Specificity of novel allosterically trans- and cis-activated connected maxizymes that are designed to suppress BCR-ABL expression

AbstractChronic myelogenous leukemia (CML) is associated with the presence of the Philadelphia chromosome, which is generated by the reciprocal translocation of chromosomes 9 and 22. In the case of L6 (b2a2) mRNA, it is difficult to cleave the abnormal mRNA specifically because the mRNA includes no sequences that can be cleaved efficiently by conventional hammerhead ribozymes near the BCR-ABL junction. We recently succeeded in designing a novel maxizyme, which specifically cleaves BCR-ABL fusion mRNA, as a result of the formation of a dimeric structure. As an extension of our molecular engineering of maxizymes, as well as to improve their potential utility, we examined whether an analogous conformational change could be induced within a single molecule when two maxizymes were connected via a linker sequence. An active conformation was achieved by binding of the construct to the BCR-ABL junction in trans, with part of the linker sequence then acting as an antisense modulator in cis (within the complex) to adjust the overall structure. Results of studies in vitro in the presence of cetyltrimethylammonium bromide (CTAB) (but not in its absence) suggested that a certain kind of connected maxizyme (cMzB) might be able to undergo a desired conformational change and, indeed, studies in vivo confirmed this prediction. Therefore, we successfully created a fully functional, connected maxizyme and, moreover, we found that the activity and specificity of catalytic RNAs in vivo might be better estimated if their reactions are monitored in vitro in the presence of CTAB

Validation of the Ten-Item Internet Gaming Disorder Test (IGDT-10) based on the clinical diagnosis of IGD in Japan

Background and aims: Although the Ten-Item Internet Gaming Disorder Test (IGDT-10) has been translated into Japanese and widely used, the Japanese version has not previously been validated. We used the clinical diagnosis of IGD as a gold standard for validating the test. Methods: The Japanese version was validated using 244 gamers drawn from the general young population in Japan. Expert interviews using the Japanese version of the Structured Clinical Interview for Internet Gaming Disorder evaluated diagnoses of Internet gaming disorder (IGD). This resulted in a diagnosis of IGD for eight individuals, categorized as the gold standard group. The screening performance of the two Japanese versions with different scoring conditions was examined: the scoring method proposed by the original study (original version) and a less stringent scoring method where responses of either “often” or “sometimes” were regarded as affirmative (modified version). Results: The results of the sensitivity and specificity analyses, the Cronbach’s alpha and the receiver operating characteristics analysis revealed a higher screening performance for the modified versus the original version. The optimum cutoff for the modified version was 5 or more – the sensitivity, specificity, and Youden’s index were 87.5, 85.2, and 72.7%, respectively. The rate of probable IGD using the original and modified versions were 1.8% and 11.3%, respectively. Discussion and conclusion: A less stringent scoring method for the Japanese version of IGDT-10 showed a higher screening performance than the original scoring method. Future studies comprising different ethnic groups and gaming cultures should further examine the suggested scoring method

A New Light on the Evolution and Propagation of Prehistoric Grain Pests: The World's Oldest Maize Weevils Found in Jomon Potteries, Japan

Three Sitophilus species (S. granarius L., S. oryzae L., and S. zeamais Mots.) are closely related based on DNA analysis of their endosymbionts. All are seed parasites of cereal crops and important economic pest species in stored grain. The Sitophilus species that currently exist, including these three species, are generally believed to be endemic to Asia's forested areas, suggesting that the first infestations of stored grain must have taken place near the forested mountains of southwestern Asia. Previous archaeological data and historical records suggest that the three species may have been diffused by the spread of Neolithic agriculture, but this hypothesis has only been established for granary weevils in European and southwestern Asian archaeological records. There was little archeological evidence for grain pests in East Asia before the discovery of maize weevil impressions in Jomon pottery in 2004 using the “impression replica” method. Our research on Jomon agriculture based on seed and insect impressions in pottery continued to seek additional evidence. In 2010, we discovered older weevil impressions in Jomon pottery dating to ca. 10 500 BP. These specimens are the oldest harmful insects in the world discovered at archaeological sites. Our results provide evidence of harmful insects living in the villages from the Earliest Jomon, when no cereals were cultivated. This suggests we must reconsider previous scenarios for the evolution and propagation of grain pest weevils, especially in eastern Asia. Although details of their biology or the foods they infested remain unclear, we hope future interdisciplinary collaborations among geneticists, entomologists, and archaeologists will provide the missing details

A Report on Overseas Teaching Practicum by Graduate Students in Elementary/Secondary Schools in the United States（Ⅺ）

This paper reports on the 11th overseas teaching practicum in the U.S. 12 students joined this year’s program and they observed and conducted lessons in English in three local public schools in North Carolina after careful and repeated preparation sessions in Japan. Many of them did lessons on crosscultural understandings and a few taught subject contents. Through the trail to convey messages in English, their foreign language, students learned the role of verbal and nonverbal language and the more universal way to explain topics to children who are unfamiliar with what re taught. And they also learned and noticed the cultural differences and similalities between the two countries. It seemed that students realized that the two countries share many things in common such as what chidren are like, teachers’ attitude toward children and challenges they are facing, and people’s kindness. These learning was no substitute experience for the participants and it is hoped that their experience will be passed to the next generation when they become teachers

Five doses of the mRNA vaccination potentially suppress ancestral-strain stimulated SARS-CoV2-specific cellular immunity: a cohort study from the Fukushima vaccination community survey, Japan

The bivalent mRNA vaccine is recommended to address coronavirus disease variants, with additional doses suggested for high-risk groups. However, the effectiveness, optimal frequency, and number of doses remain uncertain. In this study, we examined the long-term cellular and humoral immune responses following the fifth administration of the mRNA severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in patients undergoing hemodialysis. To our knowledge, this is the first study to monitor long-term data on humoral and cellular immunity dynamics in high-risk populations after five doses of mRNA vaccination, including the bivalent mRNA vaccine. Whereas most patients maintained humoral immunity throughout the observation period, we observed reduced cellular immune reactivity as measured by the ancestral-strain-stimulated ELISpot assay in a subset of patients. Half of the individuals (50%; 14/28) maintained cellular immunity three months after the fifth dose, despite acquiring humoral immunity. The absence of a relationship between positive controls and T-Spot reactivity suggests that these immune alterations were specific to SARS-CoV-2. In multivariable analysis, participants aged ≥70 years showed a marginally significant lower likelihood of having reactive results. Notably, among the 14 individuals who received heterologous vaccines, 13 successfully acquired cellular immunity, supporting the effectiveness of this administration strategy. These findings provide valuable insights for future vaccination strategies in vulnerable populations. However, further research is needed to evaluate the involvement of immune tolerance and exhaustion through repeated vaccination to optimize immunization strategies

An attenuated vaccinia vaccine encoding the severe acute respiratory syndrome coronavirus-2 spike protein elicits broad and durable immune responses, and protects cynomolgus macaques and human angiotensin-converting enzyme 2 transgenic mice from severe acute respiratory syndrome coronavirus-2 and its variants

As long as the coronavirus disease-2019 (COVID-19) pandemic continues, new variants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) with altered antigenicity will emerge. The development of vaccines that elicit robust, broad, and durable protection against SARS-CoV-2 variants is urgently required. We have developed a vaccine consisting of the attenuated vaccinia virus Dairen-I (DIs) strain platform carrying the SARS-CoV-2 S gene (rDIs-S). rDIs-S induced neutralizing antibody and T-lymphocyte responses in cynomolgus macaques and human angiotensin-converting enzyme 2 (hACE2) transgenic mice, and the mouse model showed broad protection against SARS-CoV-2 isolates ranging from the early-pandemic strain (WK-521) to the recent Omicron BA.1 variant (TY38-873). Using a tandem mass tag (TMT)-based quantitative proteomic analysis of lung homogenates from hACE2 transgenic mice, we found that, among mice subjected to challenge infection with WK-521, vaccination with rDIs-S prevented protein expression related to the severe pathogenic effects of SARS-CoV-2 infection (tissue destruction, inflammation, coagulation, fibrosis, and angiogenesis) and restored protein expression related to immune responses (antigen presentation and cellular response to stress). Furthermore, long-term studies in mice showed that vaccination with rDIs-S maintains S protein-specific antibody titers for at least 6 months after a first vaccination. Thus, rDIs-S appears to provide broad and durable protective immunity against SARS-CoV-2, including current variants such as Omicron BA.1 and possibly future variants

2018～2020年度 教育研究高度化促進費 エコメディカル社会システムのための体系的健康都市評価指標に基づく健康コミュニティ創生 研究成果報告書

本研究は，生活圏レベルでの健康行動に着目し，評価指標の体系化と，まちとして人々の健康を支えられる自律的コミュニティ形成の制度設計を目的とした．健康行動に着目した分析例として，年齢に応じて減少する「特に目的なく外出」する機会を改善するためには，具体的な生活シーンでの都市機能アクセス評価のきめ細やかな段階整備が必要であることを指摘した．また，生活習慣病の例として糖尿病を取り上げ，健常者との要因比較が可能な分析手法により重要要因の抽出を行った．その上で，総合的評価のために，身体，医療，日常，精神，介護の５つの側面から体系的に構築した指標群を取り上げ，具体的に大阪に適用することで妥当性を示した．また，健康コミュニティ形成のために，合わせて運営しているリビングラボの仕組みを援用し，国内外の価値創造の手法や自律的実践プロセスの取組を，健康に関する共創に適用可能なように改良し，健康及び環境に関するテーマを自分事と捉えつつ社会へとコミュニティの関心を向けることを狙いとしたワークショップに適用した．具体的には，市民自身が可能となる問題解決を見出すコミュニティと位置づけ，大学研究者が議論の経緯を見ながら適切な情報をタイムリーに提供することで支援しつつ参加者が自ら考えを具体化していくプロセスを実現し，参加者の発言に関するテキスト分析によって妥当性を確認した．さらに，具体的な指標に基づく市民の反応を知るため，一般社会人30名を対象に3ヶ月間の活動量を計測するプログラムを実践した．期間中の平均歩数は男女それぞれ約9,000，12,000歩/日であり，目標歩数と比べて，男性は目標値どおり，女性は大幅に上回る結果を得るとともに，本プログラムの全体的な満足度として90％以上の参加者から「満足」あるいは「やや満足」の結果を得て，実践面，満足面で有用であることを確認した．【出典】・2．北詰恵一・黒田研二：エコメディカル社会における健康コミュニテクのあり方，第23回関西大学先端科学技術シンポジウム，2019.・3.1 井ノ口弘昭・秋山孝正：健康まちづくりにおける総合的健康度の評価方法に関する研究，第62回土木計画学研究発表会講演集，Vol.62，CD-ROM，2020，4p．・3.2 金ヨンキョン，尹禮分，尹敏，中山弘隆：グラフィカルラッソの糖尿病診断への適用性に関する検証，第60回土木計画学研究発表会講演集，Vol.60，CD-ROM，2019，4p.・3.3 尾崎平：スマートヘルシ倶楽部2018終了時アンケート結果，14ｐ, 2019.・4.1 北詰恵一・道越亮介：健康まちづくりのためのリビングラボのあり方，第46回環境システム研究論文発表会，2018，4p・4.2 岡村雄介・沙海拓真・北詰恵一：リビングラボにおける初期構想段階のステークホルダー間の関係分析，令和３年度土木学会全国大会第76回年次学術講演会，WEB，2P，2021.・5.1 井ノ口弘昭・秋山孝正：健康まちづくりにおける総合的健康度の評価方法に関する研究，第60回土木計画学研究発表会講演集，Vol.62，CD-ROM，2020，4p.研究成果リスト1) 北詰恵一・黒田研二：エコメディカル社会における健康コミュニテクのあり方，第23回関西大学先端科学技術シンポジウム，2019.3) 金ヨンキョン，尹禮分，尹敏，中山弘隆: グラフィカルラッソの糖尿病診断への適用性に関する検証，第60回土木計画学研究発表会講演集，No.60，CD-ROM 4P，2019．4) 尾﨑平, 安部寛喜：健康増進型公園の利用特性と暑熱環境の関係性分析，土木学会論文集G（環境），土木学会論文集G（環境），Vol.75，No.6，pp.29-38，2019．5) 北詰恵一・江斌・市橋愛彩：健康まちづくりのための外出意向と健康関連指標の関係性分析，第60回土木計画学研究発表会講演集，Vol.60，CD-ROM，2019，3p，無.6) 北詰恵一：外出に対する意向と健康自己評価との関係性分析，令和元年度土木学会第74回年次学術講演会，CD-ROM，2019，Ⅳ-15(2p)，無.7) 北詰恵一：エコメディカル社会構築のための健康まちづくり，第24回関西大学先端科学技術シンポジウム，2020.8) 岡村雄介・北詰恵一：リビングラボにおける価値創造のためのツールの効果分析，土木学会関西支部年次学術講演会講演概要集，WEB，2P，2020.9) 秋山孝正: 健康まちづくりプロジェクトに対する市民意識からみた健康都市形成に関する考察,都市計画学会関西支部だより，No.34．pp.10-11，2020.10) 秋山孝正・井ノ口弘昭：感染症予防の新しい生活様式に着目した健康まちづくりに関する考察，第62回土木計画学研究発表会講演集，Vol.62，CD-ROM，2020，5p，無.11) 井ノ口弘昭・秋山孝正：健康まちづくりにおける総合的健康度の評価方法に関する研究，第62回土木計画学研究発表会講演集，Vol.62，CD-ROM，2020，4p，無.12) 尾崎平・櫻井順平・北詰恵一：日常生活行動と暑熱環境の関係性分析，第62回土木計画学研究発表会講演集，Vol.62，CD-ROM，2020，6p，無.13) 岡村雄介・北詰恵一：健康まちづくり政策を推進するためのリビングラボの方法論に関する研究，第62回土木計画学研究発表会講演集，Vol.62，CD-ROM，2020，5p，無.14) 北詰恵一・市橋愛彩・田中萌子：自治体における健康をテーマとしてSDGs現状分析，第25回関西大学先端科学技術シンポジウム，ポスター，2021.01.28,29，関西大学.概要1. はじめに……22. エコメディカル社会における健康コミュニティのあり方……33. 健康都市指標開発……6　3.1 総合的健康度の評価方法……6　3.2 手法検討の取組み（グラフィカルラッソの糖尿病診断への適用性）……10　3.3 活動量指標の見える化……154. 健康コミュニティ創生の取組み……19　4.1 健康まちづくりのためのリビングラボ……19　4.2 ステークホルダー間関係分析……235. 健康都市指標にもとづく健康コミュニティのモデル……27　5.1 システム思考型モデルを用いた健康まちづくりの展開過程……276. まとめ……36研究成果リス