Development of an oxygen-sensitive degradable peptide probe for the imaging of hypoxia-inducible factor-1-active regions in tumors.

[Purpose]We aimed to develop a radiolabeled peptide probe for the imaging of hypoxia-inducible factor-1 (HIF-1)-active tumors. [Procedures]We synthesized the peptide probes that contain or lack an essential sequence of the oxygen-dependent degradation of HIF-1α in proteasomes ([123/125]I-DKOP30 or [125]I-mDKOP, respectively). The degradation of probes was evaluated in vitro using cell lysates containing proteasomes. In vivo biodistribution study, planar imaging, autoradiography, and comparison between probe accumulation and HIF-1 transcriptional activity were also performed. [Results]The [125]I-DKOP30 underwent degradation in a proteasome-dependent manner, while [125]I-mDKOP was not degraded. Biodistribution analysis showed [125]I-DKOP30 accumulation in tumors. The tumors were clearly visualized by in vivo imaging, and intratumoral distribution of [125]I-DKOP30 coincided with the HIF-1α-positive hypoxic regions. Tumoral accumulation of 125I-DKOP30 was significantly correlated with HIF-1-dependent luciferase bioluminescence, while that of [125]I-mDKOP was not. [Conclusion] [123]I-DKOP30 is a useful peptide probe for the imaging of HIF-1-active tumors

Hansenʼs Disease Reflected by Literature Consider “discrimination” and “segregation” at Hansenʼs disease through Sherlock Holmesʼ The Blanched Soldier.

　2020年４月，日下喬史川崎医科大名誉教授が逝去された。日下先生は，同大学生化学教室の教授として長らく本学の医学教育にご尽力された一方，ご専門のハンセン病の研究でも優れた功績を残された。「ハンセン病」は，人類が経験してきた感染症として，コロナ禍の今（2020年９月），その歴史にまた新たな光が当たっている。そこで，本稿では主にハンセン病の「差別」や「隔離」の歴史に焦点を当て考察した。　まず，主に20世紀の日本におけるハンセン病の差別の歴史を簡潔に振り返り，その一方で差別を克服するための一例として，名称の変更を取り上げた。具体的には，シャーロック・ホームズシリーズの短編『白面の兵士』に言及し，文学と差別的表現との複雑な関係性について考察した。次に，強制的な隔離政策について言及し，その背景に「疎外の理論」があったことを述べた。最後に，『癩者へ』という詩を紹介し，内省のきっかけとするものである。本稿は，日下先生への追悼であるとともに，特に若い世代とハンセン病に関する考察を共にする機会になればと考える。　In April 2020, Department of Biochemistry received the sad news that Honorary professor Kusaka Takashi had passed away. As a professor at Department of Biochemistry at Kawasaki Medical School, he had not only contributed a great deal to medical education but also succeeded in identifying lipid component which is specific to the Mycobacterium leprae in Hansenʼs disease and revealed its chemical structure.　Speaking of Hansenʼs disease, as one of infections which afflicted humanity, its history has come to draw some degree of attention again since our facing the difficulties of the Covid-19 in 2020. In this paper, first I introduce the history of discrimination against Hansenʼs disease and then refer to the transition of the term from “leprosy” to “Hansenʼs disease” by way of example to eliminate the discrimination註1). Specifically, I develop the argument citing Sherlock Holmesʼ The Blanched Soldier (1927), which story is related to “Hansenʼs disease” and includes some discriminatory expressions against the patients. This consideration reveals what relationship there is between literature and the discriminatory expressions.　Next, I deal with the compulsory segregation policy, which started around 1930 in Japan and but was not abolished even after the WW2. Behind such national neglectfulness was so-called “theory to eliminate the weak”, which means the patientsʼ human rights were relatively disrespected in favor of the more immediate needs of rapid economic growth. Last, I quote a poem composed by Kamiya Mieko in 1943 in order to expect to help us introspect to our own minds. Here, I would like to pay my final respect to Honorary professor Kusaka Takashi and share the opportunity to think the history of Hansenʼs disease especially with the younger generation

Hungarian Biochemists

　ハンガリーの生化学研究のルーツは，20世紀初頭にまで遡る。ビタミンC を発見したセント＝ジェルジ，筋収縮に関わるタンパク質アクチンを発見したシュトラウブ，タンパク質－リガンド相互作用に関する「ゆらぎの適合」の概念を提示したサボルチなど，彼らの発見はどれも生化学の歴史において重要である。ところが，その功績によってノーベル医学生理学賞を受賞したセント＝ジェルジを除いて，それ以降のシュトラウブやサボルチの研究成果は，正当な評価が得られているとは言い難い。　こうした研究成果の埋没には，ハンガリーが東欧諸国として20世紀に歩んだ苦難の歴史が背景としてあるのだろう。地政学的にもハンガリーは，20世紀前半には破竹の勢いのあるドイツ，そして後半は共産圏の長として超大国となったソ連との関係性において暗い時代を経験した。　本稿では，こうした苦難の時代を過ごした生化学者を，特にシュトラウブに焦点を当てて紹介する。Ｆ・ブルノ・シュトラウブは，一人の優れた生化学者として研究成果を残した一方で，共産主義体制の中で科学の発展や国の未来のために尽力した人物である。その活動の領域は，1989年というハンガリーにとって鉄のカーテンからの夜明けを意味する年には，国家元首を務めるまで広がっていた。本稿では，ハンガリーの近代史を簡潔に振り返りながら，東欧諸国の厳しい時代や，そうした状況下でもそれぞれの道を真摯に貫いた科学者たちの軌跡をたどる。　The roots of Hungarian biochemical research go back to the early 20th century. Albert Szent-Györgyi discovered vitamin C; F. Brunó Straub discovered actin, a protein involved in muscle contraction; Gertrúd Szabolcsi proposed the concept of‘fluctuation fit’as protein-ligand interactions all these scientists made discoveries indispensable to the later development of history of biochemistry. But while in 1937 Szent-Györgyi was awarded the Nobel Prize in Physiology or Medicine, the achievements of the other biochemists did not receive due evaluation. 　The burial of these achievements can be ascribed to the difficult situation in which Hungary, as an Eastern European country, was placed. Geopolitically, Hungary experienced a dark period in its relationship with Nazi-Germany in the first half of the 20th century, and in the latter half of the century with the Soviet Union, the superpower which played the leading role in the East’santagonism to the West.　This article portrays the biochemists who lived through these difficult times, with a particular focus on F. Brunó Straub. Straub was an outstanding biochemist who tried to promote research under the communist regime and contributed to the development of science of the country. The range of his activities was expanded to the politics in the years 1988 and 1989; he was then the last head of the old state, and, with the fall of the Iron Curtain, people saw the dawn of a new era for Hungary. This was a critical moment in the modern history of Hungary, of which a brief account is given in this article; also the pursuits of scientists are described here the scientists who faithfully fulfilled their respective lives even in the hardships they suffered

Nature 誌へのある科学者の書簡を読み直す : テロの21世紀と科学者のアイデンティティに思うこと

　2001年9月11日，アメリカ同時多発テロが発生すると，その衝撃に科学界を含めた世界中から声明が寄せられた。中でもNature誌に掲載された一通の書簡には，科学に携わる者にとって考えさせられるものがあった。「科学は普遍的であり，いかなる宗教の一部でもない」とタイトルされたこの書簡の著者は，イスラエルの生化学者Edgar Pick。彼は，およそ2か月前の同誌Natureに編集部の見解として既に掲載されていたOpinion articleに対して，批判的な書簡を投稿したのである。　20年近く経てなお，テロの脅威が一向に減じることのない現在，このピック書簡を読み直すことは，一定の価値があるように思われる。したがって本稿では，主にピック書簡の紹介を通して彼の主張を考察する。その過程で，元となったオピニオン記事の概要を示したり，E・W・サイードやブッシュ大統領（当時）の言葉を引用したりすることによって，ピック書簡の解釈に普遍性を見出す。こうした回想の機会を共有することが，科学に携わる者としての在り方に想いを致す，そのきっかけに資することを期待するものである。　Unfortunately, the September 11 attacks were a symbolic event for the dawn of the new century. The impact of the terror attacks on the scientific societies forced some scientists to express their thoughts openly. Among those statements was a Correspondence published in Nature, to which I was attracted at the time. The author was Edgar Pick, a famous biochemist at Sacker School of Medicine, Tel Aviv University in Israel. He replied sharply to an Opinion article “Fighting against terrorism, engaging with Islamic science", which had been published soon after the attacks, 20 September, in the same journal.　Now, about 20 years after the event, most people still agree that the terrorism is not only the worldwide problem but also the urgent one. Under such circumstances, as one of those engaged with science, what action or inaction could you take? Clearly, this is not a simple matter, but to be worth considering. On this paper I introduce and re-read the Pick Correspondence, titled “Science is Universal, not part of any religion". Specifically, first I refer to the chemical terrorism ever happened in Japan, next I introduce the Pick Correspondence by translating it into Japanese, then outline the Opinion article, and lastly give my overall opinion on the subject. I would like to share the opportunity to keep questioning the matter

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