血中の2,3,4,7,8-五塩化ダイベンゾフラン(PeCDF)の個人の半減期：油症患者における臨床症状並びに検診結果との関係

BACKGROUND: In 1968, many people developed dioxin poisoning (Yusho) in Japan. Ingestion of 2,3,4,7,8-pentachlorodibenzofuran (2,3,4,7,8-PeCDF) was considered to be the cause of this poisoning. Although some patients had high concentrations of 2,3,4,7,8-PeCDF in their blood, individuals' half-lives of 2,3,4,7,8-PeCDF were long. OBJECTIVES: To evaluate the relationship between clinical and laboratory parameters and the individual half-life of 2,3,4,7,8-PeCDF in blood. METHODS: Clinical and laboratory data were collected during annual check-ups from 2001 to 2008. We enrolled 71 patients, who were measured more than 3 times, and who had 2,3,4,7,8-PeCDF concentrations in blood >50pgg(-1) lipid. The half-life of 2,3,4,7,8-PeCDF for each patient was estimated using linear regression. Moreover, relationships between clinical and laboratory parameters and individual half-life were investigated by linear regression. RESULTS: A shortened individual half-life for 2,3,4,7,8-PeCDF was significantly correlated with an increased red blood cell count, increased viscous secretions from the meibomian glands, existing black comedones, and severe cedar pollen allergy. CONCLUSIONS: Symptoms that accelerate excretion of lipids from the body, such as viscous secretions from the meibomian glands, may lead to a shorter half-life of 2,3,4,7,8-PeCDF. Red blood cells are related to the half-life of 2,3,4,7,8-PeCDF. However, further studies are required to investigate the excretory mechanism of 2,3,4,7,8-PeCDF.博士（医学）・乙1325号・平成26年3月17

MiR-33a is a therapeutic target in SPG4-related hereditary spastic paraplegia human neurons

Recent reports, including ours, have indicated that microRNA (miR)-33 located within the intron of sterol regulatory element binding protein (SREBP) 2 controls cholesterol homeostasis and can be a potential therapeutic target for the treatment of atherosclerosis. Here, we show that SPAST, which encodes a microtubule-severing protein called SPASTIN, was a novel target gene of miR-33 in human. Actually, the miR-33 binding site in the SPAST 3′-UTR is conserved not in mice but in mid to large mammals, and it is impossible to clarify the role of miR-33 on SPAST in mice. We demonstrated that inhibition of miR-33a, a major form of miR-33 in human neurons, via locked nucleic acid (LNA)-anti-miR ameliorated the pathological phenotype in hereditary spastic paraplegia (HSP)-SPG4 patient induced pluripotent stem cell (iPSC)-derived cortical neurons. Thus, miR-33a can be a potential therapeutic target for the treatment of HSP-SPG4

C/EBPβ Promotes Transition from Proliferation to Hypertrophic Differentiation of Chondrocytes through Transactivation of p57Kip2

BACKGROUND: Although transition from proliferation to hypertrophic differentiation of chondrocytes is a crucial step for endochondral ossification in physiological skeletal growth and pathological disorders like osteoarthritis, the underlying mechanism remains an enigma. This study investigated the role of the transcription factor CCAAT/enhancer-binding protein beta (C/EBPbeta) in chondrocytes during endochondral ossification. METHODOLOGY/PRINCIPAL FINDINGS: Mouse embryos with homozygous deficiency in C/EBPbeta (C/EBPbeta-/-) exhibited dwarfism with elongated proliferative zone and delayed chondrocyte hypertrophy in the growth plate cartilage. In the cultures of primary C/EBPbeta-/- chondrocytes, cell proliferation was enhanced while hypertrophic differentiation was suppressed. Contrarily, retroviral overexpression of C/EBPbeta in chondrocytes suppressed the proliferation and enhanced the hypertrophy, suggesting the cell cycle arrest by C/EBPbeta. In fact, a DNA cell cycle histogram revealed that the C/EBPbeta overexpression caused accumulation of cells in the G0/G1 fraction. Among cell cycle factors, microarray and real-time RT-PCR analyses have identified the cyclin-dependent kinase inhibitor p57(Kip2) as the transcriptional target of C/EBPbeta. p57(Kip2) was co-localized with C/EBPbeta in late proliferative and pre-hypertrophic chondrocytes of the mouse growth plate, which was decreased by the C/EBPbeta deficiency. Luciferase-reporter and electrophoretic mobility shift assays identified the core responsive element of C/EBPbeta in the p57(Kip2) promoter between -150 and -130 bp region containing a putative C/EBP motif. The knockdown of p57(Kip2) by the siRNA inhibited the C/EBPbeta-induced chondrocyte hypertrophy. Finally, when we created the experimental osteoarthritis model by inducing instability in the knee joints of adult mice of wild-type and C/EBPbeta+/- littermates, the C/EBPbeta insufficiency caused resistance to joint cartilage destruction. CONCLUSIONS/SIGNIFICANCE: C/EBPbeta transactivates p57(Kip2) to promote transition from proliferation to hypertrophic differentiation of chondrocytes during endochondral ossification, suggesting that the C/EBPbeta-p57(Kip2) signal would be a therapeutic target of skeletal disorders like growth retardation and osteoarthritis

Development of a Distributed Modeling Framework to Estimate Thermal Comfort along 2020 Tokyo Olympic Marathon Course

Heat stress is an issue for marathon races in the summer, such as the one planned for the 2020 Tokyo Summer Olympic games. The Tokyo Metropolitan Government is planning to grow existing street trees’ canopies to enlarge their shade to reduce air temperature and solar radiation. To formulate a baseline to assess the effect of street trees and buildings on human thermal comfort, Distributed-COMfort FormulA (D-COMFA), a prototype of a distributed computer model using a geographic information system (GIS) was developed. D-COMFA calculates the energy budget of a human body on a 1 m cell basis, using readily available datasets such as weather measurements and polygon data for street structures. D-COMFA was applied to a street segment along the marathon course in Tokyo on an hourly-basis on 9 August 2016, the hottest day in Tokyo in 2016. Our case study showed that the energy budget was positively related to the sky view factor, air temperature, and solar radiation. The energy budget was reduced on average by 26–62% in the shade throughout the day

Hydrogen Peroxide Measurement Can Be Used to Monitor Plant Oxidative Stress Rapidly Using Modified Ferrous Oxidation Xylenol Orange and Titanium Sulfate Assay Correlation

Various methodologies, sensitivities, and types of interference affect the quantification of plant hydrogen peroxide (H2O2) concentration. Modified ferrous oxidation xylenol orange (eFOX) assay and titanium sulfate (Ti(SO4)2 assay are relatively accessible methods. However, their correlation is unknown, for example whether we can get the same results for different species in different environments. Leaf samples of Ambrosia trifida, Solidago altissima, Artemisia princeps, and Sicyos angulatus were collected from a riparian vegetation zone on sunny days. The H2O2 concentration in the plant leaves was evaluated in two groups. Nonfrozen leaf samples were prepared for analysis soon after arriving at the laboratory, and frozen leaf samples were stored at −80 °C for 25 days and prepared afterwards. The eFOX assay can measure even lower fluctuations in H2O2 concentration than the Ti(SO4)2 assay. A substantial correlation was observed between nonfrozen and frozen samples in the eFOX (r = 0.879, p 4)2 assays (r = 0.837, p 2O2 quantification. Each species showed a substantial correlation between the eFOX and Ti(SO4)2 assays in nonfrozen conditions (Ambrosia trifida (r = 0.767, p Solidago altissima (r = 0.583, p Artemisia princeps (r = 0.672, p , and Sicyos angulatus (r = 0.828, p 2O2

Long-Lasting Graft-Derived Donor T Cells Contribute to the Pathogenesis of Chronic Graft-versus-Host Disease in Mice

Chronic graft-versus-host disease (cGVHD) is a major complication in long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Graft-derived T cells (TG) have been implicated in the induction of cGVHD; however, the extent of their contribution to the pathogenesis of cGVHD remains unclear. Using a mouse model of cGVHD, we demonstrate that TG predominate over hematopoietic stem cell-derived T cells generated de novo (THSC) in cGVHD-affected organs such as the liver and lung even at day 63 after allo-HSCT. Persisting TG, in particular CD8+ TG, not only displayed an exhausted or senescent phenotype but also contained a substantial proportion of cells that had the potential to proliferate and produce inflammatory cytokines. Host antigens indirectly presented by donor HSC-derived hematopoietic cells were involved in the maintenance of TG in the reconstituted host. Selective depletion of TG in the chronic phase of disease resulted in the expansion of THSC and thus neither the survival nor histopathology of cGVHD was ameliorated. On the other hand, THSC depletion caused activation of TG and resulted in a lethal TG-mediated exacerbation of GVHD. The findings presented here clarify the pathological role of long-lasting TG in cGVHD