Cell cycle control required for the termination of meiosis in fission yeast

学位の種別:課程博士University of Tokyo(東京大学

Maneuverable and Efficient Locomotion of a Myriapod Robot with Variable Body-Axis Flexibility via Instability and Bifurcation

Aoi Shinya, Yabuuchi Yuki, Morozumi Daiki, et al. Maneuverable and Efficient Locomotion of a Myriapod Robot with Variable Body-Axis Flexibility via Instability and Bifurcation. Soft Robotics 6, NT64 (2023); https://doi.org/10.1089/soro.2022.0177

Optimization of the analogue-sensitive Cdc2/Cdk1 mutant by in vivo selection eliminates physiological limitations to its use in cell cycle analysis

Analogue-sensitive (as) mutants of kinases are widely used to selectively inhibit a single kinase with few off-target effects. The analogue-sensitive mutant cdc2-as of fission yeast (Schizosaccharomyces pombe) is a powerful tool to study the cell cycle, but the strain displays meiotic defects, and is sensitive to high and low temperature even in the absence of ATP-analogue inhibitors. This has limited the use of the strain for use in these settings. Here, we used in vivo selection for intragenic suppressor mutations of cdc2-as that restore full function in the absence of ATP-analogues. The cdc2-asM17 underwent meiosis and produced viable spores to a similar degree to the wild-type strain. The suppressor mutation also rescued the sensitivity of the cdc2-as strain to high and low temperature, genotoxins and an anti-microtubule drug. We have used cdc2-asM17 to show that Cdc2 activity is required to maintain the activity of the spindle assembly checkpoint. Furthermore, we also demonstrate that maintenance of the Shugoshin Sgo1 at meiotic centromeres does not require Cdc2 activity, whereas localization of the kinase aurora does. The modified cdc2-asM17 allele can be thus used to analyse many aspects of cell-cycle-related events in fission yeast

冠動脈バイパス術患者における術前アスピリン投与中止時期の検討

研究科: 千葉大学大学院医学薬学府学位:千大院医薬博甲第医1081号博士(医学)千葉大

The clinical impact of macrophage polarity after Kasai portoenterostomy in biliary atresia

IntroductionBiliary atresia (BA) is a cholestatic hepatopathy caused by fibrosing destruction of intrahepatic and extrahepatic bile ducts, and its etiology has not been clearly revealed. In BA, liver fibrosis progression is often observed even after Kasai portoenterostomy (KPE), and more than half of cases require liver transplantation in their lifetime in Japan. Macrophages play an important role in liver fibrosis progression and are classically divided into proinflammatory (M1) and fibrotic macrophages (M2), whose phenotypic transformation is called “macrophage polarity.” The polarity has been reported to reflect the tissue microenvironment. In this study, we examined the relationship between macrophage polarity and the post-KPE clinical course.Materials and methodsThirty BA patients who underwent KPE in our institution from 2000 to 2020 were recruited. Multiple immunostainings for CD68, CD163, CK19, and α-SMA were carried out on liver biopsy specimens obtained at KPE. ROC curves were calculated based on each clinical event, and the correlation with the clinical data was analyzed.Results and discussionThe M2 ratio, defined as the proportion of M2 macrophages (CD163-positive cells), was correlated inversely with the occurrence of postoperative cholangitis (AUC: 0.7602). The patients were classified into M2 high (n = 19) and non-high (n = 11) groups based on an M2 ratio value obtained from the Youden index ( = 0.918). As a result, pathological evaluations (Metavir score, αSMA area fraction, and CK19 area fraction) were not significantly different between these groups. In mild liver fibrosis cases (Metavir score = 0–2), the M2 non-high group had a significantly lower native liver survival rate than the high group (p = 0.02). Moreover, 4 out of 8 cases in the M2 non-high group underwent early liver transplantation within 2 years after KPE.ConclusionsNon-M2 macrophages, including M1 macrophages, may be correlated with postoperative cholangitis, and the M2 non-high group in mild liver fibrosis cases had a significantly lower native liver survival rate than the high group, requiring early liver transplantation in this study. Preventing advanced liver fibrosis is a key factor in improving native liver survival for BA patients, and liver macrophages may play important roles in liver homeostasis and the promotion of inflammation and fibrosis

Selective peroxisome proliferator-activated receptor-α modulator K-877 efficiently activates the peroxisome proliferator-activated receptor-α pathway and improves lipid metabolism in mice

Aims/IntroductionPeroxisome proliferator-activated receptor-α (PPARα) is a therapeutic target for hyperlipidemia. K-877 is a new selective PPARα modulator (SPPARMα) that activates PPARα transcriptional activity. The aim of the present study was to assess the effects of K-877 on lipid metabolism in vitro and in vivo compared with those of classical PPARα agonists.Materials and MethodsTo compare the effects of K-877 on PPARα transcriptional activity with those of the classical PPARα agonists Wy14643 (Wy) and fenofibrate (Feno), the cell-based PPARα transactivation luciferase assay was carried out. WT and Ppara−/− mice were fed with a moderate-fat (MF) diet for 6 days, and methionine–choline-deficient (MCD) diet for 4 weeks containing Feno or K-877.ResultsIn luciferase assays, K-877 activated PPARα transcriptional activity more efficiently than the classical PPARα agonists Feno and Wy. After being fed MF diet containing 0.001% K-877 or 0.2% Feno for 6 days, mice in the K-877 group showed significant increases in the expression of Ppara and its target genes, leading to marked reductions in plasma triglyceride levels compared with those observed in Feno-treated animals. These K-877 effects were blunted in Ppara−/− mice, confirming that K-877 activates PPARα. In further experiments, K-877 (0.00025%) and Feno (0.1%) equally improved the pathology of MCD diet-induced non-alcoholic fatty liver disease, with increased expression of hepatic fatty acid oxidation genes.ConclusionsThe present data show that K-877 is an attractive PPARα-modulating drug and can efficiently reduce plasma triglyceride levels, thereby alleviating the dysregulation of lipid metabolism

First record of Stylostomum ellipse (Dalyell, 1853) (Platyhelminthes, Polycladida) from the Pacific Ocean

The polyclad flatworm Stylostomum ellipse (Dalyell, 1853) has hitherto been recorded from the Antarctic region, Mediterranean Sea, Patagonian region, Scandinavia, South Africa, and South Georgia Island. In this study, we report S. ellipse for the first time from the Pacific Ocean based on specimens collected in Hokkaido, northern Japan. Our specimens are morphologically identifiable as S. ellipse, but may represent a biologically different species from a population of the Mediterranean Sea. This is because, based on the previous genetic data of other cotylean species, the observed uncorrected p-distance 0.02160 between the two distinct populations in terms of a partial 972 bp region of the 28S rDNA sequence may be great enough to separate the species biologically

Reversible shifts between interstitial and epibenthic habitats in evolutionary history : Molecular phylogeny of the marine flatworm family Boniniidae (Platyhelminthes: Polycladida: Cotylea) with descriptions of two new species

Tiny animals in various metazoan phyla inhabit the interstices between sand and/or gravel grains, and adaptive traits in their body plan, such as simplification and size reduction, have attracted research attention. Several possible explanations of how such animals colonized interstitial habitats have been proposed, but their adaptation to this environment has generally been regarded as irreversible. However, the actual evolutionary transitions are not well understood in almost all taxa. In the present study, we show reversible evolutionary shifts from interstitial to epibenthic habitats in the lineage of the polyclad flatworm genus Boninia. In addition, we establish two new species of this genus found from different microhabitats on a single beach in Okinawa Island, Japan: (i) the interstitial species Boninia uru sp. nov. from gravelly sediments and (ii) the epibenthic species Boninia yambarensis sp. nov. from rock undersurfaces. Our observations suggest that rigid microhabitat segregation exists between these two species. Molecular phylogenetic analyses based on the partial 18S and 28S rDNA sequences of the new Boninia species and four other congeners, for which molecular sequences were available in public databases [Boninia antillara (epibenthic), Boninia divae (epibenthic), Boninia neotethydis (interstitial), and an unidentified Boninia sp. (habitat indeterminate)], revealed that the two interstitial species (B. neotethydis and B. uru sp. nov.) were not monophyletic among the three epibenthic species. According to ancestral state reconstruction analysis, the last common ancestor of the analyzed Boninia species inhabited interstitial realms, and a shift to the epibenthic environment occurred at least once. Such an interstitial to noninterstitial evolutionary route seems to be rare among Animalia; to date, it has been reported only in acochlidian slugs in the clade Hedylopsacea. Our phylogenetic tree also showed that the sympatric B. uru sp. nov. and B. yambarensis sp. nov. were not in a sister relationship, indicating that they colonized the same beach independently rather than descended in situ from a common ancestor that migrated and settled at the beach