フェノリシスに関する機構論的研究

京都大学0048新制・論文博士工学博士乙第3025号論工博第882号新制||工||342(附属図書館)4593UT51-61-I257(主査)教授 岡本 邦男, 教授 武上 善信, 教授 市川 克彦学位規則第5条第2項該当Kyoto UniversityDA

Increasing Incidence and Age at Onset of Amyotrophic Lateral Sclerosis in Nagano Prefecture, Japan

Article信州医学雑誌 64(5): 239-246(2016)journal articl

Captan-induced increase in the concentrations of intracellular Ca2+ and Zn2+ and its correlation with oxidative stress in rat thymic lymphocytes

Captan, a phthalimide fungicide, is considered to be relatively nontoxic to mammals. There is a possibility that captan affects membrane and cellular parameters of mammalian cells, resulting in adverse effects, because of high residue levels. To test the possibility, we examined the effects of captan on rat thymic lymphocytes using flow-cytometry with appropriate fluorescent probes. Treatment with 10 and 30 μM captan induced apoptotic and necrotic cell death. Before cell death occurred, captan elevated the intracellular concentrations of Ca2+ and Zn2+ and decreased the concentration of cellular thiol compounds. These captan-induced phenomena are shown to cause cell death and are similar to those caused by oxidative stress. Captan also elevated the cytotoxicity of hydrogen peroxide. Results indicate that 10 and 30 μM captan cause cytotoxic effects on mammalian cells. Despite no report on the significant environmental toxicity hazard of captan in humans, it may exhibit adverse effects, described above, on wild organisms

Calciphylaxis as a Catastrophic Complication in a Patient with POEMS Syndrome

Calciphylaxis is a vascular calcification-cutaneous necrosis syndrome, usually seen in patients with end-stage renal disease and secondary hyperparathyroidism. We report a 57-year-old polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome patient complicated with extensive skin ulcers due to calciphylaxis. He first noted a painful cutaneous ulcer on his left thigh, and then skin lesions rapidly worsened, resulting in multiple intractable ulcers with gangrene on his legs and trunk in a few months. Serum vascular endothelial growth factor (VEGF) was markedly elevated. Biopsy samples from his skin ulcers showed the deposition of calcium in the medial layer of cutaneous vessels, this finding being compatible with calciphylaxis. This is the second reported case with POEMS syndrome complicated with calciphylaxis. Both patients had no evidence of renal failure, hyperparathyroidism, or clotting disorders. The pathogenic link between POEMS syndrome and calciphylaxis is still unclear, but VEGF is known to regulate vascular calcification, in cooperation with bone morphogenetic proteins. Further, corticosteroid and several proinflammatory cytokines activate nuclear factor-κB pathway, known as the final common pathway leading to vascular calcification. Taken together, we consider that POEMS syndrome can be an independent risk condition for calciphylaxis

Transition in eye gaze as a predictor of emergence from general anesthesia in children and adults : a prospective observational study

Background: It is useful to monitor eye movements during general anesthesia, but few studies have examined neurological finding of the eyes during emergence from general anesthesia maintained with short-acting opioids and volatile anesthetics. Methods: Thirty children aged 1–6 years and 30 adults aged 20–79 years were enrolled. Patients received general anesthesia maintained with sevoflurane and remifentanil. The timing of three physical-behavioral responses—eye-gaze transition (the cycle from conjugate to disconjugate and back to conjugate), resumption of somatic movement (limbs or body), and resumption of respiration—were recorded until spontaneous awakening. The primary outcome measure was the timing of the physical-behavioral responses. Secondary outcome measures were the incidence of eye-gaze transition, and the bispectral index, concentration of end-tidal sevoflurane, and heart rate at the timing of eye-gaze transition. Results: Eye-gaze transition was evident in 29 children (96.7%; 95% confidence interval, 82.8–99.9). After the end of surgery, eye-gaze transition was observed significantly earlier than resumption of somatic movement or respiration (472 [standard deviation 219] s, 723 [235] s, and 754 [232] s, respectively; p < 0.001). In adults, 3 cases (10%; 95% CI, 0.2–26.5) showed eye-gaze transition during emergence from anesthesia. The incidence of eye-gaze transition was significantly lower in adults than in children (p < 0.001). Conclusion: In children, eye-gaze transition was observed significantly earlier than other physical-behavioral responses during emergence from general anesthesia and seemed to reflect emergence from anesthesia. In contrast, observation of eye gaze was not a useful indicator of emergence from anesthesia in adults

The 3′-Phosphoadenosine 5′-Phosphosulfate Transporters, PAPST1 and 2, Contribute to the Maintenance and Differentiation of Mouse Embryonic Stem Cells

Recently, we have identified two 3′-phosphoadenosine 5′-phosphosulfate (PAPS) transporters (PAPST1 and PAPST2), which contribute to PAPS transport into the Golgi, in both human and Drosophila. Mutation and RNA interference (RNAi) of the Drosophila PAPST have shown the importance of PAPST-dependent sulfation of carbohydrates and proteins during development. However, the functional roles of PAPST in mammals are largely unknown. Here, we investigated whether PAPST-dependent sulfation is involved in regulating signaling pathways required for the maintenance of mouse embryonic stem cells (mESCs), differentiation into the three germ layers, and neurogenesis. By using a yeast expression system, mouse PAPST1 and PAPST2 proteins were shown to have PAPS transport activity with an apparent Km value of 1.54 µM or 1.49 µM, respectively. RNAi-mediated knockdown of each PAPST induced the reduction of chondroitin sulfate (CS) chain sulfation as well as heparan sulfate (HS) chain sulfation, and inhibited mESC self-renewal due to defects in several signaling pathways. However, we suggest that these effects were due to reduced HS, not CS, chain sulfation, because knockdown of mouse N-deacetylase/N-sulfotransferase, which catalyzes the first step of HS sulfation, in mESCs gave similar results to those observed in PAPST-knockdown mESCs, but depletion of CS chains did not. On the other hand, during embryoid body formation, PAPST-knockdown mESCs exhibited abnormal differentiation, in particular neurogenesis was promoted, presumably due to the observed defects in BMP, FGF and Wnt signaling. The latter were reduced as a result of the reduction in both HS and CS chain sulfation. We propose that PAPST-dependent sulfation of HS or CS chains, which is regulated developmentally, regulates the extrinsic signaling required for the maintenance and normal differentiation of mESCs

Large-scale Molecular Gas Distribution in the M17 Cloud Complex: Dense Gas Conditions of Massive Star Formation?

The non-uniform distribution of gas and protostars in molecular clouds is caused by combinations of various physical processes that are difficult to separate. We explore this non-uniform distribution in the M17 molecular cloud complex that hosts massive star formation activity using the 12CO (J = 1–0) and 13CO (J = 1–0) emission lines obtained with the Nobeyama 45 m telescope. Differences in clump properties such as mass, size, and gravitational boundedness reflect the different evolutionary stages of the M17-H ii and M17-IRDC clouds. Clumps in the M17-H ii cloud are denser, more compact, and more gravitationally bound than those in M17-IRDC. While M17-H ii hosts a large fraction of very dense gas (27%) that has a column density larger than the threshold of ~1 g cm−2 theoretically predicted for massive star formation, this very dense gas is deficient in M17-IRDC (0.46%). Our HCO+ (J = 1–0) and HCN (J = 1–0) observations with the Taeduk Radio Astronomy Observatory 14 m telescope trace all gas with a column density higher than 3 × 1022 cm−2, confirming the deficiency of high-density (≳105 cm−3) gas in M17-IRDC. Although M17-IRDC is massive enough to potentially form massive stars, its deficiency of very dense gas and gravitationally bound clumps can explain the current lack of massive star formation

Expression of human mutant cyclin dependent kinase 4, Cyclin D and telomerase extends the life span but does not immortalize fibroblasts derived from loggerhead sea turtle (Caretta caretta)

Conservation of the genetic resources of endangered animals is crucial for future generations. The loggerhead sea turtle (Caretta caretta) is a critically endangered species, because of human hunting, hybridisation with other sea turtle species, and infectious diseases. In the present study, we established primary fibroblast cell lines from the loggerhead sea turtle, and showed its species specific chromosome number is 2n = 56, which is identical to that of the hawksbill and olive ridley sea turtles. We first showed that intensive hybridization among multiple sea turtle species caused due to the identical chromosome number, which allows existence of stable hybridization among the multiple sea turtle species. Expressions of human-derived mutant Cyclin-dependent kinase 4 (CDK4) and Cyclin D dramatically extended the cell culture period, when it was compared with the cell culture period of wild type cells. The recombinant fibroblast cell lines maintained the normal chromosome condition and morphology, indicating that, at the G1/S phase, the machinery to control the cellular proliferation is evolutionally conserved among various vertebrates. To our knowledge, this study is the first to demonstrate the functional conservation to overcome the negative feedback system to limit the turn over of the cell cycle between mammalian and reptiles. Our cell culture method will enable the sharing of cells from critically endangered animals as research materials

Comparison of alterations in cerebral hemoglobin oxygenation in late life depression ans Alzheimer's disease as assessed by near-infrared spectroscopy

BACKGROUND: Patients with Alzheimer's disease (AD) often present with apathy symptoms resembling the decreased motivation observed in depressed patients. Therefore, differentiating the initial phase of AD from late life depression may be difficult in some cases. Near-infrared spectroscopy (NIRS) is a functional neuroimaging modality that uses near-infrared light to measure changes in hemoglobin concentration on the cortical surface during activation tasks. The objective of this study was to investigate differences in brain activation associated with late life depression and with AD by means of NIRS. METHODS: NIRS was performed in 30 patients with depression, 28 patients with AD, and 33 healthy controls, all aged 60 years or older. During two tasks, a verbal fluency task and a visuospatial task, changes in oxygenated hemoglobin concentration in the frontal and parietal cortices were investigated. RESULTS: In the visuospatial task, cortical activation was lower in the depressed group than in the AD group, and significant differences were observed in the parietal cortex. CONCLUSIONS: NIRS can detect differences in brain activation between patients with late life depression and those with AD. NIRS is a promising tool for the differential diagnosis of late life depression and AD.ArticleBEHAVIORAL AND BRAIN FUNCTIONS. 10:8 (2014)journal articl