First-cycle oscillation excursions of Pickering-stabilised microbubbles subjected to a high-amplitude ultrasound pulse

publishedVersionPeer reviewe

On the rigidity of four hundred Pickering-stabilised microbubbles

This study explores the rigidity of Pickering-stabilised microbubbles subjected to low-amplitude ultrasound. Such microbubbles might be suitable ultrasound contrast agents. Using an adapted Rayleigh-Plesset equation, we modelled the dynamics of microbubbles with a 7.6-N m-1 shell stiffness under 1-MHz, 0.2-MPa sonication. Such dynamics were observed experimentally, too, using high-speed photography. The maximum expansions were agreeing with those predicted for Pickering-stabilised microbubbles. Subjecting microbubbles to multiple time-delayed pulses yielded the same result. We conclude that Pickering-stabilised microbubbles remain very stable at low acoustic amplitudes.acceptedVersionPeer reviewe

Novel Calcium-Binding Ablating Mutations Induce Constitutive RET Activity and Drive Tumorigenesis

がんゲノム医療のさらなる拡大へ向けた一歩 --コンピュータ解析で意義不明変異のなかに治療標的となる新たな遺伝子変異を発見--. 京都大学プレスリリース. 2022-09-29.Distinguishing oncogenic mutations from variants of unknown significance (VUS) is critical for precision cancer medicine. Here, computational modeling of 71, 756 RET variants for positive selection together with functional assays of 110 representative variants identified a three-dimensional cluster of VUSs carried by multiple human cancers that cause amino acid substitutions in the calmodulin-like motif (CaLM) of RET. Molecular dynamics simulations indicated that CaLM mutations decrease interactions between Ca²⁺ and its surrounding residues and induce conformational distortion of the RET cysteine-rich domain containing the CaLM. RET-CaLM mutations caused ligand-independent constitutive activation of RET kinase by homodimerization mediated by illegitimate disulfide bond formation. RET-CaLM mutants possessed oncogenic and tumorigenic activities that could be suppressed by tyrosine kinase inhibitors targeting RET. This study identifies calcium-binding ablating mutations as a novel type of oncogenic mutation of RET and indicates that in silico–driven annotation of VUSs of druggable oncogenes is a promising strategy to identify targetable driver mutations

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

Questionnaire survey of the occupants of high-rise residential buildings in Sapporo after the 2018 Hokkaido Eastern Iburi Earthquake

In this study, a resident questionnaire survey was conducted for three reinforced-concrete high-rise condominium buildings in Sapporo. All three were subjected to the 2018 Hokkaido Eastern Iburi Earthquake. Resident experiences of shaking and damage due to the earthquake, the seismic measures taken before and after the earthquake, and conditions during the long-term blackout were evaluated by the survey. Resident anxiety and their difficulty in taking actions due to the shaking were relatively small, because the ground motions input to the buildings were not very large. The long-term power outage due to the earthquake had a great impact on the occupants. Particularly, the inability to use elevators caused a great inconvenience to the residents of higher floors, making it difficult for them to leave their dwelling units. Each of the three buildings was equipped with an emergency power supply; however, differences in the operation methods of these supplies affected the convenience of the occupants during the power outage. The inconvenience and anxiety caused by the shaking and the power outage left a strong impression on the residents. This may have resulted in motivation to make further earthquake preparations, such as stockpiling of flashlights, lanterns, food, and water, after the complex disaster

Ultrasound homogenises suspensions of hydrophobic particles

International audienc

Nucleation threshold of carbon black ultrasound contrast agent

Most ultrasound contrast agents used in ultrasonic imaging comprise shell-encapsulated microbubbles, whose ingredients have been associated with adverse bioeffects. In this study, we investigated the nucleation behaviour of carbon black dispersion, whose hydrophobic nanoparticles are used intradermally. For a hypothetical, perfectly spherical carbon black particle surrounded by a perfectly spherical gaseous void, we derived a theoretical nucleation threshold of only 1.3× the resting radius. Carbon black particles and aggregates thereof were investigated using high-speed photography during 1.0 MHz sonication. The nucleation threshold found experimentally is lower than the Blake cavitation threshold of 2.0 the resting radius of free, unencapsulated microbubbles. Therefore, carbon black dispersion may be a promising ultrasound contrast agent.acceptedVersionPeer reviewe