Bone marrow transplantation improves outcome in a mouse model of congenital muscular dystrophy

AbstractWe examined whether pathogenesis in dystrophin-deficient (mdx) mice and laminin-α2-deficient (dy) mice is ameliorated by bone marrow transplantation (BMT). Green fluorescent protein (GFP) mice were used as donors. In mdx mice, BMT failed to produce any significant differences in muscle pathology, although some GFP-positive fibers with restored dystrophin expression were observed. In contrast, in the dy mice, BMT led to a significant increase in lifespan and an increase in growth rate, muscle strength, and respiratory function. We conclude that BMT improved outcome in dy mice but not mdx mice

Efficient Assay for Total Antioxidant Capacity in Human Plasma Using a 96-Well Microplate

In the present study, we tried to establish an efficient assay for total antioxidant capacity (TAC) in human plasma using a 96-well microplate. TAC was assessed using lag time by antioxidants against the myoglobin-induced oxidation of 2,2'-azino-di(3-ethylbenzthiazoline-6-sulfonic acid (ABTS) with hydrogen peroxide, and expressed as Trolox equivalent. The linearity of the calibration curve with Trolox was maintained with the Trolox concentration range from 2.5 µM to 25 µM (R2 = 0.997). The assay was applied to the measurement of TAC in healthy human plasma. Coefficient of variation in intraday assay was 2.4%. Difference was not observed in interday assay. Plasma TAC of men ((569 ± 41) µM Trolox equivalent; n = 6) was higher than that of women ((430 ± 28) µM Trolox equivalent; n = 4). After the vegetable juice was drunk for 1 week, the increase in plasma TAC was observed in almost all the volunteers. In summary, we developed the efficient assay for plasma TAC using a 96-well microplate

Sutimlimab suppresses SARS-CoV-2 mRNA vaccine-induced hemolytic crisis in a patient with cold agglutinin disease

Cold agglutinin disease (CAD) is a rare form of acquired autoimmune hemolytic anemia driven mainly by antibodies that activate the classical complement pathway. Several patients with CAD experience its development or exacerbation of hemolysis after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or after receiving the SARS-CoV-2 mRNA vaccine. Therefore, these patients cannot receive an additional SARS-CoV-2 mRNA vaccination and have a higher risk of severe SARS-CoV-2 infection. Sutimlimab is a monoclonal antibody that inhibits the classical complement pathway of the C1s protein and shows rapid and sustained inhibition of hemolysis in patients with CAD. However, whether sutimlimab could also inhibit hemolysis caused by SARS-CoV-2 mRNA vaccination is uncertain. Here, we present the case of a 70-year-old man with CAD who repeatedly experienced a hemolytic crisis after receiving SARS-CoV-2 mRNA vaccines. The patient eventually underwent SARS-CoV-2 mRNA vaccination safely, without hemolytic attack, under classical pathway inhibition therapy with sutimlimab. This report suggests that appropriate sutimlimab administration can suppress SARS-CoV-2 mRNA vaccination-induced CAD exacerbation, and that it could be a preventive strategy to minimize hemolytic attacks in susceptible populations

Mice with defects in HB-EGF ectodomain shedding show severe developmental abnormalities

Heparin-binding EGF-like growth factor (HB-EGF) is first synthesized as a membrane-anchored form (proHB-EGF), and its soluble form (sHB-EGF) is released by ectodomain shedding from proHB-EGF. To examine the significance of proHB-EGF processing in vivo, we generated mutant mice by targeted gene replacement, expressing either an uncleavable form (HBuc) or a transmembrane domain–truncated form (HBΔtm) of the molecule. HBuc/uc mice developed severe heart failure and enlarged heart valves, phenotypes similar to those in proHB-EGF null mice. On the other hand, mice carrying HBΔtm exhibited severe hyperplasia in both skin and heart. These results indicate that ectodomain shedding of proHB-EGF is essential for HB-EGF function in vivo, and that this process requires strict control

A Report on Overseas Teaching Practicum by Graduate Students in Elementary/Secondary Schools in the United States (IX)

This short paper reports on the 9th overseas teaching practicum in the United States by 12 graduate students of Hiroshima University, Japan, partly organized by Hiroshima University Global Partnership School Center (GPSC). The grand total has become 89 since this project started in 2006. The participants this year were those majoring in elementary/secondary school education, including one in-service teacher. They observed and conducted lessons in English in four local public schools in North Carolina. The aim of this project was threefold: 1) to self-develop practical instructional competence by teaching pupils with different cultural backgrounds; 2) to enhance the abilities in developing teaching materials through hands-on teaching experiences in English; and 3) to acquire the abilities to design, implement and evaluate programs for promoting global partnership. Like past years, their teachings were very positively covered by the local newspapers and websites. Later, the project was followed by cross-cultural field study visits to NC State Capitol, Raleigh and the U.S. Capitol, Washington, D.C. It is hoped that this intensive experience overseas will broaden the young future Japanese teachers’ global awareness and confidence in teaching

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