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

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

太陽風を利用した磁気プラズマセイル推進の推進特性に関する研究

低コストかつ短期間での太陽系探査を実現するための推進機の開発が現在進められており，いくつかの推進システムが提案されている．その１つの候補が太陽起源の超音速のプラズマ流である太陽風を，宇宙機に搭載したコイルの作る磁場とプラズマ流との干渉によって形成される磁気圏で受け止めることにより推進力を得る磁気プラズマセイル(MagnetoPlasma Sail:MPS)である．しかし，コイルの作る磁場だけで十分な推力を得るためには数十km という大きさのコイルが必要となり非現実的である．そこで，宇宙機からプラズマを噴射することにより磁気圏を拡大し，小さなコイルで大きな磁気圏を形成するアイデアが提案され，その研究が進められている．本研究では，MPS の実験的研究を行った．MPS の実験室実験はスケーリング則に基づいたスケールモデル実験を真空チャンバ内で実施するものであり，太陽風シミュレータと宇宙機を模擬したソレノイドコイル，磁気圏拡大用プラズマ源から構成される．太陽風シミュレータとして電磁プラズマ力学アークジェット(MPD-Arcjet: Magneto-Plasma Dynamic Arcjet）を採用するが，MPD アークジェットはこれまで推進機としての研究が主であり太陽風シミュレータのようなプラズマ風洞としての特性評価は行われていない．また，磁気圏拡大したMPS の全系試験を行うためにはこれまでより大口径のプラズマ流が要求され，非定常な推進特性や磁気圏拡大を行った場合の推力計測実験は地未実施のままである．地上試験では，磁気圏拡大は未だ計測されていない．磁気プラズマセイルの研究の最終目標はMPS の実用化である．その目標に向けて本研究では以下の3 つを目的とする．１．太陽風シミュレータのプラズマ風洞としての特性評価と大口径化２．磁気セイルの非定常推進特性の解明３．磁気プラズマセイルの磁気圏拡大の改善と推力特性評価本論文は10 章から構成され，各章は以下のように要約される．第１章は序論であり，本研究の背景として深宇宙探査の現状と過去の磁気プラズマセイルの研究を紹介している．第2 章は磁気プラズマセイルの基礎物理とスケーリング則について述べており，スケールモデル実験のパラメータ設計について述べている．第3 章は実験装置と計測システムについて記述し，各装置の特性を示している．第4 章では，単体動作の太陽風シミュレータのプラズマ風洞としての特性評価を記述している．ダブルプローブを用いて放電室近傍から遠方域までの広い領域でのプラズマ計測を実施しプラズマ流の構造を明らかにした．放電室近傍では1x1020 m-3，放電室から1250 mmの位置では1x1018 m-3 の数密度となり，放電室からの距離に対して-2 乗で減衰していた．また，放電室から500 mm の位置までには中心軸上に高温・高密度のカソードジェットと呼ばれる領域が存在するが，下流に行くに従い散逸していくプラズマ流の構造を明らかにした．放電室から750 mm以上の下流域ではφ600 mm以上の一様なプラズマ流となっているなど，磁気プラズマセイル用のプラズマ風洞としての要求性能を満たしていることを示した．また，非定常特性として，プラズマ流の変動の原因についての議論を行った．第5 章は磁気セイル実験の非定常特性について述べている．宇宙空間では太陽風は常に変動していることが知られており，太陽風を受けて進むMPS の非定常特性を把握することは不可欠である．磁場分布ならびに誘導電流分布の計測から磁気圏構造を調査し撮像結果との対応を明らかにした．その上で，磁気圏の変動は高速度カメラの撮像により得られた磁気圏の高速度動画より，磁気圏サイズの変動として評価した．本研究の実験条件では磁気圏サイズの変動は60 kHz の振動が支配的であるという結果が得られた．この振動数は，Alfven 波が磁気圏を伝わる時間に対応していることを明らかにした．以上の結果から，実機における推進性能の非定常特性を予測した．6 章では，磁気圏拡大試験を実施した．プラズマをコイル磁場の極方向，赤道方向にそれぞれ噴射しその時の磁気圏サイズを磁場計測によって同定した．結果として，極方向噴射では太陽風上流側へは明確な磁気圏拡大は計測されなかったが，極方向には150 mm から250 mm 以上へ大きく拡大していることが分かった．また，赤道方向噴射では太陽風上流方向に1.5 倍の推力増分に相当する磁気圏拡大を達成し，初めて明確な磁気圏拡大を実験的に示した．第7 章では，磁気圏拡大させたMPS をプラズマ流に収めるために模擬太陽風の大口径化を目的とし，3 台のMPD アークジェットを同時動作させる新型の太陽風シミュレータの開発とその特性評価について記述している．放電室から750 mm までは，プラズマ流が非均一であるが，1000 mm以上の下流域ではプラズマ流は1x1018 m-3 の数密度で一様になっており，これまでのφ600 mm からφ1200 mm 以上のプラズマ流径への大口径化を達成した．また，クラスター化したMPDアークジェットがプラズマ風洞としての要求条件を満たしていることを示した．第8 章では，第7 章で開発した3 台同時駆動太陽風シミュレータを用いて磁気プラズマセイルの推力計測を実施した．振り子式のスラストスタンドを用いて推力計測を行い，磁気圏拡大前に約0.09 N，磁気圏拡大後に約0.17 N の推力が計測され，最大1.9 倍の推力増分が得られた．この結果より，初めて磁気プラズマセイルの推力の増加が実証された．第9 章ではこれまでの章の結果について考察を行い，磁気プラズマセイルの推力特性評価ならびに今後の改善案について述べている．第10 章は結言として，本研究で得られた新しい結果を要約している．AbstractFor deep space exploration, a variety of spacecraft propulsion systems were proposed and some ofthem are under study. One of the next-generation interplanetary propulsion systems isMagnetoplasma Sail (MPS) capturing the solar wind energy by the magnetopshere. This thesis iswritten about the experimental study of MPS. However, in the case of MPS consisting of only a coil,the huge coil is required to obtain a high thrust level. The idea to expand the magnetosphere byplasma injection was proposed instead of employing a huge coil. This phenomenon is called asmagnetosphere inflation. To conduct a scale model experiment in a vacuum chamber, MPS groundsimulator consists of a solar wind simulator (SWS), a solenoid coil which simulated on MPSspacecraft and a plasma source for the magnetosphere inflation. We employ a Magneto-PlasmaDynamic (MPD) arcjet as the SWS, because the MPD arcjet can generate a high-velocity andhigh-density plasma jet. Previous studies of MPD arcjet concentrated on performance improvementas electric propulsion. Plasma jet characteristics evaluation of the MPD arcjet as a plasma windtunnel is remaining as an unresolved issue. In the previous researches of MPS, thrust measurementof MPS without plasma injection was conducted. In this study, the unsteady characteristics survey ofMPS and thrust measurement of MPS with plasma injection are conducted. Toward the final goal ofMPS study is practical realization, the purposes of this research are following three.1. Evaluation of the characteristics of the solar wind simulator plasma jet as a plasma tunnel withlarge test region2. Clarification of the unsteady characteristics of MPS without plasma injection3. Improvement of the magnetosphere inflation and thrust characteristics evaluation of MPS withplasma injectionThis thesis consists of 10 chapters, and each chapter is summarized as follows. Chapter 1 isintroduction. The current status of deep space exploration as background of this study and theprevious studies of MPS are introduced in this chapter. Chapter 2 describes the fundamental physicsand the scaling law of MPS. The design of the scale model experiment is stated in the last section ofthis chapter. Chapter 3 introduces the experimental system, the measurement system andcharacteristics of each device.Chapter 4 is described the characteristics evaluation of plasma jet of SWS. We measured theplume characteristics of the MPD arcjet such as electron temperature, electron density, velocity andfluctuation of the ion saturation current at several distances from the MPD arcjet by using a doubleprobe. The electron number density is 1×1020 m-3 near the MPD arcjet and is inversely proportionalto the square of the distance from the MPD arcjet. Although a high electron temperature (~5 eV) andthe high number density (~8 × 1019 m-3) region, so-called “cathode jet” is found along the centralaxis of the plasma plume close to the MPD arcjet. Moreover, the plasma plume radial profile isconstant in a downstream plume region (≥ 750 mm from the MPD arcjet). The plasma diameter isover φ600 mm. In addition, the unsteady characteristics of the plasma jet of SWS are discussed. Inthis chapter, it is indicated that the plasma jet of the MPD arcjet satisfies the requirement diameter asthe solar wind simulator of MPS experiment.Experimental result of the unsteady characteristics of MPS without plasma jet is shown in chapter5. In space, the solar wind and the interplanetary magnetic field are constantly fluctuating. It isnecessary that clarification of the unsteady characteristics of MPS by the external fluctuation.Structure of a magnetosphere was clarified from magnetic field distribution and current distribution.The fluctuation of the magnetospheric size is measured by the high speed camera. The dominantfrequency of 60 kHz of magnetospheric size fluctuation is measured in all experimental condition inthis study. This frequency is estimated by the propagating time of Alfven wave.The magnetosphere inflation experiment is in chapter 6. Plasma jet is injected in the direction of apole and the direction of the equator of the coil magnetic field, and the magnetospheric size wasidentified by magnetic field measurement. In the case of plasma injection in the pole direction, themagnetosphere inflation toward the upstream direction of the solar wind is not measured. However,the magnetosphere inflation in the polar direction is large. In the plasma injection of equatordirection, the increasing rate of the magnetospheric size of upstream direction of the solar wind isabout 1.23 which corresponds to 1.5 thrust increasing rate. Clear magnetosphere inflation ismeasured in laboratory experiment for the first time.In order to enlarge the test section of SWS, development of a new solar wind simulator with threesets of the MPD arcjets and characteristics evaluation of its plasma jet is described in chapter 7. Theplasma jet of the MPD arcjet became a constant plasma flow at a distance of 1250 mm from theMPD arcjets and the plasma diameter is over φ1200 mm. The plasma jet of the MPD arcjets withthree set is satisfying as the solar wind simulator of MPS experiment and enlargement of the testsection of a plasma jet was attained.In chapter 8, the thrust measurement of MPS with plasma injection using the new SWS in chapter7 is indicated. The thrust of about 0.09 N increased to about 0.17 N by magnetosphere inflation. Themaximum thrust increasing rate which is the ratio between the thrust with magnetosphere inflationand the thrust without magnetosphere inflation is 1.9 (rLi_inf/L=0.024 and βk=0.04: rLi_inf/L is the ratiobetween the ion Larmor radius at the magnetopause and the magnetospheric size). From this result,the increase in the thrust of MPS with plasma injection was proved for the first time in theexperiment.In Chapter 9, the consideration about the results in Chapter 4-8 and thrust characteristic evaluationof MPS are described. Chapter 10 describes the conclusion of this study