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Covid-19 の大流行により、私たちの教育機関では、これまで行っていた対面授業をすべてオンライン授業に移行しなければならなくなるといった多くの課題に取り組まなくてはならなくなりました。急にオンライン化を進める状況になったため、日本学術振興会の科研費補助金（18K02924）を用いた研究（タイトル：ホスピタリティサービス産業のグローバル化を支援するための語学教育大規模公開オンライン講座（MOOC）の開発）を一時的にストップせざるを得なくなりました。パンデミックを取り巻く不確実性と制限がある中で研究活動を行うため、我々研究者とホスピタリティ業界との間でのやりとりにおいて、慎重な対応が必要となりました。そのため、このプロジェクトを進められないのではないかと危惧されました。しかし、2020年の後期もオンライン授業が続き、我々は科研費を用いたプロジェクトの方向性を転換し、ホスピタリティサービス業界との直接の連携ではなく、教育機関での英語学習者のためのオンデマンド授業のカリキュラム開発に焦点を当てました。現在、同大学で提供されているホスピタリティを中心とした専門分野（国際観光学、社会福祉、健康栄養学、薬学）の性質上、学生は「ホスピタリティ・サービス産業」の一面に触れることができます。さらに、この MOOC の最大の特徴は、参加者が広く「オンデマンド」を利用できることです。学生が後期の学習目標を達成するため、我々が「MOOC 方式」で効果的なオンデマンド授業を開発するという新たな目標を提示できたことは、研究チームにとって“救い”となりました。

Background Antibodies to the aquaporin-4 (AQP4) water channel in neuromyelitis optica spectrum disorder (NMOSD) are reported to trigger the complement cascade, which is implicated in astrocyte damage and subsequent neuronal injury. The PREVENT study demonstrated that the terminal complement inhibitor eculizumab reduces adjudicated relapse risk in patients with anti-AQP4 immunoglobulin G-positive (AQP4+) NMOSD. The objective of this analysis was to evaluate the efficacy of eculizumab in reducing relapse risk and its safety in AQP4+ NMOSD across clinically relevant subgroups in PREVENT. Methods In the randomized, double-blind, time-to-event, phase 3 PREVENT trial, 143 adults received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo (2:1), with stable-dose concomitant immunosuppressive therapy (IST) permitted (except rituximab and mitoxantrone). Post hoc analyses of relapses and adverse events were performed for prespecified and post hoc subgroups based on concomitant IST and prior rituximab use, demographic and disease characteristics, and autoimmune comorbidity. Results The significant reduction in relapse risk observed for eculizumab versus placebo in the overall PREVENT population was consistently maintained across subgroups based on concomitant IST and previous rituximab use, age, sex, region, race, time since clinical onset of NMOSD, historical annualized relapse rate, baseline Expanded Disability Status Scale score, and history of another autoimmune disorder. The serious infection rate was lower with eculizumab than placebo regardless of rituximab use in the previous year, concomitant IST use, or history of another autoimmune disorder. Conclusion Across a wide range of clinically relevant AQP4+ NMOSD patient subgroups in PREVENT, eculizumab therapy was consistently effective versus placebo in reducing relapse risk, with no apparent increase in serious infection rate. Trial registration NCT01892345 (ClinicalTrials.gov).

When conducting histopathological evaluation of lymphoid tissues, it is necessary to know the variability and strain differences in histological features of different sites of lymphoid tissues. To investigate in detail the variability of lymphoid tissues and strain differences of control rats as well as those of immune reactivity and sensitivity to immunosuppression, we performed a histopathological analysis of various lymphoid tissues in conjunction with the evaluation of immune function in a T cell-dependent antibody response (TDAR) assay with cyclophosphamide (CP) in Sprague Dawley (SD) and F344 rats. Six-week-old male SD and F344 rats were orally treated with CP at 0 (control) or 4 mg/kg/day for 28 days; keyhole limpet hemocyanin (KLH) was introduced intravenously on Days 14 and 23, and the serum concentrations of anti-KLH antibodies were measured. HE staining and immunohistochemistry for T-cell (CD3) and B-cell (CD45RA) markers were performed using tissues from the spleen, thymus, and various lymph nodes. In CP-treated rats of both strains, decreased concentrations of anti-KLH antibodies were observed. Histopathological analysis revealed decreased lymphocytes mainly in the B-cell area, and these changes induced by CP treatment were more prominent in the F344 rats than in the SD rats. The present study also demonstrated that some of the lymphoid tissues of the control F344 rats were less developed than those of the control SD rats, suggesting that F344 rats might be easily affected by CP-induced immunosuppression. This information concerning rat strain differences in lymphoid tissues will be useful in histopathological evaluation for drug-induced immunotoxicity.

Extensive summer sea ice loss has occurred within the Beaufort, Chukchi, East Siberian, and Laptev Seas over the last decade. Associated anomalies in sensible and latent heat fluxes in autumn have increased Arctic atmospheric precipitable water and air temperatures, with the potential to impact autumn and winter cyclone activity. To examine if a connection exists between recent Arctic sea ice loss and cyclone activity, several cyclone metrics from 60° to 90°N are analyzed. Results show that following years with less September sea ice, there is a subsequent increase in moisture availability, regional baroclinicity, and changes in vertical stability that favor cyclogenesis. However, tracking of individual cyclones indicates no coherent increase in cyclone frequency or intensity associated with sea ice loss. Furthermore, no robust northward progression of extreme cyclones is observed.

The Northern Sea Route (NSR) is becoming a practical passage for transport during the warm season due to Arctic sea ice reduction. There is a need for new navigational support as LNG shipments are increasing in recent years. In this research, a non-heuristic optimal route search is attempted near the New Siberian Islands. The assumption is that an optimal route is related to the surrounding conditions. Accordingly, an empirical formula considering vessel specifications, and environmental condition parameters can predict transit time along a specific course. Then, a route corresponding to the shortest predicted transit time becomes the optimal route. Multi linear and LASSO regressions are applied over the surroundings of the New Siberian Islands, where three routes lie. While the obtained functions are both overfitting models and not suitable for practical prediction, the LASSO one can estimate a more reasonable range of the standardized velocities. The ranges of the standardized velocities to transit through the domain is from 310 to 1640 km and from 310 to 602 km per day predicted by multi linear and LASSO models, respectively. The LASSO regression analysis might be expected to identify points where all the cautions are necessary along the NSR.

When conducting vaginal irritation studies, ovariectomized rats or rabbits are typically used according to practical reports. In the present study, we evaluated the influence of the estrus cycle in a vaginal irritation study using intact rats and ovariectomized rats, which exhibit a late diestrus-like condition, to determine whether intact rats can be useful for evaluating vaginal irritancy. Rats were divided into 4 groups: proestrus, estrus, and metestrus or diestrus in intact rats and ovariectomized rats. All the rats in each group were treated with a vehicle or sodium dodecyl sulfate, as the irritant, in single-dose and 4-day repeat-dose vaginal irritation studies. Each rat's vagina was examined histopathologically, and the irritation score was calculated using a semiquantitative scoring system. In the single-dose study, the irritation scores for the proestrus or ovariectomized groups treated with sodium dodecyl sulfate were higher than those of the estrus group or metestrus or diestrus group. In the 4-day repeat-dose study, a significant histopathological difference was not found among the intact rats (proestrus, estrus, and metestrus or diestrus groups), and the irritation score range of the intact rats was similar to that of the ovariectomized rats, though the mean score of the intact rats was slightly lower than that of the ovariectomized rats. These results suggest that intact rats might be well suited for 4-day vaginal irritation studies and useful for evaluating vaginal irritancy using not only the mean score, but also individual irritation score ranges, whereas the estrus cycle would need to be identified in single-dose vaginal irritation studies.

Understanding, predicting, and responding to a rapidly changing Arctic requires sustained observations that capture variability and transformative change of the Arctic systems with all its major co...

The Ninth Symposium on Polar Science/Interdisciplinary sessions: [IA] Open session for the interdisciplinary Arctic Science, Thu. 6 Dec. / Entrance Hall (1st floor), National Institute of Polar Research

Developing selective inhibitors for a particular kinase remains a major challenge in kinase-targeted drug discovery. Here we performed a multi-step virtual screening for dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) inhibitors by focusing on the selectivity for DYRK1A over cyclin-dependent kinase 5 (CDK5). To examine the key factors contributing to the selectivity, we constructed logistic regression models to discriminate between actives and inactives for DYRK1A and CDK5, respectively, using residue-based binding free energies. The residue-based parameters were calculated by molecular mechanics-generalized Born surface area (MM-GBSA) decomposition methods for kinase-ligand complexes modeled by computer ligand docking. Based on the findings from the logistic regression models, we built a three-dimensional (3D) pharmacophore model and chose filter criteria for the multi-step virtual screening. The virtual hit compounds obtained from the screening were assessed for their inhibitory activities against DYRK1A and CDK5 by in vitro assay. Our screening identified two novel selective DYRK1A inhibitors with IC50 values of several μM for DYRK1A and >100μM for CDK5, which can be further optimized to develop more potent selective DYRK1A inhibitors.

To determine whether the mitochondria or cytoplasm produces superoxide during ischemia-reperfusion of the brain, we analyzed lucigenine-enhanced chemiluminescence emission in slices of brain tissue prepared from manganese-superoxide dismutase (Mn-SOD)-deficient (Sod2-deficient) and copper and zinc-superoxide dismutase (Cu,Zn-SOD)-deficient (Sod1-deficient) mice during oxygenation and hypoxia-reoxygenation. The steady-state level of chemiluminescence under oxygenated conditions was significantly enhanced by a lack of either Sod. We hypothesize that the enhanced chemiluminescence produced by Sod2 and Sod1 deficiency reflects in situ superoxide generation in the mitochondria and cytoplasm, respectively. Based on this hypothesis, the major site of intracellular superoxide generation was assumed to be the cytoplasm. However, mitochondria occupy less cellular space than the cytoplasm. In terms of volume, the superoxide concentration is assumed to be higher in mitochondria than in the cytoplasm. Mn-SOD activity was 18% of the Cu,Zn-SOD activity observed in the wild-type mouse brain. However, when mitochondrial SOD activity was expressed as per volume, it was assumed to be equal to that observed in the cytoplasm. This imbalance between superoxide and SOD activity is expected to cause mitochondrial oxidative damage. The chemiluminescence intensity increased significantly during reoxygenation and was enhanced by Sod2 deficiency but was not significantly affected by Sod1 deficiency. The superoxide concentration in the reoxygenated brain would be higher in the mitochondria than in the cytoplasm. The present study indicated that the major site of intracellular superoxide generation in the brain during oxygenation is the cytoplasm, whereas it is the mitochondria during reoxygenation. © 2011 Wiley-Liss, Inc.

SDZ PSC833 (PSC833), an analogue of cyclosporines, is one of the most potent modulators of multi-drug resistance (MDR). We previously reported that MRK-16, an anti-P-glycoprotein MAb, enhanced MDR reversal activity of cyclosporin A (CsA) through inhibition of P-glycoprotein-mediated CsA transport. We have examined here whether MRK-16 can enhance MDR reversal activity of PSC833. We found that MRK-16 potentiated the MDR reversal activity of PSC833, and of CsA, in MDR sublines of human myelocytic leukemia K562 and human ovarian cancer A2780 cells. Like MRK-16 combined with CsA, MRK-16 enhanced the effect of a sub-optimum dose of PSC833 on vincristine accumulation in MDR cells. However, MRK-16 could not increase cellular accumulation of PSC833 in MDR tumor cells, yet it could increase cellular accumulation of CsA. P-glycoprotein could not transport PSC833 but could transport CsA. Our results indicate that MRK-16 potentiates the MDR reversal activity of both PSC833 and CsA, yet also suggest that the molecular mechanism of the potentiation differs between the two substances.

It is essential to have qualitative information of a satellite instrument, images observed by the instrument, etc. The purpose of this presentation is to verify the degree of infrared (IR) detectors deterioration of the Visible Infrared Spin Scan Radiometer (VISSR) on the fifth Geostationary Meteorological Satellite (GMS-5). The International Satellite Cloud Climatology Project (ISCCP) calibration results and GMS-5 VISSR/IR raw counts of infrared channels were statistically studied. The degradation and uncertainty (noise level) were estimated from 1995 to 2001. As the result, the three GMS-5 infrared channels show no significant trend over the study period except the unstable conditions of the first year. In the end, a comparison between SST observations and brightness levels at cloud-free points is suggested as a possible verification technique.

BACKGROUND Drug resistance is a major obstacle to successful cancer chemotherapy. P-glycoprotein, which transports certain antitumor agents out of resistant tumor cells, is known to be a major factor in some types of multidrug resistance. Studies have shown that verapamil and the immunosuppressors cyclosporine and FK-506 can reverse multidrug resistance in vitro and in vivo and that the P-glycoprotein monoclonal antibody MRK-16 increases drug toxicity in multidrug-resistant tumors. PURPOSE The purpose of this in vitro study was to establish effective treatment modalities for overcoming multidrug resistance. We assessed the synergistic effects of verapamil, cyclosporine, or FK-506 in combination with MRK-16 and antitumor agents. METHODS Human myelogenous leukemia K562 cells and multidrug-resistant K562/ADM cells were treated with vincristine or doxorubicin combined with MRK-16 and cyclosporine alone or together; MRK-16 and verapamil alone or together; or MRK-16 and FK-506. The effects of MRK-16 and cyclosporine or verapamil on the accumulation of vincristine and doxorubicin were examined in K562/ADM cells, and the mechanisms of action were analyzed. RESULTS MRK-16 and cyclosporine synergistically enhanced the antitumor effects of vincristine and of doxorubicin in K562/ADM cells. However, the combined use of MRK-16 with verapamil or FK-506 did not show such synergistic effects in these cells. Studies of the effect of MRK-16 on cellular accumulation of cyclosporine and verapamil revealed that MRK-16 substantially increased accumulation of cyclosporine in K562/ADM cells, but did not increase accumulation of verapamil. CONCLUSIONS MRK-16 and cyclosporine synergistically enhanced the antitumor effects of vincristine and doxorubicin because MRK-16 increased cellular accumulation of cyclosporine. IMPLICATIONS These results, together with our previous finding that intravenous administration of MRK-16 induced regression of multidrug-resistant subcutaneous tumors in athymic mice, support the hypothesis that the combined use of MRK-16 and cyclosporine might increase the efficacy of antitumor agents against multidrug-resistant tumors expressing P-glycoprotein. Clinical phase I trials of MRK-16 in the treatment of multidrug-resistant tumors are under consideration.

Recently, an optical nonregeneration 1R repeater system that uses an optical amplifier has come to be regarded as a key component for longspan, high bit rate transmission systems. However, a high-speed optical transmission system, especially a multigigabit transmission system, suffers from wavelength dispersion of the fiber. The dispersion compensation techniques1–3 such as the so-called prechirp technique3 can remove the impediment, thus expanding the transmission distance between 3R repeaters. However, the total span of the nonregenerative chain could be expanded further by the use of optically transparent preequalizating 1R repeaters. In addition, this expansion would be useful for future optical cross-connect networks using optical switches.4