Interference of CLN6 mutants

CLN6 (Ceroid Lipofuscinosis, Neuronal, 6) is a 311-amino acid protein spanning the endoplasmic reticulum membrane. Mutations in CLN6 are linked to CLN6 disease, a hereditary neurodegenerative disorder categorized into the neuronal ceroid lipofuscinoses. CLN6 disease is an autosomal recessive disorder and individuals affected with this disease have two identical (homozygous) or two distinct (compound heterozygous) CLN6 mutant alleles. Little has been known about CLN6’s physiological roles and the disease mechanism. We recently found that CLN6 prevents protein aggregate formation, pointing to impaired CLN6’s anti-aggregate activity as a cause for the disease. To comprehensively understand the pathomechanism, overall anti-aggregate activity derived from two different CLN6 mutants needs to be investigated, considering patients compound heterozygous for CLN6 alleles. We focused on mutant combinations involving the S132CfsX18 (132fsX) prematurely terminated protein, produced from the most frequent mutation in CLN6. The 132fsX mutant nullified anti-aggregate activity of the P299L CLN6 missense mutant but not of wild-type CLN6. Wild-type CLN6’s resistance to the 132fsX mutant was abolished by replacement of amino acids 297–301, including Pro297 and Pro299, with five alanine residues. Given that removal of CLN6’s C-terminal fifteen amino acids 297–311 (luminal tail) did not affect the resistance, we suggested that CLN6’s luminal tail, when unleashed from Pro297/299-mediated conformational constraints, is improperly positioned by the 132fsX mutant, thereby blocking the induction of anti- aggregate activity. We here reveal a novel mechanism for dissipating CLN6 mutants’ residual functions, providing an explanation for the compound heterozygosity-driven pathogenesis

早産で子どもの誕生を迎えた父親の困難な体験とレジリエンス―はじめて子どもをもつ父親の語りから―

Purpose: The purpose of this study was to elucidate the difficulties experienced by fathers upon the premature birth of their first child, as well as their resilience, based on their narratives. Methods: We conducted semi-structured interviews with nine fathers whose first child was born prematurely. Each father was given the opportunity to talk freely about the difficulties he had experienced when his child was born and how he overcame them. The data obtained from the interviews were analyzed using a hermeneutic phenomenological approach. Results: Upon the premature birth of their first child, the fathers experienced the following difficulties: unrealistic feelings of having met an alien from another planet, a feeling of being compelled to be constantly busy, a constant fear of facing obstacles associated with the situation and a fear of death, a conflict with morality and ethics, and an uncomfortable feeling of being in a place where they could not fit in. The fathers expressed the following ideas, which were examples of resilience during the recovery process: trust in the strength of their child and the people around them and leaving things to them (omit?), thinking positively about things and assigning significance to the birth of their child, looking at the situation from a wider perspective, and maintaining a moderate psychological distance. Conclusion: The interviews showed that the fathers almost did not believe that their child had been born prematurely and therefore, could not accept the reality of their experience. However, they trusted the strength of their children, their wives, and the healthcare professionals, and supported their families by looking for opportunities to become involved. It is important that healthcare professionals acknowledge the experience of fathers whose children are born prematurely, provide support to help them assign subjective significance to the birth of their child, and help them to find their strength

Human Blood Concentrations of Cotinine, a Biomonitoring Marker for Tobacco Smoke, Extrapolated from Nicotine Metabolism in Rats and Humans and Physiologically Based Pharmacokinetic Modeling

The present study defined a simplified physiologically based pharmacokinetic (PBPK) model for nicotine and its primary metabolite cotinine in humans, based on metabolic parameters determined in vitro using relevant liver microsomes, coefficients derived in silico, physiological parameters derived from the literature, and an established rat PBPK model. The model consists of an absorption compartment, a metabolizing compartment, and a central compartment for nicotine and three equivalent compartments for cotinine. Evaluation of a rat model was performed by making comparisons with predicted concentrations in blood and in vivo experimental pharmacokinetic values obtained from rats after oral treatment with nicotine (1.0 mg/kg, a no-observed-adverseeffect level) for 14 days. Elimination rates of nicotine in vitro were established from data from rat liver microsomes and from human pooled liver microsomes. Human biomonitoring data (17 ng nicotine and 150 ng cotinine per mL plasma 1 h after smoking) from pooled five male Japanese smokers (daily intake of 43 mg nicotine by smoking) revealed that these blood concentrations could be calculated using a human PBPK model. These results indicate that a simplified PBPK model for nicotine/cotinine is useful for a forward dosimetry approach in humans and for estimating blood concentrations of other related compounds resulting from exposure to low chemical doses

Exploring the Landscape of Home-Based Teleradiology in Japan: A Qualitative Analysis of Radiologists’ and Neurosurgeons’ Experiences to Elucidate Advantages, Challenges, and Future Directions

This study aimed to investigate the advantages, disadvantages, working methods, and support needs of physicians practicing teleradiology from home in Japan, as well as to explore challenges related to the COVID-19 pandemic. We conducted semi-structured interviews with 15 physicians (12 radiologists and 3 neurosurgeons) engaged in teleradiology services. Participants were recruited through purposive sampling to ensure diversity in age, gender, and experience. Data were analyzed using inductive thematic analysis following Braun and Clarke’s six-step approach. Five main themes were generated: (1) the ability to work from home according to one’s lifestyle, allowing for better work-life balance; (2) reduced quality and efficiency of reading work, due to limited patient information and lack of immediate consultation; (3) self-management and reliance on available resources, including literature searches and networking with colleagues; (4) need for comfortable infrastructure facilities, such as high-quality monitors and stable internet connections; and (5) provision of resources to resolve questions and concerns, including platforms for peer discussions. Interestingly, no specific themes related to the COVID-19 pandemic were identified, suggesting that the challenges of teleradiology were not uniquely affected by the pandemic. While home-based teleradiology offers lifestyle flexibility, it presents challenges in maintaining work quality and efficiency. Physicians employ self-management strategies and rely on available resources to mitigate these challenges. The findings highlight the need for improved infrastructure and support systems to enhance the practice of home-based teleradiology in Japan. This study contributes to the growing body of literature on remote healthcare delivery and may inform policy decisions and best practices in diagnostic radiology both in Japan and internationally

Clinical significance and origin of leukocytes that lack HLA-A allele expression in patients with acquired aplastic anemia

To gain insight into the origin and clinical significance of leukocytes that lack human leukocyte antigen A (HLA-A) allele expression caused by a copy-number-neutral loss of heterozygosity in the short arm of chromosome 6 in patients with acquired aplastic anemia (AA), we used a high-sensitivity flow cytometry assay to investigate the presence of HLA-A allele-lacking leukocytes (HLA-LLs) in 144 AA patients. HLA-LLs, accounting for 0.2–99.8% of each leukocyte population, were detected in 18 of 71 (25.4%) newly diagnosed patients and in 25 of 73 (34.2%) previously treated patients. The lineage combination patterns of the HLA-LLs in the 43 HLA-LL+ patients were granulocytes (Gs), monocytes (Ms), B cells (Bs), and T cells (Ts; GMBT) in 13 cases, GMB in 16 cases, GM in 11 cases, and B alone in three cases. The response rate to antithymocyte globulin plus cyclosporine therapy (100%) and the 2-year, failure-free survival rate (100%) in 8 newly diagnosed HLA-LL+ patients were significantly higher than in 23 HLA-LL− patients (52.2% for both). These data suggest that HLA-LLs are a useful marker of the presence of immune pathophysiology in AA and that T-cell attacks against hematopoietic progenitor cells, rather than against hematopoietic stem cells, can trigger bone marrow failure in AA patients. © 2016 ISEH - International Society for Experimental HematologyEmbargo Period 12 month

病名における「-性」の分析 : 一般書籍との比較から

Osaka UniversityOsaka UniversitySeinan Jo Gakuin UniversitySeinan Jo Gakuin UniversityNational Institute for Japanese Language and Linguistics会議名: 言語資源活用ワークショップ2020, 開催地: オンライン, 会期: 2020年9月8日−9日, 主催: 国立国語研究所 コーパス開発センター医療用語（病名）には，「-性」という語構成要素を含む合成語が多いが，どのような要素と「性」が結合するのか，また，どのように病名を構成するのかについては未だ詳らかではないといえる。本発表では，実践医療用語辞書ComeJisyo の見出し語を対象に「-性」を含む病名を調査し，その特徴について分析した。また，BCCWJ の書籍サブコーパスにおける「-性」の用例と比較することで，得られた特徴が病名特有のものであるかを検討した。病名における「-性」では「先天性」「多発性」「急性」などが高頻度に用いられ，「急性細菌性髄膜炎」のように他の「-性」との共起も見られる一方，書籍では「-性」の連続は見られず，「可能性」「必要性」のようにそれ自体が主語となる（体言用法の）ものが高頻度であるという違いが見られた。病名においては，一語で的確に症状を表現する必要があるため，「-性」を用いた細分化が行われていると考えられる

実践医療用語の語構成要素への分割と意味ラベル付与の試み

National Institute for Japanese Language and LinguisticsSeinan Jo Gakuin UniversitySeinan Jo Gakuin UniversityMejiro UniversityOsaka University会議名: 言語資源活用ワークショップ2019, 開催地: 国立国語研究所, 会期: 2019年9月2日−4日, 主催: 国立国語研究所 コーパス開発センター本発表では、電子医療記録に含まれる実践医療用語の語構成を明らかにするために、独自に設計した語構成要素への分割とそれに対する意味ラベルの付与を行い、意味ラベルによる語構成のパターンを調査した。調査対象は、ComeJisyoSjis-1（111,664語）から、『分類語彙表 増補改訂版』に収録されている語を含む約7,000語から抽出した1,000語である。これらを短単位よりやや長めの語構成要素に分割し、意味ラベルを付与した。意味ラベルは、石井（2007）の複合名詞の語構造把握のための意味分類を参考にしたが、実践医療用語のために独自に設けたものも多い。分析結果から、以下のような点が明らかになった。(1)語構成要素数が2個と3個のものが全体の8割以上を占める。(2)意味ラベルは、「疾患」「身体部位」「状態」「症状」「医療行為」「時間」「生理」の7つで全体の約8割を占める。(3)意味ラベルは、語頭により多く出現するもの（「身体部位」「時間」）や語末により多く出現するもの（「医療行為」「症状」「障害」）などがあり、分布に偏りが見られる

病名を表す合成語の語末調査

Seinan Jo Gakuin UniversitySeinan Jo Gakuin UniversityOsaka UniversityOsaka UniversityNational Institute for Japanese Language and Linguistics会議名: 言語資源活用ワークショップ2020, 開催地: オンライン, 会期: 2020年9月8日−9日, 主催: 国立国語研究所 コーパス開発センター本研究では合成語の語末により病名の判別が可能か否かを確認するために合成語の語末調査を行った。具体的には、病名を表す合成語5,465 語について語末のunigram、bigram、trigram を調べた。加えて、筆者等が着手している電子カルテに記載された合成語を対象とした語構成要素解析で定めた語単位で、合成語を分割した場合に語末となる語構成要素の頻度を調べた。その結果、（1）右側主要部の規則による意味を用いた判別が可能なこと、（2）病名の末尾には「ヘモクロマトーシス」のようなカタカナ語があり、文字単位での判別より語単位の判別の方が適していることが分かった。また、意味ラベル「接尾語」が付与された語構成要素と、「病名」が付与された語構成要素の内「接尾語」を含まない要素を用いることで「病名」の機械的な判別が可能であることが示唆された

「急性」を含む病名の語構成

Seinan Jo Gakuin UniversitySeinan Jo Gakuin University, PhysicianOsaka UniversityPhysicianNational Institute for Japanese Language and Linguistics会議名: 言語資源ワークショップ2022, 開催地: オンライン, 会期: 2022年8月30日-31日, 主催: 国立国語研究所 言語資源開発センター「急性骨髄性白血病」のように「～性」が複数含まれ、かつ「急性」を含む病名において、「急性」の緊急度と語順の関係を調べるために、『現代日本語書き言葉均衡コーパス』(BCCWJ)に出現した当該の病名28語について、BCCWJ、医師経過記録、多職種共有の経過記録での出現頻度を求めた。その結果、①「急性」は語頭に多く出現すること、②医療現場では使われない病名があること、③医療現場では「急性」無しの病名が多く使われていること、④「急性」とその他の「～性」の語順を変えた同義語が存在することが分かった

Word Component Database for “Hands-On Medical Terms” (Version 3) Specification

会議名: 言語資源ワークショップ2023, 開催地: オンライン, 会期: 2023年8月28日-29日, 主催: 国立国語研究所 言語資源開発センター我々は、医療用語の合成語の語構造および語構成要素とその意味を明らかにすることを目的に、合成語7,087語を分析し『実践医療用語_語構成要素語彙試案表 Ver.2』を作成した。この作成の過程で、(1)医療用語の選定方法、(2)分割単位の曖昧性、(3)語構造の記述方法、(4)意味ラベルの命名と付与方法に課題がみつかった。そこでこれらの課題を検討し、改良版の試案表Ver.3の作成に着手している。本発表では、改訂版Ver.3の公開にむけて、これらの問題点と当面の方針について述べる。application/pdf奈良先端科学技術大学院大学杏林大学大阪大学京都大学関西大学国立国語研究所Nara Institute of Science and TechnologyKyorin UniversityOsaka UniversityKyoto UniversityKansai UniversityNational Institute for Japanese Language and Linguisticsconference pape