Antipsychotic olanzapine-induced misfolding of proinsulin in the endoplasmic reticulum accounts for atypical development of diabetes

オランザピンの非典型的糖尿病誘発機構を解明 --体重増加以外にも注意が必要--. 京都大学プレスリリース. 2020-12-02.Second-generation antipsychotics are widely used to medicate patients with schizophrenia, but may cause metabolic side effects such as diabetes, which has been considered to result from obesity-associated insulin resistance. Olanzapine is particularly well known for this effect. However, clinical studies have suggested that olanzapine-induced hyperglycemia in certain patients cannot be explained by such a generalized mechanism. Here, we focused on the effects of olanzapine on insulin biosynthesis and secretion by mouse insulinoma MIN6 cells. Olanzapine reduced maturation of proinsulin, and thereby inhibited secretion of insulin; and specifically shifted the primary localization of proinsulin from insulin granules to the endoplasmic reticulum. This was due to olanzapine’s impairment of proper disulfide bond formation in proinsulin, although direct targets of olanzapine remain undetermined. Olanzapine-induced proinsulin misfolding and subsequent decrease also occurred at the mouse level. This mechanism of olanzapine-induced β-cell dysfunction should be considered, together with weight gain, when patients are administered olanzapine

Risk factors for CAR-T cell manufacturing failure among DLBCL patients: A nationwide survey in Japan

CAR-T細胞製造を成功させるためのレシピ --アフェレーシス前の下ごしらえでの工夫--. 京都大学プレスリリース. 2023-04-27.For successful chimeric antigen receptor T (CAR-T) cell therapy, CAR-T cells must be manufactured without failure caused by suboptimal expansion. In order to determine risk factors for CAR-T cell manufacturing failure, we performed a nationwide cohort study in Japan and analysed patients with diffuse large B-cell lymphoma (DLBCL) who underwent tisagenlecleucel production. We compared clinical factors between 30 cases that failed (7.4%) with those that succeeded (n = 378). Among the failures, the proportion of patients previously treated with bendamustine (43.3% vs. 14.8%; p < 0.001) was significantly higher, and their platelet counts (12.0 vs. 17.0 × 10⁴/μL; p = 0.01) and CD4/CD8 T-cell ratio (0.30 vs. 0.56; p < 0.01) in peripheral blood at apheresis were significantly lower than in the successful group. Multivariate analysis revealed that repeated bendamustine use with short washout periods prior to apheresis (odds ratio [OR], 5.52; p = 0.013 for ≥6 cycles with washout period of 3–24 months; OR, 57.09; p = 0.005 for ≥3 cycles with washout period of <3 months), low platelet counts (OR, 0.495 per 105/μL; p = 0.022) or low CD4/CD8 ratios (<one third) (OR, 3.249; p = 0.011) in peripheral blood at apheresis increased the risk of manufacturing failure. Manufacturing failure remains an obstacle to CAR-T cell therapy for DLBCL patients. Avoiding risk factors, such as repeated bendamustine administration without sufficient washout, and risk-adapted strategies may help to optimize CAR-T cell therapy for DLBCL patients

Reconstruction of variations of isotopic ratios of atmospheric methane: measurements of firn air /ice core and applications of firn air transport model

第6回極域科学シンポジウム分野横断セッション：[IA] 急変する北極気候システム及びその全球的な影響の総合的解明―GRENE北極気候変動研究事業研究成果報告2015―11月19日（木）　国立極地研究所１階交流アトリウ

Variations of tropospheric methane over Japan during 1988–2010

We present observations of CH4 concentrations from the lower to upper troposphere (LT and UT) over Japan during 1988–2010 based on aircraft measurements from the Tohoku University (TU). The analysis is aided by simulation results using an atmospheric chemistry transport model (i.e. ACTM). Tropospheric CH4 over Japan shows interannual and seasonal variations that are dependent on altitudes, primarily reflecting differences in air mass origins at different altitudes. The long-term trend and interannual variation of CH4 in the LT are consistent with previous reports of measurements at surface baseline stations in the northern hemisphere. However, those in the UT show slightly different features from those in the LT. In the UT, CH4 concentrations show a seasonal maximum in August due to efficient transport of air masses influenced by continental CH4 sources, while LT CH4 reaches its seasonal minimum during summer due to enhanced chemical loss. Vertical profiles of the CH4 concentrations also vary with season, reflecting the seasonal cycles at the respective altitudes. In summer, transport of CH4-rich air from Asian regions elevates UT CH4 levels, forming a uniform vertical profile above the mid-troposphere. On the other hand, CH4 decreases nearly monotonically with altitude in winter–spring. The ACTM simulations with different emission scenarios reproduce general features of the tropospheric CH4 variations over Japan. Tagged tracer simulations using the ACTM indicate substantial contributions of CH4 sources in South Asia and East Asia to the summertime high CH4 values observed in the UT. This suggests that our observations over Japan are highly sensitive to CH4 emission signals particularly from Asia

Dissecting the genetic control of natural variation in salt tolerance of Arabidopsis thaliana accessions

Many accessions (ecotypes) of Arabidopsis have been collected. Although few differences exist among their nucleotide sequences, these subtle differences induce large genetic variation in phenotypic traits such as stress tolerance and flowering time. To understand the natural variability in salt tolerance, large-scale soil pot experiments were performed to evaluate salt tolerance among 350 Arabidopsis thaliana accessions. The evaluation revealed a wide variation in the salt tolerance among accessions. Several accessions, including Bu-5, Bur-0, Ll-1, Wl-0, and Zu-0, exhibited marked stress tolerance compared with a salt-sensitive experimental accession, Col-0. The salt-tolerant accessions were also evaluated by agar plate assays. The data obtained by the large-scale assay correlated well with the results of a salt acclimation (SA) assay, in which plants were transferred to high-salinity medium following placement on moderate-salinity medium for 7 d. Genetic analyses indicated that the salt tolerance without SA is a quantitative trait under polygenic control, whereas salt tolerance with SA is regulated by a single gene located on chromosome 5 that is common among the markedly salt-tolerant accessions. These results provide important information for understanding the mechanisms underlying natural variation of salt tolerance in Arabidopsis

ナンボク リョウキョクイキ ニオケル タイキチュウ ノ オンシツ コウカ キタイ ト カンレン キタイ ノ ヘンドウ

南北両極域における温室効果気体の変動を明らかにし,それらの放出源・吸収消滅源の変動に関する知見を得るために,南極・昭和基地および北極・スバールバル諸島ニーオルスンにおいて系統的な温室効果気体及び関連気体観測を開始し,現在も継続している.大気中のCO_2 濃度は,両極域共に明瞭な季節変化を伴いながら,化石燃料消費と森林破壊によるCO_2 の放出を反映して約1.9 ppmv yr^ の割合で増加している.CH_4 濃度にも明瞭な季節変化と不規則な経年変化が見られ,両極域において1999年までの濃度増加と2000年以降の濃度停滞,そして2007年には再び濃度増加が観測された.CH_4 の同位体比観測から,CH_4 濃度の季節変化,経年変化の原因に関する情報が得られた.大気中のO_2 濃度(δ(O_2 N_2))は両極域において,季節変化と化石燃料消費に起因する経年的減少を示した.Atmospheric Potential Oxygen(APO)とCO_2 濃度の増加率から見積もられた,陸上生物圏と海洋によるCO_2 吸収量(2001-2009年の平均)はそれぞれ1.1,2.7 GtC yr^ であった.ニーオルスンで観測されたN_2O濃度の季節変化を3次元化学輸送モデルによる計算結果と比較することにより,N_2O濃度の季節変化振幅は,夏季に成層圏起源のN_2O濃度が低い気塊が地表付近まで流入することによって,拡大している可能性が示唆された.昭和基地におけるCO濃度の連続観測と3次元化学輸送モデルを用いた解析により,2003年2-3月と2007年2月に,オーストラリアでの大規模な林野火災によって発生したCOが昭和基地に達していることが示された.昭和基地における地上オゾン濃度連続観測によって,1988-2008年までの間に計40例以上の地上オゾン破壊現象を観測した.To elucidate temporal variations of greenhouse gases and their related gases in the Arctic and Antarctic regions and to investigate their sources and sinks, systematic measurements of atmospheric CO_2, CH_4CO, N_2O, O_2 and tropospheric O_3 concentrations have been carried out at Syowa Station, Antarctica and Ny-Alesund, Svalbard. The CO_2 concentrations at both polar sites have increased at a rate of about 1.9 ppmv yr^, reflecting fossil fuel combustion and land use change. The CH_4 concentrations also showed clear seasonal cycles superimposed on complex secular trends. The increase rate of the CH_4 concentration varied with time. CH_4 increases were observed until 1999, the concentrations remained steady from 2000 to 2006 and then rapid increases were observed in 2007. Stable isotope data of CH_4 revealed causes of the seasonal cycles and the secular variations of the CH_4 concentrations. The O_2 concentrations (δ(O_2 N_2)) at both polar sites showed prominent seasonal cycles and secular decreasing trends. From analyses of the Atmospheric Potential Oxygen (APO) and CO_2 concentrations, the CO_2 uptake rates by the terrestrial biosphere and the ocean were estimated to be 1.1 and 2.7 GtC yr^, respectively. By comparing the N_2O concentrations observed at Ny-Alesund and numerical model results, it was suggested that the observed seasonal N_2O cycle could be enlarged by intrusion of a stratospheric air mass with low N_2O concentration into the troposphere in summer. With an analysis using a three dimensional chemical-transport model and the CO concentration at Syowa Station, sporadic increases of CO concentration observed in February-March, 2003 and February, 2007 were ascribed to CO release by large-scale forest fires in Australia. Surface ozone depletion events were observed more than 40 times at Syowa Station from 1988 to 2007

Overview of seafarming and searanching technology in Japan

In 1989, artificial seed production was attained in 37 species of fishes, 16 species of Crustacea, 25 species of shellfishes, and 9 species of other fishery animals in Japan. Eighty species of fishery animal seed, including natural and artificial production, were released in natural fishery grounds during this year. The total mariculture production was 1.3 million tons. This composed of 18% fish, 35% shellfish, 46% seaweed, and 1% of other fishery animals.In recent years, Japan achieved some success in Seafarming and searanching projects. Among these are searanching of Japanese scallop in northern Japan and acoustic habituation system of red sea bream. Searanching of striped jack using artificial seed is also explained

Power Electronics Device Applications of Diamond Semiconductors

International audienc

Vers l'etude des interactions eau-proteine-sels dans les tissus biologiques : analyse enthalpique differentielle des solutions mimetiques des liquides biologiques

CNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueSIGLEFRFranc