Silencing of p53 and CDKN1A establishes sustainable immortalized megakaryocyte progenitor cells from human iPSCs

iPS細胞を用いた人工血小板の作製の効率化に成功 血小板のテイラーメイド医療に向けた一歩. 京都大学プレスリリース. 2021-12-03.Platelet transfusions are critical for severe thrombocytopenia but depend on blood donors. The shortage of donors and the potential of universal HLA-null platelet products have stimulated research on the ex vivo differentiation of human pluripotent stem cells (hPSCs) to platelets. We recently established expandable immortalized megakaryocyte cell lines (imMKCLs) from hPSCs by transducing MYC, BMI1, and BCL-XL (MBX). imMKCLs can act as cryopreservable master cells to supply platelet concentrates. However, the proliferation rates of the imMKCLs vary with the starting hPSC clone. In this study, we reveal from the gene expression profiles of several MKCL clones that the proliferation arrest is correlated with the expression levels of specific cyclin-dependent kinase inhibitors. Silencing CDKN1A and p53 with the overexpression of MBX was effective at stably inducing imMKCLs that generate functional platelets irrespective of the hPSC clone. Collectively, this improvement in generating imMKCLs should contribute to platelet industrialization and platelet biology

三重県地域住民に対するみそ汁の減塩指導の実践についての検討

昭和55年において,三重県地域住民に対する各保健所の健康教室,集団検診などの参加者1,201世帯を対象とし,参加者に持参させたみそ汁の食塩濃度を測定した。その結果について検討をおこなった。(1)三重県下地域住民のみそ汁の食塩濃度の平均値は1.08%であったが,各保健所ともにその値に著しいバラツキがみられた。(2)上記みそ汁の適正濃度(0.8%)以上のからずき世帯率を保健所別にみた場合は,桑名では67.8%,四日市では62.5%,鈴鹿では79.5%,津では74.6%,松阪では72.8%,上野では81.2%であった。このからすぎ世帯率において,高血圧者在宅世帯と非高血圧者在宅世帯との間には相関関係はみられなかった。(3)ついで,保健所別脳血管疾患死亡率とからずき世帯率との間には相関関係は認められなかった。In 1980 having 1,201 families participated in the health school and mass examination was held by the Regional Health Centers in Mie Prefecture. And, salt concentrations of miso soup brought by those participants were measured. The results were analyzed as follows: (1) The mean concentration of salt in miso soup referring to the regional inhabitants in Mie Prefecture was 1.08%, however, the values were markedly fluctuated by Health Centers. (2) Those families in favor of the saltier taste than the adequate concentration (0.8%) of the miso soup were noted at 67.8% in Kuwana, 62.5% in Yokkaichi, 79.5% in Suzuka, 74.6% in Tsu, 72.8% in Matsuzaka and 81.2% in Ueno. Among those families of salty taste lovers, no correlation was observed between hypertension and nonhypertension. (3) When classified by Health Centers, no correlation was observed between the mortality from cerebrovascular diseases and the percentage of salty taste loving families

Using a machine learning algorithm to predict acute graft-versus-host disease following allogeneic transplantation

Acute graft-versus-host disease (aGVHD) is 1 of the critical complications that often occurs following allogeneic hematopoietic stem cell transplantation (HSCT). Thus far, various types of prediction scores have been created using statistical calculations. The primary objective of this study was to establish and validate the machine learning–dependent index for predicting aGVHD. This was a retrospective cohort study that involved analyzing databases of adult HSCT patients in Japan. The alternating decision tree (ADTree) machine learning algorithm was applied to develop models using the training cohort (70%). The ADTree algorithm was confirmed using the hazard model on data from the validation cohort (30%). Data from 26 695 HSCT patients transplanted from allogeneic donors between 1992 and 2016 were included in this study. The cumulative incidence of aGVHD was 42.8%. Of >40 variables considered, 15 were adapted into a model for aGVHD prediction. The model was tested in the validation cohort, and the incidence of aGVHD was clearly stratified according to the categorized ADTree scores; the cumulative incidence of aGVHD was 29.0% for low risk and 58.7% for high risk (hazard ratio, 2.57). Predicting scores for aGVHD also demonstrated the link between the risk of development aGVHD and overall survival after HSCT. The machine learning algorithms produced clinically reasonable and robust risk stratification scores. The relatively high reproducibility and low impacts from the interactions among the variables indicate that the ADTree algorithm, along with the other data-mining approaches, may provide tools for establishing risk score

Molecular characterization and phylogenetic analysis of Trypanosoma spp. detected from striped leaf-nosed bats (Hipposideros vittatus) in Zambia

Bat trypanosomes consist of more than 30 trypanosome species from over 70 species of bats. Recent studies suggest that bats play a role in disseminating trypanosomes from African continent to the terrestrial mammals both in the Afrotropic-Palearctic Ecozones and Nearctic Ecozone. However, the diversity, distribution, and evolution of bat trypanosomes are still unclear. To better understand their evolution, more genetic data of bat trypanosomes from a variety of locations are required. During a survey of Borrelia spp. of bats inhabiting a cave in Zambia, we observed flagellate parasites from 5 of 43 hemocultures. Sequence and phylogenetic analyses of the glycosomal glyceraldehyde 3-phosphate dehydrogenase gene (gGAPDH; 572 bp) and the 18S ribosomal RNA gene (18S rRNA gene; 1,079-1,091 bp) revealed that all were Trypanosoma spp. belonged to the Trypanosoma cruzi Glade. Three and two of them exhibited the similarity with T. conorhini and T. dionisii, respectively. The present study provides the first genetic data on Trypanosoma spp. of bats inhabiting Zambia

A novel model for treatment of hypertrophic pachymeningitis

Objective Immunoglobulin (Ig)G4-related disease is a major cause of hypertrophic pachymeningitis (HP), presenting as a progressive thickening of the dura mater. HP lacks an animal model to determine its underlying mechanisms. We developed a suitable animal model for the treatment of HP. Methods We longitudinally evaluated dura in mice with a mutation (Y136F) in the linker for activation of T cells (LAT), which induced type 2 T helper (Th2) cell proliferation and IgG1 (IgG4 human equivalent) overexpression. Mice were therapeutically administered daily oral irbesartan from 3 to 6 weeks of age. Human IgG4-related, anti-neutrophil cytoplasmic antibody-related, and idiopathic HP dura were also immunohistochemically examined. Results LATY136F mice showing dural gadolinium enhancement on magnetic resonance imaging had massive infiltration of B220(+) B cells, IgG1(+) cells, CD138(+) plasma cells, CD3(+) T cells, F4/80(+) macrophages, and polymorphonuclear leukocytes in the dura at 3 weeks of age, followed by marked fibrotic thickening. In dural lesions, transforming growth factor (TGF)-beta 1 was produced preferentially in B cells and macrophages while TGF-beta receptor I (TGF-beta RI) was markedly upregulated on fibroblasts. Quantitative western blotting revealed significant upregulation of TGF-beta 1, TGF-beta RI, and phosphorylated SMAD2/SMAD3 in dura of LATY136F mice aged 13 weeks. A similar upregulation of TGF-beta RI, SMAD2/SMAD3, and phosphorylated SMAD2/SMAD3 was present in autopsied dura of all three types of human HP. Irbesartan abolished dural inflammatory cell infiltration and fibrotic thickening in all treated LATY136F mice with reduced TGF-beta 1 and nonphosphorylated and phosphorylated SMAD2/SMAD3. Interpretation TGF-beta 1/SMAD2/SMAD3 pathway is critical in HP and is a potential novel therapeutic target