Novel method to rescue a lethal phenotype through integration of target gene onto the X-chromosome.

The loss-of-function mutations of serine protease inhibitor, Kazal type 1 (SPINK1) gene are associated with human chronic pancreatitis, but the underlying mechanisms remain unknown. We previously reported that mice lacking Spink3, the murine homologue of human SPINK1, die perinatally due to massive pancreatic acinar cell death, precluding investigation of the effects of SPINK1 deficiency. To circumvent perinatal lethality, we have developed a novel method to integrate human SPINK1 gene on the X chromosome using Cre-loxP technology and thus generated transgenic mice termed "X-SPINK1". Consistent with the fact that one of the two X chromosomes is randomly inactivated, X-SPINK1 mice exhibit mosaic pattern of SPINK1 expression. Crossing of X-SPINK1 mice with Spink3+/- mice rescued perinatal lethality, but the resulting Spink3-/-;XXSPINK1 mice developed spontaneous pancreatitis characterized by chronic inflammation and fibrosis. The results show that mice lacking a gene essential for cell survival can be rescued by expressing this gene on the X chromosome. The Spink3-/-;XXSPINK1 mice, in which this method has been applied to partially restore SPINK1 function, present a novel genetic model of chronic pancreatitis

Bullying victimisation in adolescence: prevalence and inequalities by gender, socioeconomic status and academic performance across 71 countries

Background Bullying victimisation is of global importance due to its long-term negative consequences. We examined the prevalence of victimisation and its inequalities in 15-year-olds across 71 countries. Methods Data were from the Programme for International Student Assessment (March-August 2018). Students reported frequencies of relational, physical, and verbal victimisation during the last 12 months, which were analysed separately and combined into a total score. Prevalence of frequent victimisation (> a few times a month) was estimated, followed by mean differences in total score by gender, wealth and academic performance quintiles in each country. Meta-analyses were used to examine country differences. Findings Of 421,437 students included, 113,602 (30·4%) experienced frequent victimisation, yet this varied by country—from 9·3% (Korea) to 64·8% (Philippines). Verbal and relational victimisation were more frequent (21·4%, 20.9%, respectively) than physical victimisation (15·2%). On average, boys (vs girls +0·23SD, 95%CI: 0·22–0·24), students from the lowest wealth (vs highest +0·09SD, 0·08–0·10) and with lowest academic performance (vs highest +0·49SD, 0·48–0·50) had higher scores. However, there was substantial between-country heterogeneity in these associations (I2=85%–98%). Similar results were observed for subtypes of victimisation—except relational victimisation, where gender inequalities were smaller. Interpretation Globally, bullying victimisation was high, although the size, predominant subtype and strength of associations with risk factors varied by country. The large cross-country differences observed require further replication and empirical explanation, and suggest the need to and the large scope for reducing bullying victimisation and its inequity in the future. Funding Japan Foundation for Pediatric Researc

西之島の海底の溶岩を採る : 「TAIRIKUプロジェクト」大陸生成の新しい仮説と西之島における検証

西之島は東京の1000 km南、父島の130 km西に位置しており，伊豆小笠原海洋島弧の火山島に数えられ，水深3 000 mから立ち上がる巨大火山である．また，西之島周辺の地殻は20 kmに満たず，伊豆小笠原弧で最も地殻が薄い“マントルに近い島”であり初期地球のアナログと見なせる重要な研究対象である．2013年11月に西之島の噴火活動が40年ぶりに再開して以降，現在も活動を続けている．40年前の噴火で発生した噴出物や溶岩は採取されており，それらは大陸を形成する安山岩であることが確認された．そこで今回は，なぜ海洋の真ん中で安山岩が噴出するのかを調べるために，深海曳航体（ディープ・トウ）を潜航させ箱形ドレッジ（ドレッジ）による溶岩の採取を行った．海洋理工学会平成27年度秋季大会（2015年10月29日～30日, 京都大学

Brain Metastasis from Gastrointestinal Stromal Tumor: A Case Report and Review of the Literature

Metastasis of gastrointestinal stromal tumor (GIST) into the central nervous system is extremely rare. We report a patient with synchronous GIST and brain metastasis. At disease onset, there was left hemiplegia and ptosis of the right eyelids. Resection cytology of the brain tumor was reported as metastasis of GIST. After positron emission tomography examination, another tumor in the small bowel was discovered, which suggested a small bowel GIST associated with intracranial metastasis. Immunohistochemical analysis of the intestinal tumor specimen obtained by double balloon endoscopy showed a pattern similar to the brain tumor, with the tumors subsequently identified as intracranial metastases of jejunal GIST. After surgical resection of one brain tumor, the patient underwent whole brain radiation therapy followed by treatment with imatinib mesylate (Gleevec; Novartis Pharma, Basel, Switzerland). Mutational analysis of the original intestinal tumor revealed there were no gene alterations in KIT or PDGFRα. Since the results indicated the treatment had no apparent effect on either of the tumors, and because ileus developed due to an intestinal primary tumor, the patient underwent surgical resection of the intestinal lesion. However, the patient's condition gradually worsen and she subsequently died 4 months after the initial treatment

遠隔操作による西之島海底の溶岩採取装置の開発 : 「TAIRIKUプロジェクト」大陸生成の新しい仮説と西之島における検証

西之島は活発な火山活動を続けているため，周辺4kmの立ち入りが禁止されている．その海域の水深10mの海底から溶岩を採取するため，遠隔操作が可能な溶岩採取機器の開発に着手した．機器の構成を紹介し，手動による動作試験の結果を報告する． 西之島は、2013年11月に40年ぶりに爆発的な噴火がはじまり、2014年10月現在も噴火は衰えを見せておらず、最近になって専門家からは数年規模で噴火継続する可能性も指摘されている。西之島噴火による現在までの総噴出量は7,000万m3と推定され、東西1.6km、南北1.7kmの島へと成長したが、活発な噴火活動のための、西之島近海は立入りが禁止されており、今回の噴火による噴出物は採取されていない。 一方、40年前の噴火で発生した噴出物や溶岩は採取され、大陸を形成する安山岩であることが確認されており、「なぜ海洋のど真ん中で大陸地殻を構成する安山岩マグマが噴出するのか？」という問いが残されている。 仮説検証のためには、西之島近海の溶岩試料を採取することが必須であるが、前述のとおり、有人での調査は困難な状況にある。そこで、そのための解決策として、本共同研究により、東京海洋大学の保有する電気推進船「らいちょうI」を改造した、遠隔操作が可能な自航型無人作業艇を開発し、溶岩試料の採取を目指す。作業艇には、ドレッジ・採泥器等の各種機器・ウインチ等を搭載し、西之島近海、水深10m前後の海底から今回の噴火によって生じた溶岩試料を採取する。海洋理工学会平成27年度春季大会（2015年5月25日～26日, 東京海洋大学品川キャンパス

Pitavastatin suppresses diethylnitrosamine-induced liver preneoplasms in male C57BL/KsJ-db/db obese mice

<p>Abstract</p> <p>Background</p> <p>Obesity and related metabolic abnormalities, including inflammation and lipid accumulation in the liver, play a role in liver carcinogenesis. Adipocytokine imbalances, such as decreased serum adiponectin levels, are also involved in obesity-related liver tumorigenesis. In the present study, we examined the effects of pitavastatin - a drug used for the treatment of hyperlipidemia - on the development of diethylnitrosamine (DEN)-induced liver preneoplastic lesions in C57BL/KsJ-<it>db/db </it>(<it>db/db</it>) obese mice.</p> <p>Methods</p> <p>Male <it>db/db </it>mice were administered tap water containing 40 ppm DEN for 2 weeks and were subsequently fed a diet containing 1 ppm or 10 ppm pitavastatin for 14 weeks.</p> <p>Results</p> <p>At sacrifice, feeding with 10 ppm pitavastatin significantly inhibited the development of hepatic premalignant lesions, foci of cellular alteration, as compared to that in the untreated group by inducing apoptosis, but inhibiting cell proliferation. Pitavastatin improved liver steatosis and activated the AMPK-α protein in the liver. It also decreased free fatty acid and aminotransferases levels, while increasing adiponectin levels in the serum. The serum levels of tumor necrosis factor (TNF)-α and the expression of <it>TNF-α </it>and <it>interleukin-6 </it>mRNAs in the liver were decreased by pitavastatin treatment, suggesting attenuation of the chronic inflammation induced by excess fat deposition.</p> <p>Conclusions</p> <p>Pitavastatin is effective in inhibiting the early phase of obesity-related liver tumorigenesis and, therefore, may be useful in the chemoprevention of liver cancer in obese individuals.</p

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target