Time-lapse imaging に基づくがん幹細胞の生物像の解明

学位の種別: 課程博士審査委員会委員 : （主査）東京大学客員教授 石井 源一郎, 東京大学教授 山本 一夫, 東京大学准教授 久恒 辰博, 東京大学准教授 尾田 正ニ, 東京大学客員教授 落合 淳志, 東京大学客員教授 藤田 直也University of Tokyo(東京大学

Visualization of superposition of macroscopically distinct states

We propose a method of visualizing superpositions of macroscopically distinct states in many-body pure states. We introduce a visualization function, which is a coarse-grained quasi joint probability density for two or more hermitian additive operators. If a state contains superpositions of macroscopically distinct states, one can visualize them by plotting the visualization function for appropriately taken operators. We also explain how to efficiently find appropriate operators for a given state. As examples, we visualize four states containing superpositions of macroscopically distinct states: the ground state of the XY model, that of the Heisenberg antiferromagnet, a state in Shor's factoring algorithm, and a state in Grover's quantum search algorithm. Although the visualization function can take negative values, it becomes non-negative (hence becomes a coarse-grained joint probability density) if the characteristic width of the coarse-graining function used in the visualization function is sufficiently large.Comment: 12pages, 21figure

Metabolic Characterization of Antifolate Responsiveness and Non-responsiveness in Malignant Pleural Mesothelioma Cells

Antifolates are a class of drugs effective for treating malignant pleural mesothelioma (MPM). The majority of antifolates inhibit enzymes involved in purine and pyrimidine synthesis such as dihydrofolate reductase (DHFR), thymidylate synthase (TYMS), and glycinamide ribonucleotide formyltransferase (GART). In order to select the most suitable patients for effective therapy with drugs targeting specific metabolic pathways, there is a need for better predictive metabolic biomarkers. Antifolates can alter global metabolic pathways in MPM cells, yet the metabolic profile of treated cells has not yet been clearly elucidated. Here we found that MPM cell lines could be categorized into two groups according to their sensitivity or resistance to pemetrexed treatment. We show that pemetrexed susceptibility could be reversed and DNA synthesis rescued in drug-treated cells by the exogenous addition of the nucleotide precursors hypoxanthine and thymidine (HT). We observed that the expression of pemetrexed-targeted enzymes in resistant MPM cells was quantitatively lower than that seen in pemetrexed-sensitive cells. Metabolomic analysis revealed that glycine and choline, which are involved in one-carbon metabolism, were altered after drug treatment in pemetrexed-sensitive but not resistant MPM cells. The addition of HT upregulated the concentration of inosine monophosphate (IMP) in pemetrexed-sensitive MPM cells, indicating that the nucleic acid biosynthesis pathway is important for predicting the efficacy of pemetrexed in MPM cells. Our data provide evidence that may link therapeutic response to the regulation of metabolism, and points to potential biomarkers for informing clinical decisions regarding the most effective therapies for patients with MPM

Spatial and temporal variation in the distribution of juvenile southern bluefin tuna Thunnus maccoyii: implication for precise estimation of recruitment abundance indices

Acoustic tags were used to examine the spatial and temporal distribution of southern bluefin tuna (SBT) in southern Western Australia, which is in a region where fishery-independent acoustic surveys of the recruitment abundance index of SBT have been historically undertaken. We investigated patterns of SBT distribution within and inshore of the acoustic survey area during three summer seasons. Annual differences in distribution patterns were characterized by two distinctive migration pathways. An inshore-migrating pathway was observed in two seasons (2004/2005 and 2006/2007), with a relatively high proportion of tagged SBT (84.5, 65.0%) migrating inshore of the acoustic survey area. The other pathway was concentrated along the shelf (2005/2006 season), with an estimated 63.3% of tagged SBT moving within the survey area. These variable migration patterns may bias the interannual fluctuations in abundance indices. Current survey methods can be modified to include both inshore and continental shelf areas. This contribution shows that the accuracy of acoustic surveys can be improved by including ecological patterns

Podoplanin: An Emerging Cancer Biomarker and Therapeutic Target

Podoplanin (PDPN) is a transmembrane receptor glycoprotein that is upregulated on transformed cells, cancer associated fibroblasts and inflammatory macrophages that contribute to cancer progression. In particular, PDPN increases tumor cell clonal capacity, epithelial mesenchymal transition, migration, invasion, metastasis and inflammation. Antibodies, CAR-T cells, biologics and synthetic compounds that target PDPN can inhibit cancer progression and septic inflammation in preclinical models. This review describes recent advances in how PDPN may be used as a biomarker and therapeutic target for many types of cancer, including glioma, squamous cell carcinoma, mesothelioma and melanoma

Transcriptional repression induces a slowly progressive atypical neuronal death associated with changes of YAP isoforms and p73

Transcriptional disturbance is implicated in the pathology of polyglutamine diseases, including Huntington's disease (HD). However, it is unknown whether transcriptional repression leads to neuronal death or what forms that death might take. We found transcriptional repression-induced atypical death (TRIAD) of neurons to be distinct from apoptosis, necrosis, or autophagy. The progression of TRIAD was extremely slow in comparison with other types of cell death. Gene expression profiling revealed the reduction of full-length yes-associated protein (YAP), a p73 cofactor to promote apoptosis, as specific to TRIAD. Furthermore, novel neuron-specific YAP isoforms (YAPΔCs) were sustained during TRIAD to suppress neuronal death in a dominant-negative fashion. YAPΔCs and activated p73 were colocalized in the striatal neurons of HD patients and mutant huntingtin (htt) transgenic mice. YAPΔCs also markedly attenuated Htt-induced neuronal death in primary neuron and Drosophila melanogaster models. Collectively, transcriptional repression induces a novel prototype of neuronal death associated with the changes of YAP isoforms and p73, which might be relevant to the HD pathology

Forebrain Ptf1a Is Required for Sexual Differentiation of the Brain

The mammalian brain undergoes sexual differentiation by gonadal hormones during the perinatal critical period. However, the machinery at earlier stages has not been well studied. We found that Ptf1a is expressed in certain neuroepithelial cells and immature neurons around the third ventricle that give rise to various neurons in several hypothalamic nuclei. We show that conditional Ptf1a-deficient mice (Ptf1a cKO) exhibit abnormalities in sex-biased behaviors and reproductive organs in both sexes. Gonadal hormone administration to gonadectomized animals revealed that the abnormal behavior is caused by disorganized sexual development of the knockout brain. Accordingly, expression of sex-biased genes was severely altered in the cKO hypothalamus. In particular, Kiss1, important for sexual differentiation of the brain, was drastically reduced in the cKO hypothalamus, which may contribute to the observed phenotypes in the Ptf1a cKO. These findings suggest that forebrain Ptf1a is one of the earliest regulators for sexual differentiation of the brain