Visualization of spatiotemporal activation of Notch signaling: Live monitoring and significance in neural development

AbstractNotch signaling plays various key roles in cell fate determination during CNS development in a context-dependent fashion. However, its precise physiological role and the localization of its target cells remain unclear. To address this issue, we developed a new reporter system for assessing the RBP-J-mediated activation of Notch signaling target genes in living cells and tissues using a fluorescent protein Venus. Our reporter system revealed that Notch signaling is selectively activated in neurosphere-initiating multipotent neural stem cells in vitro and in radial glia in the embryonic forebrain in vivo. Furthermore, the activation of Notch signaling occurs during gliogenesis and is required in the early stage of astroglial development. Consistent with these findings, the persistent activation of Notch signaling inhibits the differentiation of GFAP-positive astrocytes. Thus, the development of our RBP-J-dependent live reporter system, which is activated upon Notch activation, together with a stage-dependent gain-of-function analysis allowed us to gain further insight into the complexity of Notch signaling in mammalian CNS development

Traditional Japanese Kampo Medicine: Clinical Research between Modernity and Traditional Medicine—The State of Research and Methodological Suggestions for the Future

The Japanese traditional herbal medicine, Kampo, has gradually reemerged and 148 different formulations (mainly herbal extracts) can be prescribed within the national health insurance system. The objective of this article is to introduce Kampo and to present information from previous clinical studies that tested Kampo formulae. In addition, suggestions on the design of future research will be stated. The literature search was based on a summary, up until January 2009, by the Japanese Society of Oriental Medicine and included only those trials which were also available in either Pubmed or ICHUSHI (Japan Medical Abstracts Society). We included 135 studies, half of these studies (n = 68) used a standard control and 28 a placebo control. Thirty-seven trials were published in English [all randomized controlled trials (RCTs)] and the remaining articles were in Japanese only. The sample size for most studies was small (two-third of the studies included less than 100 patients) and the overall methodological quality appeared to be low. None of the studies used Kampo diagnosis as the basis for the treatment. In order to evaluate Kampo as a whole treatment system, certain aspects should be taken into account while designing studies. RCTs are the appropriate study design to test efficacy or effectiveness; however, within the trial the treatment could be individualized according to the Kampo diagnosis. Kampo is a complex and individualized treatment with a long tradition, and it would be appropriate for further research on Kampo medicine to take this into account

From Russia to Eurasia: Specific Features of the “Russosphere” from the Perspective of Business Activities of Japanese Firms

In this paper, we demonstrate the trends and prospects of Japanese foreign direct investment (FDI) in European Emerging Markets (EEMs) against the background of the recent development of emerging markets and explore the specificities of the Russian market, the biggest EEM in terms of market size and inward FDI received. More specifically, we give an overview of foreign capital flows from Japan to major EEMs and describe the achievements and problems of Japanese investors as related to business with Russia We find that the Russian market seems to be a lucrative option for Japanese firms, despite unfavorable investment conditions and limited institutional freedom afforded to outsiders, including a language barrier due to the wide usage of Russian in the business field. Although use of the Russian language is one of major business obstacles affecting foreign investors, making matters more challenging in the country, it nonetheless provides us with a common language as a hub of business operations in the former Soviet Union countries or "Russosphere," where Russia has still economic leverage and maintains cultural domination.This research was financially supported by a Nihon University Research Subsidy (FY2014), the Kansai University Subsidy for Supporting Young Scholars (FY2015–16), the Joint Research Program of the Japan Arctic Research Network Center of Hokkaido University (FY2017), and a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science & Technology of Japan (No.17H04553: FY2017–19)2015年度関西大学若手研究者育成経

マウスリンパ組織のレプチンレセプター発現細胞の検出

Leptin, the product of the ob gene expressed in adipocytes, is shown to influence energy intake and expenditure, proliferation of CD^ T cells, neovascularization and intracellular triglycerides homeostasis in non-adipocytes. Leptin acts on target cells through receptor (OB-R). There are at least five different types of OB-R in mouse due to alternative splicing from db gene transcripts.OB-Ra〜OB-Rd share identical extracellular and transmembrane domains and JAK binding consensus sequence at cytoplasmic domain. Only OB-Rb has an additional STAT binding motif and is essential for most of leptin' s physiological functions through JAK-STAT pathway. OB-Ra is also reported to transduct weakly leptin's signal through JAK-phospholyration pathway. On this paper we examined which kinds of cell express OB-Ra or OB-Rb in lymphoid and fat tissues of the mouse. Both types of OB-R were detected in thymus, spleen and gastrolienal fat tissue by RTPCR method, then the constitutive cells were separated from dissected tissues and cultured in GIT medium with 10% heat-inactivated FBS. Primary cultured lymphocytes isolated from thymus or spleen expressed both OB-Ra and OB-Rb. On the other hand, in adhesive cells dispersed with enzymatic digestion and primary cultured OB-Rb was not detected, though OB-Ra detectable.Similarly, primary cultured adhesive cells of gastrolienal fat tissue expressed only OB-Ra. It is therefore most parsimonious to conclude that only lymphocytes express OB-Rb and response effectively to leptin in thymus

A case of thrombotic thrombocytopenic purpura induced by acute pancreatitis

Thrombotic thrombocytopenic purpura (TTP) is a multisystemic microvascular disorder that may be caused by an imbalance between unusually large von Willebrand factor multimers and the cleaving protease ADAMTS13. In acquired TTP, especially in secondary TTP with various underlying diseases, the diagnosis is difficult because there are many cases that do not exhibit severe deficiency of ADAMTS13 or raised levels of ADAMST13 inhibitors. It is well known that collagen disease, malignancy, and hematopoietic stem cell transplantation can be underlying conditions that induce TTP. However, TTP induced by acute pancreatitis, as experienced by our patient, has rarely been reported. Our patient completely recovered with treatments using steroids and plasma exchange (PE) only. In cases where patients develop acute pancreatitis with no apparent causes for hemolytic anemia and thrombocytopenia, the possibility of TTP should be considered. Treatments for TTP including PE should be evaluated as soon as a diagnosis is made

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