Somatic chromosomal translocation between Ewsr1 and Fli1 loci leads to dilated cardiomyopathy in a mouse model

A mouse model that recapitulates the human Ewing's sarcoma-specific chromosomal translocation was generated utilizing the Cre/loxP-mediated recombination technique. A cross between Ewsr1-loxP and Fli1-loxP mice and expression of ubiquitous Cre recombinase induced a specific translocation between Ewsr1 and Fli1 loci in systemic organs of both adult mice and embryos. As a result Ewsr1-Fli1 fusion transcripts were expressed, suggesting a functional Ews-Fli1 protein might be synthesized in vivo. However, by two years of age, none of the Ewsr1-loxP/Fli1-loxP/CAG-Cre (EFCC) mice developed any malignancies, including Ewing-like small round cell sarcoma. Unexpectedly, all the EFCC mice suffered from dilated cardiomyopathy and died of chronic cardiac failure. Genetic recombination between Ewsr1 and Fli1 was confirmed in the myocardial tissue and apoptotic cell death of cardiac myocytes was observed at significantly higher frequency in EFCC mice. Moreover, expression of Ews-Fli1 in the cultured cardiac myocytes induced apoptosis. Collectively, these results indicated that ectopic expression of the Ews-Fli1 oncogene stimulated apoptotic signals, and suggested an important relationship between oncogenic signals and cellular context in the cell-of-origin of Ewing's sarcoma

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

Impact of the Boreholes on the Surrounding Ground

The infrastructures that were constructed decades ago do not meet the present structural benchmark, and they need to be demolished. In order to reclaim these lands, the existing pile foundations must be removed; otherwise, the land will lose its value. Since the piles are pulled out, vacant spaces are created in the ground. This causes the surrounding ground to experience settlement, jeopardizing its stability. The degree of influence depends upon the number of boreholes, the saturated condition of the ground, the time period of the vacant condition, the presence of loading, etc. It is important to understand the scope of the probable settlement under various situations. This study focused on determining the amount of displacement and its range for three different saturated soil types under loaded and unloaded conditions using the finite element method (FEM) analysis. It was observed that stiff ground underwent maximum deformation, while soft ground experienced the maximum influence from external factors. Moreover, the presence of loading not only increased the displacement amount and range, but it also caused a change in the location of the maximum displacement

Influence of Perforated Soils on Installation of New Piles

In recent years, there has been an increasing demand to replace ancient structures. The removal of such structures also involves the removal of the existing piles that supported the structures, and the backfilling of the pulling-out holes that formed during the removal. However, there are no standard guidelines for the backfilling of pulling-out holes. At present, therefore, each owner or contractor must determine the material and the construction method to use for backfilling. This results in a difference between the mechanical properties of the original soil and those of the soil that has been backfilled, namely, the soil on which a newly built structure will be constructed. In this study, it was assumed that a new pile would be installed on a perforated soil (that is, the soil left after removing the existing piles) where the mechanical properties differ between the original soil and the backfilled soil. The behavior of the new pile, when installed on the boundary of a soil between two types of mechanical properties, was evaluated by a three-dimensional linear elastic analysis. When the new pile was installed at the boundary between the two types of soil with different mechanical properties, most of the new pile was inclined to the soil side where the N value was relatively small. However, the inclination of the new pile was able to be suppressed by increasing the distance from the boundary between the two types of soil

Influence of Perforated Soils on Installation of New Piles

In recent years, there has been an increasing demand to replace ancient structures. The removal of such structures also involves the removal of the existing piles that supported the structures, and the backfilling of the pulling-out holes that formed during the removal. However, there are no standard guidelines for the backfilling of pulling-out holes. At present, therefore, each owner or contractor must determine the material and the construction method to use for backfilling. This results in a difference between the mechanical properties of the original soil and those of the soil that has been backfilled, namely, the soil on which a newly built structure will be constructed. In this study, it was assumed that a new pile would be installed on a perforated soil (that is, the soil left after removing the existing piles) where the mechanical properties differ between the original soil and the backfilled soil. The behavior of the new pile, when installed on the boundary of a soil between two types of mechanical properties, was evaluated by a three-dimensional linear elastic analysis. When the new pile was installed at the boundary between the two types of soil with different mechanical properties, most of the new pile was inclined to the soil side where the N value was relatively small. However, the inclination of the new pile was able to be suppressed by increasing the distance from the boundary between the two types of soil

Numerical Analysis for Ground Subsidence Caused by Extraction Holes of Removed Piles

Around the world, and especially in Japan, the tearing down of social infrastructure, including civil engineering structures, has been increasing due to the aging of these constructions, which were built during a period of high economic growth, and a decrease in their utilization caused by a recent drop in the population. The number of existing pile foundations being pulled out has gradually risen to a higher number than that of pile foundations being newly installed. However, after the pulling-out of a pile foundation, the mechanical characteristics of the surrounding ground are of great concern due to the existence of the holes that form when the existing piles are removed (extraction holes). In this study, a three-dimensional elasto-plastic consolidation analysis was performed to examine the effect of the extraction holes of removed piles on the static properties of the surrounding ground. As examples of the results of the analysis, if an extraction hole of a removed pile is left as it is, large ground subsidence will occur near the extraction hole of removed pile, especially at the lower part of the clay layer near the hole. The greater the number of extraction holes of removed piles, the greater the compressive stress acting on the extraction holes after the pile removal. Therefore, the filler should exhibit strength early as the number of extraction holes of removed piles increases