line SH-SY5Y Effect of Folic Acid Supplementation on Risk of Cardiovascular Diseases Efficacy of folic acid supplementation in stroke prevention: a meta-analysis Folic Acid Supplementation and the Risk of Cardiovascular Diseases: A Meta-Analysis of Randomized Controlled Trials Goldman, R. Z. & Folate, I. D. and Thiamine Transporters mediated by Facilitative Carriers (SLC19A1-3 and SLC46A1) and Folate Receptors. Mol Asp. Med. 34, https://doi.org/10.1016/j.mam.2012.07.006 (2013) How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression Homocysteine induces PUMA-mediated mitochondrial apoptosis in SH-SY5Y cells Neuroprotective effects of genistein and folic acid on apoptosis of rat cultured cortical neurons induced by β-amyloid 31–35 Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance FOLR3) and Reduced Folate Carrier (SLC19A1) Genes with Meningomyelocele Kathryn Importance of elevated plasma homocysteine levels as a risk factor for atherosclerosis Plasma Homocysteine Levels in Patients With Normal Tension Glaucoma and metabolic syndrome scores: The Kakegawa cohort study Green Tea Polyphenol EGCG Upregulates Tollip Expression by Suppressing Elf-1 Expression Download references We thanks to the Center for Advanced Instrumental and Educational Supports, Faculty of Agriculture, Kyushu University for technical advice for LC-MS analysis. We also thanks Enago (www.enago.jp) for the English language review This work was supported in part by JSPS KAKENHI grant JP22228002 and JP15H02448 to H Department of Bioscience and Biotechnology Yoshinori Fujimura & Hirofumi Tachibana National Agriculture and Food Research Organization Tohoku University Graduate School of Medicine had primary responsibility for the final content The authors declare no competing interests 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/s41598-020-67288-9 Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology Wayne Yoshitomi knew only English and his grandfather mostly spoke Japanese but they didn’t need to talk on summer nights in the mid-1960s when the San Francisco Giants were playing At the kitchen table or in the backyard of their family’s Richmond neighborhood flat 6-year-old Yoshitomi and his grandpa would tune in a Zenith transistor radio Shigeo Ogawa would play solitaire as Russ Hodges narrated the game yelling “Bye Bye Baby!” to call a home run Their shared love of baseball is the only strong memory Yoshitomi has of his grandfather Baseball has since taken Yoshitomi around the country meeting others who share his love for the sport and for being an umpire Yoshitomi’s maternal grandparents and both of his parents had suffered through some of America’s darkest times rounded up and bused to the Topaz internment camp in Utah after Japan’s attack on Pearl Harbor (Yoshitomi only met his paternal grandparents once and doesn’t know their history.) Yoshitomi doesn’t know much about their time in Topaz but his parents’ senior yearbook from their time at Topaz High School inside the camp left a few clues “… plans to become a stenographer.” His father’s description a few pages later reads “… hopes to become the ideal husband.” stands taller than the other students in a yearbook photo of the Junior Red Cross group He has thick hair parted neatly down the middle Wayne Yoshitomi’s parents and grandparents have since passed away but he thinks they met at this camp since his dad signed his mom’s yearbook “They never talked about it,” Yoshitomi said Yoshitomi and his siblings could choose how they wanted to spend their birthdays Yoshitomi always chose to go to Candlestick Park he liked to wear a black zip-up windbreaker to games with “Giants” stretched across the chest in orange lettering His thick black eyebrows stuck out beneath the bill of his plastic Giants batting helmet Baseball overlays the chronology of his life The camp his family was sent to is the same one featured in the movie “American Pastime,” a fictional drama based on true events about the role of baseball in internment camps decided to move to San Francisco from New York The first Japanese man to play in Major League Baseball played for the Giants about the same time Yoshitomi started listening to games with his grandfather mustache and full head of hair are speckled with gray And he’s found a way to stay involved with the game he’s loved since childhood through umpiring really umpiring is the only thing that I can do,” Yoshitomi said At George Washington High School in San Francisco who has been his friend for about 40 years Yoshitomi started coaching Justin’s tee-ball team about 16 years ago Justin was rolling baseballs on the ground before he could even walk so he learned the fundamentals from his “Uncle Wayne.” and I remember he used to come over after I got out of school and he would test my baseball IQ,” said Justin who is finishing his last season as a pitcher for Cal Lutheran Yoshitomi would describe or scribble out possible scenarios for Justin and ask him what he would do in each circumstance Justin recalled one of his games that Yoshitomi umpired he remembered people wondering if Uncle Wayne was going to favor him “I’m pretty sure we went out to dinner after and I was like ‘I don’t want to go to dinner with Uncle Wayne His strike zone was too small,’” Justin said who retired from being an airplane mechanic last year He spent a week in Santa Rosa to learn how to roller skate at Snoopy’s Home Ice He’s a loyal Apple Keynote user who has traveled to three cities in one day to take classes at Apple Stores to improve his presentations for umpire training lessons Yoshitomi and his sister Elaine Tong take a trip to Disneyland when Sleeping Beauty’s castle is decorated with icicles of light and artificial snow falls each night on Main Street The pair goes to the Walt Disney Family Museum in San Francisco to attend talks by Disney animators He also taught his older sister to mountain bike nearly 20 years ago and he even started his own bicycle business at one point But he ended his business after realizing he didn’t want another job While his other hobbies have come and gone his love for Disney and umpiring have stuck He’s spent about $20,000 going to eight umpire training schools around the country “I tell people it’s kind of like someone [for whom] photography is a hobby,” Yoshitomi said his hobby led him to make an annual trip to Cooperstown where he umpired youth baseball games all day he bunked with 11 other umpires in barracks that had nothing but a pillow on the bed Yoshitomi created a home for himself in the barracks One year he even got a mini refrigerator on sale He slept on the bottom bunk and put his gear on the top He always ended his trips with a visit to the Hall of Fame museum “He does everything by the book,” said Kenny Kim who sits on the board of Palo Alto Little League but he takes a lot of pride in what he’s doing.” I had some guy tell me I need to put personality in my calls I look so stupid,’” Yoshitomi said with a laugh He learned the basics from the many umpire training camps he’s attended One particularly influential camp was Jim Evan’s training camp The handout he received while attending the MLB umpire’s classes last October lists the many rules and procedures umpires should abide by Yoshitomi leans in slightly at the start of every pitch ready to cut to the next position if there are extra bases he keeps his toe right on the edge of the baseline behind first base “Conduct pre-game and post-game meetings with your partners.” open hand if the catcher dropped the ball and closed if she caught it he told his partner before a high school softball game at Half Moon Bay High School When there are only two umpires covering an entire diamond they have to communicate with hand signals throughout the game Yoshitomi wears black steel-toed Reeboks; he bought three extra pairs when he discovered the ones he liked were being discontinued He has to wear different uniforms depending on what kind of game he’s umpiring too He had to buy two portable closets from Walmart to fit his 50 or so uniforms he wears sleeves to prevent a rash if he gets hit with the ball When he got hit in the arm in Burlingame at a game in April but the long sleeve shirt didn’t prevent the nasty bruise he had the next day But it’s less common for him to get hit in high school softball than during Little League games one of his traditions is going to his favorite restaurant in whatever city he’s in He makes sure to take a business card for each restaurant he visits and keeps a list of his favorites that includes categories titled “breakfast and lunch,” “ramen” and “miscellaneous.” He’s been exploring new restaurants with his friend Brian Fong since the 1970s “[We would] go down the street and see what we can find,” Fong said Yoshitomi gets dinner by himself after a game before heading back to his home in San Mateo I always have my iPad because I’m always reading.” Yoshitomi makes friends easily and enjoys spending time with people He’s matter-of-fact when he talks with a calming and higher register voice He often pauses in between words and laughs easily in conversations “He’s just so friendly,” his sister Tong said over the phone at Oracle Park before a Giants game “You’ll be standing in the line of any place and all of a sudden Wayne’s talking with the person next to him he will give you the shirt off his back,” Brian Fong said “I can recall any time that I had a problem with my car it was Wayne helping me out and he’d be there no matter where it was.” His affable demeanor makes it even more surprising when he gets on the field at a softball or baseball game The soft voice is unrecognizable as it’s replaced with a booming Parents and coaches reach out to him with questions about the game calls and inquiries before games explaining the rules he doesn’t escape the classic grumbles coming from players When he calls a ball: “That was a great pitch,” a parent squawked That hasn’t been a strike all day,” the third base coach yelled clapping his hands But Yoshitomi doesn’t pay much attention to it His experiences have been mild in comparison with the stories he’s heard from other umpires who have been physically attacked by upset spectators He’s only had someone confront him after a game once Yoshitomi’s biggest concerns aren’t rowdy parents getting hit by the ball or the minimal pay not just baseball umpires but all officials because people are just getting tired of being abused.” It’s a crisis facing youth sports around the nation and Yoshitomi and some of his fellow umpires have noticed it happening in the Bay Area too the Palo Alto Little League started a formal umpire training program for junior high and high schoolers that Yoshitomi now leads a former Palo Alto Little League coach whom Wayne mentored was frustrated that umpires weren’t showing up to games he was asked to start an umpire training program for kids who had recently aged out of Little League Yoshitomi also helped lead some of these classes The program has worked for Palo Alto Little League in solving the official shortage “Maybe one or two games a season and that was because of some freak accident and there were hundreds of positions that were covered and those kids were so diligent about being there early … I loved how serious they took it.” Yoshitomi watches the kids officiate after they have completed the training and gives them feedback after the game “He treats [the kids] with a lot of respect,” said Kenny Kim I’ve seen Wayne umpire games with other kids and he doesn’t undermine them or anything.” He also volunteers with Little League Challenger Division games a baseball program for young people who have physical and intellectual disabilities But the highlight of Yoshitomi’s career was getting to umpire at the Little League Baseball West Regionals in 2013 which is the tournament that determines what team in that region will go to the Little League World Series It’s a once in a lifetime opportunity and a necessary step to umpire at the Little League World Series came to watch Wayne umpire at the West Region tournament the most important spectator was his mother Mary Yoshitomi elderly and unable to drive to any of Yoshitomi’s games had never seen her son umpire and was able to watch the game on TV “She was able to see me umpire on ESPN and then she passed away the following year,” Wayne Yoshitomi said Archive siteLooking for stories published 2010 to September 2014 Peninsula Press is a project of the Stanford Journalism Program The June issue of Akita Shoten's Champion RED magazine published the final chapter of Akihito Yoshitomi's 24-ku no Hanako-san (Hanako in the 24th Ward) manga on Tuesday The manga's fourth volume will ship on June 20 The manga takes place in a Tokyo with a "24th Ward," an extradimensional space where physics obeys different laws and is sealed off from the rest of the city due to the danger it poses a high school boy who enters the 24th Ward to search for his missing younger brother a mysterious girl who he initially rebuffs they unveil the mysteries of the 24th Ward as they search for Kōsuke's brother Yoshitomi published the manga as a one-shot in Champion RED in August 2019, before launching the manga as a serialization in the magazine in January 2020 Akita Shoten published the manga's third volume in October 2021 Yoshitomi's Eat-Man The Main Dish manga launched in Kodansha's Monthly Shonen Sirius magazine in May 2014 and ended in June 2019 Kodansha published six volumes for the series The one compiled volume shipped in April 2016 Yoshitomi launched the Kyō kara Mirai (The Future From Today) on Hero's Inc.'s Flat Heros website in October 2019 Geophysical Institute Japanese mountaineer Yoshitomi Okura will soon attempt to reach two lofty goals—the repair of a weather station high on Mt McKinley and then a walk uphill to stand on its summit for the fifteenth consecutive year lives in Japan but travels to Alaska each summer to climb Mt McKinley with a team of young climbers from Japan and a few Americans who assist with repair and maintenance of the weather station six aluminum poles bolted together to provide perches for weather instruments sits above Denali Pass in perhaps one of the windiest places on Earth “There’s certainly bursts of 100 miles per hour plus winds that go through that pass,” said Roger Robinson chief mountaineering ranger for Denali National Park The weather station recorded an unofficial wind speed of 188 miles per hour three days before it stopped working in January 2003 When Okura and a climbing team took the West Buttress route to the station in 2003 they found that a whip antenna was missing Okura and a team climbed back up the mountain’s West Buttress route with replacement equipment in June 2003 but the equipment stopped transmitting to a satellite a few minutes after its installation Though Okura and another team member returned to the station to check cable connections the supervisor of the electronics shop at UAF’s Geophysical Institute will join Okura’s team on the climb to repair the station Abnett designed previous configurations of the weather station which now includes an ultrasonic wind gauge with no moving parts The station will also use batteries and a transmitter to send data back to the International Arctic Research Center via satellite Tohru Saito of the International Arctic Research Center is also joining the team for his third consecutive summer The team approaches the task of working on the weather station as any group of climbers attempting Mt They plan to take an air taxi from Talkeetna to the southwest fork of Kahiltna Glacier where the Park Service maintains a base camp at 7,300 feet Team members will then spend three weeks on the mountain climbing Their last camp before reaching the weather station is at about 17,000 feet near Denali Pass Since the weather station is located just off the West Buttress climbing route at 18,733 feet team members will leave from the 17,000-foot “high camp” on a nice day and install new components while removing others to carry down team members who feel up to the challenge will attempt to reach the 20,320-foot summit which is a few hours’ climb from the weather station Okura installed the weather station on the ridge above Denali Pass in 1990 because he believes three of his countrymen disappeared there while attempting a winter climb in February 1989 which also may have been the fate of Japanese adventurer Naomi Uemura who vanished while attempting to climb the mountain solo in February 1984 Though fierce winds have battered the weather instruments each winter with the help of the International Arctic Research Center Okura has persevered in his quest to find a combination of weather instruments that will endure on the high ridge and transmit information to the Internet “He has a keen interest in what happens with the weather up there,” Roger Robinson said adding that Okura has stood on the summit of North America’s tallest mountain more times than any other Japanese climber Since it was established by an Act of Congress in 1946 scientists at the Geophysical Institute have studied geophysical processes from the center of the Earth to the surface of the sun and beyond turning data and observations into information useful for state The GI is located on the West Ridge of the University of Alaska Fairbanks campus We acknowledge the Alaska Native nations upon whose ancestral lands our campuses reside our Troth Yeddha' Campus is located on the ancestral lands of the Dena people of the lower Tanana River The University of Alaska is an equal opportunity/equal access employer and educational institution. The university is committed to a policy of nondiscrimination against individuals on the basis of any legally protected status UA is committed to providing accessible websites. Learn more about UA’s notice of web accessibility Please report any problems or feedback concerning this website to uaf-gi-public-info@alaska.edu Yoshitomi drew his original Eat-Man manga from 1996 to 2002. The story follows Bolt Crank, a man who can eat anything and reproduce it in his right hand. Eat-Man The Main Dish launched in Shonen Sirius in May 2014 but it has been on hiatus for two and a half years The third compiled volume shipped in October 2015 Viz Media published part of the original manga in North America The fifth and final compiled book volume for School Ningyo is slated for February 20 Yoshitomi launched the manga in Shōnen Champion and Champion RED in 2013, and ended it in the same year. That first story received two volumes. The manga relaunched with a new story but similar premise in Champion RED in July 2016 Akita Shoten published the manga'a fourth volume in September 20 The manga is set in a school where students tell of an urban legend of mermaids appearing in the school swimming pool at night The legend says that whoever eats the meat from one of those mermaids will be able to make their wish of true love come true In renewal follows two girls named Sakura and Shinobu and use an incantation to summon the mermaids The October issue of Akita Shoten's Champion RED magazine revealed on Monday that manga creator Akihito Yoshitomi is preparing a new manga series The magazine did not reveal a date for the new manga's debut If your idea of a good restaurant experience includes a nice conversation and interaction with the waiting staff then Ichiran Ramen is probably not a place you want to visit The popular Japanese chain is all about solo dining taking extraordinary measures to ensure that patrons avoid human interaction as much as possible came up with the concept for his famous restaurants when he was just a high-school student after seeing his female friends attempting to cover their mouths when eating ramen Yoshitomi discovered that their reluctance to being watched by other people as they slurped noodles was actually a huge barrier to them visiting ramen shops This information inspired the young man to open a tonkotsu (pork bone) ramen restaurant that offered almost total privacy instead of human interaction Upon entering a typical Japanese ramen shop patrons are usually treated to a crowd of hungry eaters crowded together at tables or counters and the clatter of bowls and noodle slurping and Yoshitomi believes it prevents people from focusing on the delicious ramen So you’re not going to see much of that at Ichiran As you enter one of the chain’s dozens of restaurants across Japan Hong Kong and most recently the United States you are welcomed by a large ticket selling machine This is where you select what type of ramen you want to eat and reserve your seat at one of the very private booths After inserting the money into the machine and you’re ready to head to your seat Ichiran Ramen features small booths separated by wooden panels So even if you feel the need to peek at your neighbor while he’s eating you’ll have to settle for hearing them slurp their noodles In case you’ve made a huge mistake and brought a date to this place you do have the option to retract the wooden separators so you can see and talk to each other This definitely not a dinner date restaurant you are presented with the option of customizing your bowl of ramen by circling various toppings and ingredients on a paper card all you have to do is press a call button and a server will pick up the order The way they’ll do that is also unique to Ichiran Ramen and a pair of human hands picks up the customization card and the same hands place the bowl of ramen in front of you So all the human interaction you have to deal with is seeing a stranger’s hands and maybe their midsection for a few moments you can either order seconds by placing your bowl on a rectangle in front of you or simply leave the restaurant without having to wait for the server or even saying a simple ‘good bye’ Ichiran Ramen claims that its unique concept helps combat the stigma of eating alone at a restaurant while also allowing people to focus on the taste of the food without having to put up with any distractions The popular restaurant chain numbers 60 eateries in Japan and Hong Kong – all of which are open 24/7 – and has recently opened it’s first U.S Photos: Ichiran Ramen/Facebook Sources: Gurunavi, Gaijin Pot, Timeline Manga creator Akihito Yoshitomi (Eat-Man) began serializing his Sakura Device manga in the July issue of Shonengahosha's Young Comic Cherry magazine on Monday Sakura Device is a harem-style comedy that revolves around a 14-year-old boy's daily life with his older sister and his childhood friend's sisters The hero of the story is trying to think about his future and become an upstanding adult but the girls around him may or may not know this In addition, manga creator Ryū Shinonome (Ningyo Hime) began serializing his Tadashikunai Ren'ai no Susume (The Incorrect Way to Advance in Love) manga in the same issue The story of the manga begins when a 21-year old virgin man meets a woman older than himself Having a strong complex towards women due to a certain incident the protagonist somehow gets a crush on this woman Source: Comic Natalie The July issue of Kodansha's Monthly Shonen Sirius magazine revealed on Saturday that Akihito Yoshitomi's Eat-Man The Main Dish manga will end in the magazine's next issue on June 26 The manga's sixth and final volume will ship on August 8 The manga's fourth compiled book volume previously revealed in May 2018 that the manga had entered its final arc The manga launched in Monthly Shonen Sirius in May 2014. Kodansha shipped the fifth volume on January 9. The manga resumed in January 2018 after a two-and-a-half year hiatus 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 “We are the champions!” shouted men’s captain Shintaro Imai after the Waseda University Tennis Team achieved its ninth consecutive win at the All-Japan Men’s and Women’s Collegiate Tennis Championships in 2014 Three members of the club in their last year at Waseda selected to participate in the Universiade as well spoke of their enthusiasm in anticipation of achieving their 10th consecutive win at the same championship to be held on October 22 (Thu.) Shintaro Imai: “The only way to conquer the pressure is to train daily Photo credit: Waseda Sports Newspaper Society The Waseda University official website <<https://www.waseda.jp/inst/weekly/en/>> doesn't support your system Please update to the newest version of your browser and try again Continue  Google ChromeWindows version 38 laterMacintosh version38 laterWebSite Fire FoxWindows version 33 laterMacintosh version 33 laterWebSite SafariWindows version 38 laterMacintosh version38 laterWebSite Internet ExplorlerWindows version 10 laterWebSite The magazine describes the manga as a high school girls' love story that "sensitively depicts the feeling of wavering in adolescence." Akita Shoten's Champion RED magazine teased in August that Yoshitomi was preparing a new manga series Yoshitomi's Eat-Man The Main Dish manga launched in Kodansha's Monthly Shonen Sirius magazine in May 2014 and ended on June 26 Kodansha published the manga's sixth and final volume on August 8 Sources: Monthly Hero's November issue, Flat Heros' Twitter account