2,904 research outputs found
The application of vascular immune organoids from human pluripotent stem cells in cancer immunotherapy and SARS-CoV-2 modeling
No full textOrganoid technology has advanced our understanding of development and disease models. Organoids derived from either human pluripotent stem cells or tissue stem cells offer us the amenable platform to genetically intervene in human organ development. The advance of genetic engineering and stem cell technology pushed the limit of what organoids can do. However, the current lack of both vasculatures and immune cells hinders the understanding of how vasculatures and immune cells regulate organ development as well as their role in pathologic conditions such as cancer and infection. We have previously established a unique organoid system from human pluripotent stem cells (Ohta et al., 2019; Sugimura et al., 2020, 2017). Followed by mesodermal patterning and hemato-endothelial specification with define factors, we achieved vascular immune organoids (VIOs). We identified the highly vascularized structure of VIOs. The repertoire of cells encompasses innate immune cells such as macrophages, neutrophils, erythroblasts, and NK cells, which demonstrated functional maturity. In this talk, we will share our recent efforts in i) engineering functional immune cells for cancer immunotherapy, ii) modeling vasculitis in SARS-CoV-2 infection. We propose that VIOs could further enhance the organoid technology in both cancer immunotherapy and SARS-CoV-2 modeling. References Ohta, R., Sugimura, R., Niwa, A., Saito, M.K., 2019. Hemogenic Endothelium Differentiation from Human Pluripotent Stem Cells in A Feeder- and Xeno-free Defined Condition. J. Vis. Exp. JoVE. https://doi.org/10.3791/59823 Sugimura, R., Jha, D.K., Han, A., Soria-Valles, C., da Rocha, E.L., Lu, Y.-F., Goettel, J.A., Serrao, E., Rowe, R.G., Malleshaiah, M., Wong, I., Sousa, P., Zhu, T.N., Ditadi, A., Keller, G., Engelman, A.N., Snapper, S.B., Doulatov, S., Daley, G.Q., 2017. Haematopoietic stem and progenitor cells from human pluripotent stem cells. Nature 545, 432–438. https://doi.org/10.1038/nature22370 Sugimura, R., Ohta, R., Mori, C., Li, A., Mano, T., Sano, E., Kosugi, K., Nakahata, T., Niwa, A., Saito, M.K., Torisawa, Y.-S., 2020. Biomimetic aorta-gonad-Mesonephros-on-a-Chip to study human developmental hematopoiesis. Biomed. Microdevices 22, 34. https://doi.org/10.1007/s10544-020-00488-
The application of vascular immune organoids from human pluripotent stem cells in cancer immunotherapy and SARS-CoV-2 modeling
No full textOrganoid technology has advanced our understanding of development and disease models. Organoids derived from either human pluripotent stem cells or tissue stem cells offer us the amenable platform to genetically intervene in human organ development. The advance of genetic engineering and stem cell technology pushed the limit of what organoids can do. However, the current lack of both vasculatures and immune cells hinders the understanding of how vasculatures and immune cells regulate organ development as well as their role in pathologic conditions such as cancer and infection. We have previously established a unique organoid system from human pluripotent stem cells (Ohta et al., 2019; Sugimura et al., 2020, 2017). Followed by mesodermal patterning and hemato-endothelial specification with define factors, we achieved vascular immune organoids (VIOs). We identified the highly vascularized structure of VIOs. The repertoire of cells encompasses innate immune cells such as macrophages, neutrophils, erythroblasts, and NK cells, which demonstrated functional maturity. In this talk, we will share our recent efforts in i) engineering functional immune cells for cancer immunotherapy, ii) modeling vasculitis in SARS-CoV-2 infection. We propose that VIOs could further enhance the organoid technology in both cancer immunotherapy and SARS-CoV-2 modeling. References Ohta, R., Sugimura, R., Niwa, A., Saito, M.K., 2019. Hemogenic Endothelium Differentiation from Human Pluripotent Stem Cells in A Feeder- and Xeno-free Defined Condition. J. Vis. Exp. JoVE. https://doi.org/10.3791/59823 Sugimura, R., Jha, D.K., Han, A., Soria-Valles, C., da Rocha, E.L., Lu, Y.-F., Goettel, J.A., Serrao, E., Rowe, R.G., Malleshaiah, M., Wong, I., Sousa, P., Zhu, T.N., Ditadi, A., Keller, G., Engelman, A.N., Snapper, S.B., Doulatov, S., Daley, G.Q., 2017. Haematopoietic stem and progenitor cells from human pluripotent stem cells. Nature 545, 432–438. https://doi.org/10.1038/nature22370 Sugimura, R., Ohta, R., Mori, C., Li, A., Mano, T., Sano, E., Kosugi, K., Nakahata, T., Niwa, A., Saito, M.K., Torisawa, Y.-S., 2020. Biomimetic aorta-gonad-Mesonephros-on-a-Chip to study human developmental hematopoiesis. Biomed. Microdevices 22, 34. https://doi.org/10.1007/s10544-020-00488-
ALKBH1-regulated 6mA DNA methylation affects human lineage segregation via TGF-[beta]-signalling pathway
No full textDNA methylation is a critical epigenetic modification that regulates various biological processes, including cancer, neurodegeneration, and embryogenesis. While 5-methylcytosine (5mC) has been extensively studied in eukaryotes, the prevalence of 6-methyladenine (6mA) methylation in prokaryotes has attracted attention. Recent advancements in detection methods and high-throughput sequencing have enabled the identification of 6mA methylation signals in eukaryotes, leading to increased research into its role in mammalian cells.
In 2016, the presence of 6mA modification in mammalian stem cells was discovered, even in low abundance within mouse embryonic stem cells (mESCs). This finding highlighted the enrichment of 6mA signals in young LINE1 elements and emphasized the impact of the ALKBH1 demethylase on stemness maintenance and differentiation potential in mESCs. Subsequent studies aimed to unravel additional regulators of 6mA DNA methylation and elucidate its role in mammals.
During early development, 6mA exhibited dynamic patterns, with initial upregulation preceding the pre-implantation phase and subsequent downregulation after the blastocyst stage. This temporal pattern was conserved in zebrafish and pigs, suggesting the evolutionary importance of 6mA. Furthermore, genomic regions displaying 6mA signals often overlapped with histone H3, indicating intricate interactions with other epigenetic markers.
Depletion of ALKBH1 and subsequent accumulation of 6mA signals hindered the differentiation of mouse ESCs into trophoblast-like cells, providing an epigenetic explanation for impaired placental development. To investigate the regulatory mechanisms of 6mA in human stem cells, researchers utilized human expanded potential stem cells (hEPSCs) as an in vitro model for trophoblast differentiation. The study aimed to uncover the mechanisms and shed light on the role of 6mA in early human embryonic development.
The study disrupted ALKBH1's demethylase activity in hEPSCs using the CRISPR-Cas9 system, resulting in increased 6mA signals compared to untargeted cells. ALKBH1 knockout led to downregulation of SMAD2 and SMAD4 protein levels, reduced phosphorylation of the SMAD2/3 protein, and downregulation of STOX2 at the transcriptional level. These findings highlighted ALKBH1's role in modulating the TGF-β-signaling pathway through 6mA levels.
Changes in ALKBH1 expression significantly affected trophoblast and hematopoietic differentiation during cell fate determination. The absence of ALKBH1 hindered these processes, underscoring its importance in regulating developmental pathways. Treatment of ALKBH1 knockout cells with Activin A, an activator of the TGF-β-signaling pathway, partially rescued the observed phenotype, reinforcing the connection between ALKBH1, 6mA regulation, and the TGF-β-signaling pathway in shaping cell fate during early embryonic development. These discoveries provide insights into the molecular mechanisms of 6mA-mediated epigenetic regulation and its significance in coordinating cellular processes during early embryogenesis.published_or_final_versionBiomedical SciencesMasterMaster of Philosoph
Author Co-Citation Analysis (ACA): a powerful tool for representing implicit knowledge of scholar knowledge workers
No full textIn the last decade, knowledge has emerged as one of the most important and valuable organizational assets. Gradually this importance caused to emergence of new discipline entitled ―knowledge management‖. However one of the major challenges of knowledge management is conversion implicit or tacit knowledge to explicit knowledge. Thus Making knowledge visible so that it can be better accessed, discussed, valued or generally managed is a long-standing objective in knowledge management. Accordingly in this paper author co- citation analysis (ACA) will be proposed as an efficient technique of knowledge visualization in academia (Scholar knowledge workers)
Analysis of MicroRNA Expression in Embryonic Developmental Toxicity Induced by MC-RR
No full textAs cynobacterial blooms frequently occur in fresh waters throughout the world, microcystins (MCs) have caused serious damage to both wildlife and human health. MCs are known to have developmental toxicity, however, the possible molecular mechanism is largely unknown. This is the first toxicological study to integrate post-transcriptomic, proteomic and bioinformatics analysis to explore molecular mechanisms for developmental toxicity of MCs in zebrafish. After being microinjected directly into embryos, MC-RR dose-dependently decreased survival rates and increased malformation rates of embryos, causing various embryo abnormalities including loss of vascular integrity and hemorrhage. Expressions of 31 microRNAs (miRNAs) and 78 proteins were significantly affected at 72 hours post-fertilisation (hpf). Expressions of miR-430 and miR-125 families were also significantly changed. The altered expressions of miR-31 and miR-126 were likely responsible for the loss of vascular integrity. MC-RR significantly reduced the expressions of a number of proteins involved in energy metabolism, cell division, protein synthesis, cytoskeleton maintenance, response to stress and DNA replication. Bioinformatics analysis shows that several aberrantly expressed miRNAs and proteins (involved in various molecular pathways) were predicted to be potential MC-responsive miRNA-target pairs, and that their aberrant expressions should be the possible molecular mechanisms for the various developmental defects caused by MC-RR
The proteomic study on cellular responses of the testes of zebrafish (Danio rerio) exposed to microcystin-RR
No full textMicrocystin-RR (MC-RR) is a commonly encountered cyanotoxin and receives increasing attention due to the risk of its bioaccumulation in aquatic animals like fish. This study investigated the protein profiles of zebrafish (Danio rerio) testes after intraperitoneal injection (i.p.) with 0.5 LD50 (2000 mu g/kg). MC-RR caused a noticeable damage to testicular ultrastructure, showing widened intercellular junction, distention of mitochondria. The testes showed a rapid response of its defense systems to the oxidative stress caused by MC-RR. This is the first to use a proteomic approach to obtain an overview of the effects of MC-RR on the testes of zebrafish. The proteomic results revealed that toxin exposure remarkably altered the abundance of 24 proteins that were involved in cytoskeleton assembly, oxidative stress, glycolysis metabolism, calcium ion binding and other biological functions. In conclusion, MC-RR damaged the testes and was toxic to the reproductive system of male zebrafish mainly through causing oxidative stress.Microcystin-RR (MC-RR) is a commonly encountered cyanotoxin and receives increasing attention due to the risk of its bioaccumulation in aquatic animals like fish. This study investigated the protein profiles of zebrafish (Danio rerio) testes after intraperitoneal injection (i.p.) with 0.5 LD50 (2000 mu g/kg). MC-RR caused a noticeable damage to testicular ultrastructure, showing widened intercellular junction, distention of mitochondria. The testes showed a rapid response of its defense systems to the oxidative stress caused by MC-RR. This is the first to use a proteomic approach to obtain an overview of the effects of MC-RR on the testes of zebrafish. The proteomic results revealed that toxin exposure remarkably altered the abundance of 24 proteins that were involved in cytoskeleton assembly, oxidative stress, glycolysis metabolism, calcium ion binding and other biological functions. In conclusion, MC-RR damaged the testes and was toxic to the reproductive system of male zebrafish mainly through causing oxidative stress
So Tom has turned a poet, what a dear [first line]
No full textstrophicnasame as Box 192 Item 50Cover is duplicated in 192.050.
Music is duplicated in 192.050.Johns Hopkins University, Levy Sheet Music Collection, Box
192, Item 051Thomas M-rr-s, Author of "How They Act in Baltimore." "Mephistophiles K.G.S.
So Tom has turned a poet, what a dear [first line]
No full textstrophicnasame as Box 192 Item 50Cover is duplicated in 192.050.
Music is duplicated in 192.050.Johns Hopkins University, Levy Sheet Music Collection, Box
192, Item 051Thomas M-rr-s, Author of "How They Act in Baltimore." "Mephistophiles K.G.S.
So Tom has turned a poet, what a dear [first line]
No full textstrophicnaCover is duplicated in 192.051.
Music is duplicated in 192.051.Johns Hopkins University, Levy Sheet Music Collection, Box
192, Item 050Thomas M-rr-s, Author of "How They Act in Baltimore." "Mephistophiles K.G.S.
So Tom has turned a poet, what a dear [first line]
No full textstrophicnaCover is duplicated in 192.051.
Music is duplicated in 192.051.Johns Hopkins University, Levy Sheet Music Collection, Box
192, Item 050Thomas M-rr-s, Author of "How They Act in Baltimore." "Mephistophiles K.G.S.
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