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In this paper, we concern swing down control of the Acrobot which is a 2-link planar robot with a single actuator driving the second joint, whose control objective is to stabilize the Acrobot to the downward equilibrium point with the two links in the downward position for all initial states of the Acrobot with the exception of a set of Lebesgue measure zero. To achieve this control objective, we design a nonlinear controller by using nonnegative linear feedback of the sine function of the angle of the second joint in addition to the negative linear feedback of its angular velocity. By analyzing globally the solution of the closed-loop system consisting of the Acrobot and the presented controller and focusing on the equilibrium points of the closed-loop system and their stability, we prove that the control objective is achieved provided that some conditions on two control gains are satisfied. We design the two control gains such that the real parts of the dominant poles of the linearized model of the closed-loop system around the downward equilibrium point are minimized. We provide simulation results for two Acrobots to show the effectiveness of the presented controller.

Reprogramming of antigen-specific T lymphocytes into induced pluripotent stem cells (iPSCs) and their subsequent re-differentiation has enabled expansion of functional T lymphocytes in vitro, thus opening up new approaches for immunotherapy of cancer and other diseases. In this study, we have established a robust protocol to reprogram human invariant NKT (Vα24+ iNKT) cells, which have been shown to act as cellular adjuvants and thus exert anti-tumor activity in mice and humans, and to re-differentiate the iNKT cell-derived iPSCs into functional iNKT cells. These iPSC-derived iNKT cells (iPS-Vα24+ iNKT cells) can be activated by ligand-pulsed dendritic cells (DCs) and produce a large amount of interferon-γ upon activation, as much as parental Vα24+ iNKT cells, but exhibit even better cytotoxic activity against various tumor cell lines. The iPS-Vα24+ iNKT cells possess significant anti-tumor activity in tumor-bearing mice and can activate autologous NK cells upon activation by ligand-pulsed DCs in the NOG mouse model in vivo, further extending their therapeutic potential. This study thus provides a first proof of concept for the clinical application of human iPS-Vα24+ iNKT cells for cancer immunotherapy.

The Larval Amphibian Growth and Development Assay (LAGDA) is a globally harmonized chemical testing guideline developed by the U.S. Environmental Protection Agency in collaboration with Japan's Ministry of Environment to support risk assessment. The assay is employed as a higher tiered approach to evaluate effects of chronic chemical exposure throughout multiple life stages in a model amphibian species, Xenopus laevis. To evaluate the utility of the initial LAGDA design, the assay was performed using a mixed mode of action endocrine disrupting chemical, benzophenone-2 (BP-2). X. laevis embryos were exposed in flow-through conditions to 0, 1.5, 3.0 or 6.0 mg l-1 BP-2 until 2 months post-metamorphosis. Overt toxicity was evident throughout the exposure period in the 6.0 mg l-1 treatment due to elevated mortality rates and observed liver and kidney pathologies. Concentration-dependent increases in severity of thyroid follicular cell hypertrophy and hyperplasia occurred in larval tadpoles indicating BP-2-induced impacts on the thyroid axis. Additionally, gonads were impacted in all treatments with some genetic males showing both testis and ovary tissues (1.5 mg l-1 ) and 100% of the genetic males in the 3.0 and 6.0 mg l-1 treatments experiencing complete male-to-female sex reversal. Concentration-dependent vitellogenin induction occurred in both genders with associated accumulations of protein in the livers, kidneys and gonads, which was likely vitellogenin and other estrogen-responsive yolk proteins. This is the first study that demonstrates the endocrine effects of this mixed mode of action chemical in an amphibian species and demonstrates the utility of the LAGDA design for supporting chemical risk assessment. Copyright © 2016 John Wiley & Sons, Ltd.

Granzyme A (GzmA), together with perforin, are well-known for their cytotoxic activity against tumor or virus-infected cells. In addition to this cytotoxic function, GzmA stimulates several immune cell types and induces inflammation in the absence of perforin, however, its effect on the dendritic cell (DC) is unknown. In the current study, we showed that recombinant GzmA induced the phenotypic maturation of plasmacytoid DCs (pDCs) and conventional DCs (cDCs), but not their apoptosis. Particularly, GzmA made pDCs more functional, thus leading to production of type I interferon (IFN) via the TLR9-MyD88 pathway. We also demonstrated that GzmA binds TLR9 and co-localizes with it in endosomes. When co-administered with antigen, GzmA acted as a powerful adjuvant for eliciting antigen-specific cytotoxic CD8+ T lymphocytes (CTLs) that protected mice from tumor challenge. The induction of CTL was completely abolished in XCR1+ DC-depleted mice, whereas it was reduced to less than half in pDC-depleted or IFN-α/β receptor knockout mice. Thus, CTL cross-priming was dependent on XCR1+cDC and also type I IFN, which was produced by GzmA-activated pDCs. These results indicate that GzmA -stimulated pDCs enhance the cross-priming activity of cDCs in situ. We also showed that the adjuvant effect of GzmA is superior to CpG-ODN and LPS. Our findings highlight the ability of GzmA to bridge innate and adaptive immune responses via pDC help and suggest that GzmA may be useful as a vaccine adjuvant.

An induction of long-term cellular and humoral immunity is for the goal of vaccines, but the combination of antigens and adjuvant remain unclear. Here, we show, using a cellular vaccine carrying foreign protein antigen plus iNKT cell glycolipid antigen, designated as artificial adjuvant vector cells (aAVCs), that mature XCR1− DCs in situ elicit not only ordinal antigen-specific CD4+T cells, but also CD4+ Tfh and germinal center, resulted in inducing long-term antibody production. As a mechanism for leading the long-term antibody production by aAVC, memory CD4+ Tfh cells but not iNKTfh cells played an important role in a Bcl6 dependent manner. To develop it for influenza infection, we established influenza hemagglutinin-carrying aAVC (aAVC-HA) and found that all the mice vaccinated with aAVC-HA were protected from life-threatening influenza infection. Thus, the in vivo DC targeting therapy by aAVC would be useful for protection against viral infection.

Reprogramming of antigen-specific T lymphocytes into induced pluripotent stem cells (iPSCs) and their subsequent re-differentiation has enabled expansion of functional T lymphocytes in vitro, thus opening up new approaches for immunotherapy of cancer and other diseases. In this study, we have established a robust protocol to reprogram human invariant NKT (Vα24

高齢者糖尿病患者は増加の一途を辿っている。高齢者糖尿病患者を在宅で管理するためには訪問介護サービスは重要であり，また利用者も多い。そこで我々は糖尿病に関する研修会の参加者に対して高齢者糖尿病患者の訪問介護サービスの現状調査のためのアンケート調査を行ない，85名から回答を得た。その結果87%が糖尿病患者の介護を経験しており，低血糖や高血糖の急性合併症を経験したとの回答もあった。また多くの訪問介護者が服薬介助を経験しており，高齢者糖尿病治療に重要な役割を担っていることが確認できた。 一方，足の状態の観察不足，低血糖に対する対処方法の知識不足，服薬コンプライアンスについては訪問時間等の介護の都合で十分に遵守できないなどの問題点も抽出された。今後，高齢者糖尿病治療に関わる職種は地域の介護職員への研修と連携づくりが必要であると考える。

The Larval Amphibian Growth and Development Assay (LAGDA) is a globally harmonized chemical testing guideline developed by the U.S. Environmental Protection Agency in collaboration with Japan's Ministry of Environment to support risk assessment. The assay is employed as a higher tiered approach to evaluate effects of chronic chemical exposure throughout multiple life stages in a model amphibian species, Xenopus laevis. To evaluate the utility of the initial LAGDA design, the assay was performed using a mixed mode of action endocrine disrupting chemical, benzophenone-2 (BP-2). X. laevis embryos were exposed in flow-through conditions to 0, 1.5, 3.0 or 6.0 mg l

Sweet taste sensitivity in obese rats with lesions of the ventromedial hypothalamus (VMH) was studied by examining chorda tympani nerve responses to various taste stimuli including sugars. In the early progressive phase of obesity (2 wk after creating VMH lesions), there was no significant difference in the nerve responses to any taste stimulus between sham-operated and VMH-lesioned rats. In contrast, in the late phase of obesity (15–18 wk after VMH lesions), the magnitude of responses to sugars (except for fructose) was prominently greater than that in age-matched controls. High-fat diet-induced obese rats and streptozotocin-diabetic rats also showed greater chorda tympani nerve responses to sugars as was observed in VMH-lesioned obese rats, indicating that VMH lesions might not be specifically related to the enhanced gustatory neural responses to sugars. Although it has been demonstrated that the enhanced responses of the chorda tympani nerve to sugars in genetically diabetic db/db mice is largely attributable to the lack of the direct suppressive effect of leptin on the taste receptor cells, plasma leptin levels were not correlated with the changes in chorda tympani responsiveness to sugars in these models of obesity and diabetes. Accordingly, our results suggest that some chronic factors, including high blood glucose, inefficiency of insulin action, or leptin resistance may be related to the enhancement of chorda tympani nerve responses to sugars.

Four outer membrane proteins were purified to homogeneity from isolated outer membranes of Bacteroides fragilis; three (Mr 51000, 92000 and 125 000) had pore-forming activity in reconstituted liposomes as determined by swelling assay. Membrane vesicles containing the Mrmr 55 000 outer membrane protein showed no detectable pore-forming activity. The three B. fragilis porins formed pores that allowed the penetration of uncharged saccharides of Mr lower than 340–400, even though the efficiency of solute diffusion showed slight differences. The diffusion rates of glucose through the porins appeared to be lower than those through Escherichia coli porins.

Luminescence and absorption spectra of coronene single crystals are studied. Free-exciton luminescence is observed for the first time. The intensity of free-exciton luminescence decreases with decreasing temperature, suggesting that free excitons are in thermal equilibrium with excitons in a relaxed state which is located 1070 cm -1 below the bottom of the free-exciton band. The line shape of the O–O absorption band which is located at 23220 cm -1 at 10.4 K is Lorentzian, indicating that scattering of excitons by phonons is weak.

Non-alcoholic steatohepatitis (NASH) is a pathological liver condition that occurs in the absence of alcohol abuse and is characterized histologically by steatosis, lobular inflammation, hepatocyte ballooning and fibrosis. NASH is a progressive disease that can lead to hepatocellular carcinoma (HCC), and there is a growing need in the therapeutic field for a reliable and clinically relevant model system that recapitulates the natural history of NASH and encompasses hallmark changes in gene expression, cellular dynamics and metabolic parameters. We have developed a novel NASH mice model (STAMTM) by neonatal low-dose streptozotocin injection to induce a diabetic state in mice and high-fat diet feeding to develop steatosis and mild chronic hepatic inflammation from 4 weeks of age onwards. The STAMTM model reproduced the pathological course of NASH, with step-wise disease progression from simple steatosis to HCC in a relatively short time (NASH and HCC were evident at 8 and 18 weeks after birth, respectively). It showed typical features of human NASH especially as indicated by the following. 1) Histopathology: microand macro-vesicular fat deposition, inflammatory cell infiltration, hepatocyte ballooning and fibrosis, with NAFLD Activity score of 5 at 8 weeks of age. 2) Hepatic gene expression profiles: up-regulation of TNF-α, TGFβ, MCP-1, TIMP-1, α-SMA and collagen Type 1 and 3. In the STAMTM mice, steatohepatitis with lobular fibrosis was evident at 8 weeks of age, which was much earlier than conventional animal models. Furthermore, almost all STAMTM mice developed HCC, with macroscopic appearance of tumor nodules observed at 18 weeks of age on average. These characteristics, together with reproducibility of the disease onset and regularity of the progression, endow the STAMTM model with advantages as a useful preclinical NASH model. Body weight, fasting blood sugar, serum AST, serum ALT, Liver TG, NAS