Nara Medical University

COVID-19 vaccines elicit strong T-cell responses, but clonal-resolution analyses of these responses have not previously been performed. To address this gap, a team of researchers investigated the T- cell receptor sequence and tracked it using trammer analysis, uncovering key insights into the dynamics of T-cell responses. This study can lead to improved next-generation vaccines. mRNA vaccines developed against the spike glycoprotein of severe acute respiratory syndrome type 2 coronavirus (SARS-CoV-2), displayed remarkable efficiency in combating coronavirus 19 (COVID-19). These vaccines work by triggering both cellular and humoral immune responses against the spike protein of the virus. Cellular immunity may play a more protective role than humoral immunity to variants of concerns (VOC) against SARS-CoV-2, as it targets the conserved regions of spike protein and possibly cross-reacts with other variants. Since a single spike epitope is recognized by multiple T-cell clones, the mRNA vaccination-induced T-cell response may consist of multiple spike-reactive clones. Thus, it is important to understand the mechanism of mRNA vaccination-induced cellular immune response. However, to address this clonal-resolution analysis on T-cell responses to mRNA vaccination has not been performed yet. To bridge this gap, a team of researchers, led by Associate Professor Satoshi Ueha, including Professor Kouji Matsushima from the Tokyo University of Science (TUS), Japan, Mr. Hiroyasu Aoki from the University of Tokyo, and Professor Toshihiro Ito from Nara Medical University, aimed to develop a kinetic pro spike-reactive T-cell clones during repetitive mRNA vaccination. For this, they performed a longitudinal TCR sequencing on peripheral T cells of 38 participants who had received the Pfizer vaccine from before the vaccine to after the third vaccination and then analyzed the single-cell gene expression and epitope specificity of the clonotypes. Their findings, published in Cell Reports on March 7, 2024, revealed that while the primary T-cell response of naïve T cells generally peaked 10-18 days after the first shot, expansion of "early responders" was detected on day 7 after the first shot, suggesting that these early responders contain memory T cells against common cold coronaviruses. They also found a "main responder" that expanded after the second shot and did not expand early after the first shot and a "third responder" that appeared and expanded only after the third shot. By longitudinally tracking the total frequency of each response pattern, it was observed that, after the second shot, a shift among the clonotypes occurred, wherein the major population changed from early responders to main responders, suggestive of a shift in clonal dominance. A similar shift of responding clones was also observed in CD4+ T cells. Expanding upon the research process, Prof. Ueha says, "We next analyzed the phenotype of main responders after the second and the third vaccination. The results showed that the main responders after the second and third shots mostly consist of effector-memory T cells (TEM), with more terminally differentiated effector memory-like phenotype after the third shot." The researchers then examined the repertoire changes of main responders, revealing that the expansion of main responders, which occurred after the second shot, diminished following the third shot, and the clonal diversity decreased and was partially replaced by the third responders. This may potentially mean that the third vaccination selected better-responding clones. Due to the vaccination-induced shift in immunodominance of spike epitopes, the study supports the inter-epitope shift model. In addition, there were intra-epitope shifts of vaccine-responding clonotypes within spike epitopes. Prof. Ueha explains the significance of these results, "Our analysis suggests that T cells can "re-write" themselves and reshape their memory populations after successive vaccinations. This re-writability not only maintains the number of memory T cells but also maintains diversity that can respond to different variants of pathogens. Moreover, by tuning the replacement of memory cells, more effective vaccines can be developed that can also be tailored to an individual's unique immune response." Overall, this study provides important insights into mRNA vaccine-induced T-cell responses, which will be crucial for developing next-generation vaccines for more effective and broad protection against viruses.

NEW YORK and TOKYO, Feb. 2, 2024 /PRNewswire/ - Pixie Dust Technologies, Inc. (Nasdaq: PXDT) (the " Company"), a Japanese technology company that focuses on commercializing innovative products and materials utilizing proprietary wave control technology, today announced that a recent study suggests that its unique sound stimulation technology could synchronize gamma waves in the human brain, even among older people. This study, a collaboration with the University of Electro-Communications, a National University Corporation, Nara Medical University, and Shionogi & Co., Ltd., a pharmaceutical company in Japan, was reported at the Auditory Research Meeting Sponsored by the Technical Committee of Psychological and Physiological Acoustics, which was put on by the Acoustical Society of Japan in January 2024. The study utilized audio from television news and music programs, separating voices from background. The background sound was amplitude-modulated at 40 Hz - a novel technique patented in Japan by the Company that is designed to synchronize gamma waves in the brain without compromising speech clarity. Participants in the study included both older people (nine individuals with an average age of 66.1±4.6) and younger people (eight individuals with an average age of 22.4±1.7). The study found that both age groups showed statistically significant synchronization of 40 Hz brain waves (gamma waves) with all modulated sounds, with no notable difference in the degree of brainwave synchronization between the two groups. "This study's findings are significant in confirming that Gamma Wave Sound can synchronize brain waves in both young and older individuals," commented Chief Research Officer of the Company, Takayuki Hoshi. "We aim to further our research on Gamma Wave Sound and contribute to dementia prevention strategies." Forward-Looking Statements Certain statements contained in this press release are "forward-looking statements" made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements reflect the Company's current expectations or beliefs concerning future events and actual events may differ materially from current expectations. Any such forward-looking statements are subject to various risks and uncertainties, including the strength of the economy, changes to the market for securities, political or financial instability and other factors which are set forth in the Company's Annual Report on Form 20-F for the year ended April 30, 2023 (File No. 001-41749) filed with the SEC, and in all filings with the SEC made by the Company subsequent to the filing thereof. The Company does not undertake to publicly update or revise its forward-looking statements, whether as a result of new information, future events or otherwise. About Pixie Dust Technologies, Inc. Pixie Dust Technologies, Inc. is a Japanese technology company that focuses on commercializing innovative products and materials utilizing proprietary wave technology. The Company is currently focusing on two areas of product development: (1) "Personal Care & Diversity" - where wave control technology is applied to mechanobiology and intervention/assistance in vision, hearing, and touch; and (2) "Workspace & Digital Transformation" - where metamaterials (technology that creates properties through structure rather than material) and solutions to commercial design problems, such as in offices or construction sites, are applied. SOURCE Pixie Dust Technologies

Researchers have shown that lysosomes, key organelles for maintaining cellular stability, can be repaired once damaged by a process termed microautophagy. They identified molecules called STK38 and GABARAPs as key regulators of this process. Depletion of microautophagy regulators lead to increased cellular senescence and a shorter lifespan, indicating the importance of this process. This study is highly significant for the achievement of healthy aging and points toward new therapies for age-related diseases. To age or not to age! How does aging affect organisms on a cellular level? What mechanisms help cells survive self-inflicted or external harm? It is known that lysosomes -- critically important cellular structures -- are crucial for digesting damaged cellular components and pathogens, and maintain stability within cells and tissues. But can they also be repaired, and if so, how? In a study published this month in EMBO Reports, researchers from Osaka University and Nara Medical University have shown that damaged lysosomes are repaired by a mechanism called "microautophagy" and have identified two key regulators of this process. Microautophagy is one of the three main types of autophagy in most higher organisms. It is a regulated process by which cellular components that have become dysfunctional or are no longer required are broken down. Although it is assumed to be involved in defense mechanisms collectively called lysosomal damage responses, the details remain unknown. Lysosomes frequently become damaged and lysosomal dysfunction has been linked to accelerated aging and a shortened lifespan. In this study, the researchers tried to understand the repair mechanisms. To identify a novel regulator of lysosomal damage response, they focused a signaling pathway called Hippo pathway which controls multiple processes such as cellular growth. They knocked down individual components of the Hippo pathway in the human cells, and then observed whether the cells could respond to induced lysosomal damage. This screening revealed that a protein called Serine-threonine kinase 38 (STK38) is essential for the lysosomal damage response. They then found that STK38 works with a protein complex called the "endosomal sorting complex required for transport (ESCRT) machinery," which was already known to be linked to lysosomal repair. "STK38 recruits the protein 'vacuolar protein sorting 4' (VPS4) to damaged lysosomes and is crucial for disassembling the ESCRT machinery at the end of the repair process," explains lead author of the study Monami Ogura. They further found that lysosomal membrane repair by ESCRT machinery is mediated by microautophagy. They also identified that non-canonical lipidation of a subfamily of autophagy-related protein 8 (ATG8s) molecules -- the key autophagy proteins -- known as Gamma-aminobutyric acid receptor-associated proteins (GABARAPs) is required for this process. Lipidation, the process of modifying ATG8s with lipid extensions, is the main process involved in autophagy. In non-canonical lipidation ATG8s are lipidated into single-membrane endolysosomes, instead of double-membrane phagophore seen in canonical lipidation. The researchers showed that the GABARAPs are essential for the first step of the process of lysosomal repair. "We showed that non-canonical lipidation of ATG8s is crucial for the initial recruitment of the ESCRT machinery to damaged lysosomes and their subsequent repair," explains senior author Shuhei Nakamura. The team showed that depletion of the regulators of microautophagy increased the rate of senescent cells and shortened lifespan in C. elegans. Both STK38 and GABARAPs also have evolutionarily conserved roles, indicating the significance of this pathway in maintaining lysosomal integrity, healthy cellular function, and the prevention of cellular senescence and organismal aging. The detailed understanding provided by this study paves the way for increasing healthy aging and has great therapeutic value for the treatment of age-related diseases.