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Choline is an essential nutrient and a critical component of the membrane phospholipid phosphatidylcholine (PC), the neurotransmitter acetylcholine, while also contributing to the methylation pathway. In the liver specifically, PC is the major membrane constituent and can be synthesized by the cytidine diphosphate–choline or the phosphatidylethanolamine N‐methyltransferase pathway. With the continuing global rise in the rates of obesity and nonalcoholic fatty liver disease, we sought to explore how excess fatty acids on primary hepatocytes and diet‐induced obesity affect choline uptake and metabolism. Our results demonstrate that hepatocytes chronically treated with palmitate, but not oleate or a mixture, had decreased choline uptake, which was associated with lower choline incorporation into PC and lower expression of choline transport proteins. Interestingly, a reduction in the rate of degradation spared PC levels in response to palmitate when compared with control. The effects of palmitate treatment were independent of endoplasmic reticulum stress, which counterintuitively augmented choline transport and transporter expression. In a model of obesity‐induced hepatic steatosis, male mice fed a 60% high‐fat diet for 10 weeks had significantly diminished hepatic choline uptake compared with lean mice fed a control diet. Although the transcript and protein expression of various choline metabolic enzymes fluctuated slightly, we observed reduced protein expression of choline transporter‐like 1 (CTL1) in the liver of mice fed a high‐fat diet. Polysome profile analyses revealed that in livers of obese mice, the CTL1 transcript, despite being more abundant, was translated to a lesser extent compared with lean controls. Finally, human liver cells demonstrated a similar response to palmitate treatment. Conclusion: Our results suggest that the altered fatty acid milieu seen in obesity‐induced fatty liver disease progression may adversely affect choline metabolism, potentially through CTL1, but that compensatory mechanisms work to maintain phospholipid homeostasis., Hepatic choline transport and downstream phosphatidylcholine synthesis is negatively affected by fatty acid–induced lipotoxicity, both in primary hepatocytes and in the livers of obese mice.

Despite the intense interest in cellulose nanofibers (CNFs) for biomedical and engineering applications, no research findings about the electrical energy storage of CNF have been reported yet. Here, we present the first electroadsorption effects of an amorphous cellulose nanofiber (ACF) supercapacitor, which can store a large amount of electricity (221 mJm−2, 13.1 Wkg−1). The electric storage can be attributed to the entirely enhanced electroadsorption owing to a quantum-size effect by convexity of 17.9 nm, an offset effect caused by positive polar C6=O6 radicles, and an electrostatic effect by appearance of the localised electrons near the Na ions. The supercapacitor also captures both positive and negative electricity from the atmosphere and in vacuum. The supercapacitor could illuminate a red LED for 1 s after charging it with 2 mA at 10 V. Further gains might be attained by integrating CNF specimens with a nano-electromechanical system (NEMS).

Although programmed cell death protein 1 (PD&minus, 1)/PD-ligand 1 (PD-L1) blockade is effective in a subset of patients with hepatocellular carcinoma (HCC), its therapeutic response is still unsatisfactory. Alternatively, the potential impact of the lenvatinib in patients who showed tumor progression on PD&minus, 1/PD-L1 blockade is unknown. In this work, we evaluated the safety and efficacy of lenvatinib administration after PD-1/PD-L1 checkpoint blockade. The outcome and safety of lenvatinib administered after PD-1/PD-L1 blockade failure was analyzed retrospectively in 36 patients. Tumor growth was assessed every 4&ndash, 8 weeks using modified Response Evaluation Criteria in Solid Tumors. The mean relative dose intensity of lenvatinib was 87.6% and 77.8% in patients receiving a starting dose of 8 (interquartile range (IQR), 77.5&ndash, 100.0) mg and 12 (IQR, 64.4&ndash, 100.0) mg, respectively. Since lenvatinib therapy initiation, the median progression-free survival was 10 months (95% confidence interval (CI): 8.3&ndash, 11.8) and the median overall survival was 15.8 months (95% CI: 8.5&ndash, 23.2). The objective response rate was 55.6%, and the disease control rate was 86.1%. No particular safety concerns were observed. Lenvatinib demonstrated considerable antitumor effects with acceptable safety in patients with progressive and unresectable HCC when administered right after PD-1/PD-L1 blockade failure.

Brown adipocyte activation or beige adipocyte emergence in white adipose tissue (WAT) increases energy expenditure, leading to a reduction in body fat mass and improved glucose metabolism. We found that activin E functions as a hepatokine that enhances thermogenesis in response to cold exposure through beige adipocyte emergence in inguinal WAT (ingWAT). Hepatic activin E overexpression activated thermogenesis through Ucp1 upregulation in ingWAT and other adipose tissues including interscapular brown adipose tissue and mesenteric WAT. Hepatic activin E-transgenic mice exhibited improved insulin sensitivity. Inhibin βE gene silencing inhibited cold-induced Ucp1 induction in ingWAT. Furthermore, in vitro experiments suggested that activin E directly stimulated expression of Ucp1 and Fgf21, which was mediated by transforming growth factor-β or activin type I receptors. We uncovered a function of activin E to stimulate energy expenditure through brown and beige adipocyte activation, suggesting a possible preventive or therapeutic target for obesity., アクチビンEが脂肪燃焼細胞の増加を促進することを解明 --肥満解消の新たなプレイヤーを発見--. 京都大学プレスリリース. 2018-11-02.

In this study, we fabricated optically transparent cotton fibers composite by resin impregnation without having to prepare cellulose nanofibers. Although the surface acetylation of the cotton microfibrils aided the resin impregnation process, excess acetylation resulted in the gradual breakdown of the cellulose crystal structure, with the resulting composite showing a high coefficient of thermal expansion (CTE). To prevent this, a swelling pretreatment, namely surface carboxylation by TEMPO-mediated oxidation, was performed to facilitate the surface acetylation of the microfibrils and hence the resin impregnation process. After the swelling pretreatment and the subsequent surface acetylation process, an optically transparent cotton fiber composite with a high regular light transmittance (83.23% at 600 nm) and a low CTE (19.5 ppm/K) was obtained. Finally, when this technique was used with a commercial cotton cloth, a transparent composite with a high total transmittance (88.5% at 600 nm) could be obtained.

Nanoparticle (NP)-carbon nanomaterial hybrid structures have garnered significant attention due to their synergistic effects. Based on their interesting properties, hybrid nanomaterial-based sensing platforms have been investigated to achieve high sensitivity and selectivity detection. In our study, binary-NP-decorated carbon nanotubes (bNP-CNTs) were successfully synthesized through a simple two-step method and applied as a biosensing platform. Gold (Au)/iron-oxide magnetic NP-decorated CNTs (Au/MNP-CNT) were used for influenza and norovirus DNA sensing channels. To demonstrate biosensing, first, the Au/MNP-CNTs were magnetically aligned on a Pt-interdigitated electrode, and then, a thiol-group-functionalized probe DNA was attached to the Au NP surface on the bNP-CNT hybrid structure through thiol chemistry. DNA hybridization between the target influenza or norovirus DNA and probe DNA was measured to monitor an electrical conductivity change of the Au/MNP-CNTs. Various concentrations of target DNA from 1 pM to 10 nM were monitored, and the limits of detection for influenza virus and norovirus were calculated to be approximately 8.4 pM and 8.8 pM, respectively. The specificity was confirmed using different mismatched DNA sequences, showing high specificity. Therefore, this Au/MNP-CNT-based DNA sensing system exhibited excellent detection potential, and such hybrid materials could be universally applied as a highly sensitive and selective biosensing system.

The current epidemic caused by the Zika virus (ZIKV) and the devastating effects of this virus on fetal development, which result in an increased incidence of congenital microcephaly symptoms, have prompted the World Health Organization (WHO) to declare the ZIKV a public health issue of global concern. Efficient probes that offer high detection sensitivity and specificity are urgently required to aid in the point-of-care treatment of the virus. In this study, we show that localized surface plasmon resonance (LSPR) signals from plasmonic nanoparticles (NPs) can be used to mediate the fluorescence signal from semiconductor quantum dot (Qdot) nanocrystals in a molecular beacon (MB) biosensor probe for ZIKV RNA detection. Four different plasmonic NPs functionalized with 3-mercaptopropionic acid (MPA), namely MPA-AgNPs, MPA-AuNPs, core/shell (CS) Au/AgNPs, and alloyed AuAgNPs, were synthesized and conjugated to L-glutathione-capped CdSeS alloyed Qdots to form the respective LSPR-mediated fluorescence nanohybrid. The concept of the plasmonic NP-Qdot-MB biosensor involves using LSPR from the plasmonic NPs to mediate a fluorescence signal to the Qdots, triggered by the hybridization of the target ZIKV RNA with the DNA loop sequence of the MB. The extent of the fluorescence enhancement based on ZIKV RNA detection was proportional to the LSPR-mediated fluorescence signal. The limits of detection (LODs) of the nanohybrids were as follows: alloyed AuAgNP-Qdot646-MB (1.7 copies/mL)) > CS Au/AgNP-Qdot646-MB (LOD =2.4 copies/mL) > AuNP-Qdot646-MB (LOD =2.9 copies/mL) > AgNP-Qdot646-MB (LOD =7.6 copies/mL). The LSPR-mediated fluorescence signal was stronger for the bimetallic plasmonic NP-Qdots than the single metallic plasmonic NP-Qdots. The plasmonic NP-Qdot-MB biosensor probes exhibited excellent selectivity toward ZIKV RNA and could serve as potential diagnostic probes for the point-of care detection of the virus.

Although transcatheter arterial chemoembolization (TACE) is the standard of care for intermediate-stage hepatocellular carcinoma (HCC), this is a largely heterogeneous disease that includes a subgroup of patients who do not benefit from TACE. The treatment strategy for this subgroup of patients currently remains an unmet need in clinical practice. Here, we performed a proof-of-concept study that lenvatinib may be a more favorable treatment option over TACE as an initial treatment in intermediate-stage HCC patients with large or multinodular tumours exceeding the up-to-seven criteria. This proof-of-concept study included 642 consecutive patients with HCC initially treated with lenvatinib or conventional TACE (cTACE) between January 2006 and December 2018. Of these patients, 176 who received lenvatinib or cTACE as an initial treatment and met the eligibility criteria (unresectable, beyond the up-to-seven criteria, no prior TACE/systemic therapy, no vascular invasion, no extrahepatic spread and Child&ndash, Pugh A liver function) were selected for the study. Propensity score matching was used to adjust for patient demographics. After propensity-score matching, the outcome of 30 patients prospectively treated with lenvatinib (14 in clinical trials, one in an early access program and 15 in real world settings) and 60 patients treated with cTACE as the initial treatment was compared. The change of albumin-bilirubin (ALBI) score from baseline to the end of treatment were &minus, 2.61 to &minus, 2.61 for 30 patients in the lenvatinib group (p = 0.254) and &minus, 2.66 to &minus, 2.09 in the cTACE group (p &lt, 0.01), respectively. The lenvatinib group showed a significantly higher objective response rate (73.3% vs. 33.3%, p &lt, 0.001) and significantly longer median progression-free survival than the cTACE group (16.0 vs. 3.0 months, 0.001). Overall survival was significantly longer in the lenvatinib group than in the cTACE group (37.9 vs. 21.3 months, hazard ratio: 0.48, p &lt, 0.01). In patients with large or multinodular intermediate-stage HCC exceeding the up-to-seven criteria with Child&ndash, Pugh A liver function, who usually do not benefit from TACE, lenvatinib provides a more favorable outcome than TACE.

522 Background: Intermediate-stage HCC is a heterogenous population with subgroups of patients that do not benefit from TACE. Hence, we conducted a matched cohort study to compare the efficacy of lenvatinib to TACE in intermediate-stage HCC patients with large or multinodular tumours exceeding the up-to-7 criteria. Methods: This study first identified 642 consecutive patients with HCC initially treated with lenvatinib or conventional TACE (cTACE) between January 2006 and December 2018. Of these patients, 176 who received lenvatinib or cTACE as an initial treatment and met the eligibility criteria [unresectable, beyond the up-to-7 criteria, without prior TACE/systemic therapy, no vascular invasion, no extrahepatic spread and Child-Pugh A liver function] were selected. Propensity score matching was used to adjust for patients’ demographics. Results: After propensity-score matching, outcome of 30 patients prospectively treated with lenvatinib (14 in clinical trials [1 Phase II and 13 Phase III REFLECT trial], 1 in early access program and 15 in real world setting) and 60 patients treated with cTACE as the initial treatment was compared. The lenvatinib group showed a higher objective response rate (73.3% vs. 33.3%; p < 0.001) and longer median progression-free survival than the cTACE group (16.0 vs. 3.0 months; p < 0.001). Median overall survival was also significantly longer in the lenvatinib group than in the cTACE group (37.9 vs. 21.3 months; hazard ratio: 0.48, p < 0.01). The change of ALBI score from baseline to the end of treatment were -2.61 to -2.61 for 30 patients in lenvatinib group (p = 0.254) and -2.66 to -2.09 in cTACE group (p < 0.01), respectively. Conclusions: In patients with large or multinodular intermediate-stage HCC exceeding the up-to-7 criteria with Child-Pugh A liver function, who usually do not benefit from TACE, lenvatinib is associated with better outcome than TACE. In particular, leventinib is associated with preservation of hepatic function during treatment while TACE is associated with deterioration of hepatic function.

There is heightened interest to devise therapies that target the oncometabolome. We show that kinase inhibitors (KIs) and biguanides synergistically target melanoma, leukemia, and breast, colon and renal cancer cells, but not non-transformed cells. Metabolic profiling confirmed opposing effects of KIs and biguanides on glycolysis, but this was insufficient to explain the observed synergy between the drugs. Rather, we define a critical role for the synthesis of non-essential amino acids (NEAA) aspartate, asparagine and serine as well as reductive glutamine metabolism, in determining the sensitivity of cancer cells to KI - biguanide combinations. The mTORC1/4E-BP axis regulates aspartate, asparagine and serine synthesis by modulating translation of mRNAs encoding PC, ASNS, PHGDH and PSAT1. Ablation of 4E-BP1 and 2 results in a dramatic increase in serine, aspartate and asparagine levels and a substantial decrease in sensitivity of breast cancer and melanoma cells to KI - biguanide combinations. In turn, efficacy of KI - biguanide combinations is impeded by HIF1α and sustained reductive glutamine metabolism. These findings identify hitherto unappreciated translational reprograming of NEAA synthesis and HIF1α-dependent stimulation of reductive glutamine metabolism as critical metabolic vulnerabilities of cancer that underpin synergy between KIs and biguanides.

MicroRNAs (miRNAs) play critical roles in a variety of biological processes through widespread effects on protein synthesis. Upon association with the miRNA-induced silencing complex (miRISC), miRNAs repress target mRNA translation and accelerate mRNA decay. Degradation of the mRNA is initiated by shortening of the poly(A) tail by the CCR4–NOT deadenylase complex followed by the removal of the 5′ cap structure and exonucleolytic decay of the mRNA. Here, we report a direct interaction between the large scaffolding subunit of CCR4–NOT, CNOT1, with the translational repressor and decapping activator protein, DDX6. DDX6 binds to a conserved CNOT1 subdomain in a manner resembling the interaction of the translation initiation factor eIF4A with eIF4G. Importantly, mutations that disrupt the DDX6–CNOT1 interaction impair miRISC-mediated gene silencing in human cells. Thus, CNOT1 facilitates recruitment of DDX6 to miRNA-targeted mRNAs, placing DDX6 as a downstream effector in the miRNA silencing pathway.

Background: This study investigated the impact of baseline liver function according to the Child&ndash, Pugh score and ALBI (albumin-bilirubin) grade on the outcomes of patients with unresectable hepatocellular carcinoma treated with lenvatinib. Methods: A total of 82 lenvatinib treated patients were included. The correlations of baseline liver function according to the Child&ndash, Pugh score and ALBI grade with treatment outcomes, including objective response rate per mRECIST (modified Response Evaluation Criteria in the Solid Tumor), time to treatment failure, treatment duration, and likelihood of treatment discontinuation due to adverse events, were assessed in patients with hepatocellular carcinoma treated with lenvatinib. Patients were divided into four groups: (1) Child&ndash, Pugh score 5 and ALBI grade 1 (group 1), (2) Child&ndash, Pugh score 5 and ALBI grade 2 (group 2), (3) Child&ndash, Pugh score 6 (group 3), and (4) Child&ndash, Pugh score &ge, 7 (group 4). Univariate and multivariate analyses were performed to identify the factors contributing to the objective response rate and likelihood of discontinuation due to adverse events. Results: Among the 82 patients analyzed, group 1 had the highest objective response rate (57.1%) and the lowest likelihood of treatment discontinuation because of adverse events (11.1%) among the four groups (p &lt, 0.05 and p &lt, 0.05). Multivariate analysis identified ALBI grade 1 and baseline AFP level &lt, 200 ng/mL as the significant predictors of a high objective response rate (p &lt, 0.01), and confirmed that patients with ALBI grade 1 had the lowest probability of treatment discontinuation due to adverse events (p &lt, 0.01). Conclusions: Patients with Child&ndash, Pugh score of 5 and ALBI grade 1 predicted a higher response rate and lower treatment discontinuation due to adverse events by lenvatinib treatment.

Summary There is increasing interest in therapeutically exploiting metabolic differences between normal and cancer cells. We show that kinase inhibitors (KIs) and biguanides synergistically and selectively target a variety of cancer cells. Synthesis of non-essential amino acids (NEAAs) aspartate, asparagine, and serine, as well as glutamine metabolism, are major determinants of the efficacy of KI/biguanide combinations. The mTORC1/4E-BP axis regulates aspartate, asparagine, and serine synthesis by modulating mRNA translation, while ablation of 4E-BP1/2 substantially decreases sensitivity of breast cancer and melanoma cells to KI/biguanide combinations. Efficacy of the KI/biguanide combinations is also determined by HIF-1α-dependent perturbations in glutamine metabolism, which were observed in VHL-deficient renal cancer cells. This suggests that cancer cells display metabolic plasticity by engaging non-redundant adaptive mechanisms, which allows them to survive therapeutic insults that target cancer metabolism.

Adipogenesis is an important component of adipose tissue development and is critically related to obesity. A cascade of transcription factors is involved in adipogenesis, in which peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding proteins (C/EBPs) play pivotal roles. Bone morphogenetic proteins (BMPs) and Smad proteins are implicated in this cascade, although the precise regulatory mechanisms have yet to be elucidated. Here, we show that Tob2, a member of the Tob/BTG antiproliferative protein family, inhibits adipogenesis by interfering with Smad signaling. tob2 expression is downregulated in the white adipose tissue of high-fat diet-induced or genetically mutated obese mice. Consistent with this, tob2(-/-) mice exhibit increased adiposity with augmented expression of the genes encoding the type 1A BMP receptor (BMPR1A) and PPARγ2 as well as their target genes. We further show accelerated adipogenesis in primary tob2(-/-) preadipocytes. Furthermore, exogenously expressed Tob2 inhibits adipogenic differentiation of 3T3-L1 preadipocytes: the Tob2 protein suppresses PPARγ2 transcription by inhibiting BMP2-induced Smad1/5 phosphorylation through its interaction with Smad6 and by sequestering C/EBPα from the PPARγ2 promoter. Thus, Tob2 negatively regulates adipogenesis by inhibiting PPARγ2 expression.

We demonstrated that castration enhanced the expression of uncoupling protein 1 (Ucp1), a thermogenic protein, in brown adipose tissue (BAT) and subcutaneous (sc) white adipose tissue (WAT) in male mice. Castration of male mice increased body temperature and reduced body weight gain compared with those of sham-operated mice. BAT Ucp1 mRNA expression in castrated male mice was significantly higher than that in sham-operated mice. Histologically, cells with multilocular fat droplets were observed in the castrated inguinal scWAT. Immunohistochemical staining revealed that these cells positively reacted with the anti-Ucp1 antibody. The Ucp1-positive area near the inguinal lymph node in the castrated WAT was extensive compared with that of the sham-operated WAT. Castration-induced Ucp1 up-regulation in scWAT was suppressed by high-fat diet feeding. These findings suggest that thermogenesis by BAT activation and scWAT browning contribute to castration-induced inhibition of body weight gain. However, considering that the effect of castration was blunted by high-fat diet consumption, thermogenesis stimulation in response to castration is inhibited by chronic over-nutrition.

Lipodystrophy involves a loss of adipose tissue. In mice, disruption of adipose tissue Cnot3, a subunit of the CCR4-NOT deadenylase complex, causes adipose tissue anomalies. In Cnot3ad-/- mice, white adipose tissue (WAT) decreases concomitantly with enhanced inflammation, whereas brown adipose tissue increases and contains larger lipid droplets. Cnot3ad-/- mice show hyperinsulinemia, hyperglycemia, insulin resistance, and glucose intolerance, and cannot maintain body temperature during cold exposure. Increased expression of inflammatory genes and decreased leptin expression also occur in Cnot3ad-/- WAT, achieving levels similar to those in lipodystrophic aP2-nSrebp1c and Ppargldi/+ mice; thus, Cnot3ad-/- mice exhibit lipodystrophy.

A practical total synthesis of (2S,3S,4R)-l-O-(α-d-galactopyranosyl)-N-hexacosanoyl-2-amino-l,3,4-octadecanetriol (KRN7000), an antitumorial and immunostimulatory glycosphingolipid derived from agelasphins, was achieved in 14 steps starting from d-lyxose in a 16% overall yield.

The oxygen consumption calorimetric method is generally used to measure the heat release rate (HRR) of combustible items. However, this method might yield uncertain results in gas concentrations when water is being discharged, such as from a sprinkler head.In this study, we attempt to devise an appropriate and simple method for measuring HRR during water discharged. A relation between HRR under free-burning conditions, which is calculated from the mass loss rate, and the radiative heat flux are evaluated experimentally. The radiative heat flux during water discharge to take into account, Mie theory is applied to estimate radiative attenuation via absorption by water droplets. The effect of water droplets is verified by experimental data.

Oxygen Consumption Calorimetric Method is generally used for measuring heat release rate (HRR) of combustible items. However, this method might have an uncertain result for gas concentration in case of during water discharged such as sprinkler. In this study, we tried to find out an appropriate and simple method for measuring HRR during water discharged. A relation between HRR in free burning condition, which was calculated by mass loss rate, and radiative heat flux was obtained experimentally. The Mie theory was applied to estimate a radiative attenuation by the absorption of water droplet, because the radiative heat flux during water discharged needs to take it into account. As a result, the radiative attenuation calculated by the theory was verified by experimental data.

Poly(phenylene sulfide) (PPS) films were modified by Ar, O2, N2 and NH3 plasmas in order to improve their adhesion to copper metal. All four plasmas modified the PPS film surfaces, but the NH3 plasma modification was the most effective in improving adhesion. The NH3 plasma modification brought about large changes in the surface topography and chemical composition of the PPS film surfaces. The peel strength for the Cu/plasma-modified PPS film systems increased linearly with increasing surface roughness, R a or R rms, of the PPS film. The plasma modification also led to considerable changes in the chemical composition of the PPS film surfaces. A large fraction of phenylene units and a small fraction of sulfide groups in the PPS film surfaces were oxidized during the plasma modification process. Nitrogen functional groups also were formed on the PPS film surfaces. The NH3 plasma modification formed S—H groups on the PPS film surfaces by reduction of S—C groups in the PPS film. Not only the mechanical interlo...

A simple method for the formation of microbial biofilms of three species, Pseudomonas fluorescens, Pseudomonas aeruginosa, and Klebsiella pneumoniae, on a small glass slide was established, and its suitability for evaluation of disinfectant efficacy was examined. The biofilms formed were observed in situ by confocal laser scanning microscopy (CLSM). Using the biofilms established, biocidal efficacy of several halogen biocides, such as hypochlorite (HOCl), bromochlorodimethylhydantoin (Br, Cl-DMH), ammonia monochloramine (NH2Cl), a stabilized hypobromite biocide named STABREX®, and a mixed solution of NH4Br and HOCl, was evaluated. The formation of NHBrCl in the mixed solution was indicated by UV spectra analysis. Biofilm cells were more resistant to these biocides than planktonic cells and the extent of resistance varied with the biocide tested. Among the biocides tested, the biocidal potency of HOCl was the most susceptible to the change brought about by biofilm formation. By CLSM observation, differences in biofilm conformation were revealed between the microbial species. The efficacy of the biocide tested varied with the structure of biofilms formed. The assay method developed in the present study would be useful for further investigation on biofilm disinfection.

Mesoporous silica (MPS) was used for poly(ethylene oxide) (PEO)-based solid polymer electrolytes as novel inorganic filler. For improvement in ionic conductivity in solid state, a room temperature ionic liquid (IL), 1-ethyl-3-methylimidazolium tetrafluoroborate, was introduced into periodic nano-tunnels of MPS, and the modified MPS (IL-MPS) was filled with PEO-LiBF4 electrolyte. Ionic conductivity of neat-MPS-filled composites was approximately 4-fold higher than that of the original electrolyte. On the other hand, the conductivity was more than 11-fold enhanced by addition of IL-MPS, to be more than 10−6 S/cm at 30°C and at least 10 wt% silica contents. The conductivity increased with increasing IL-MPS contents, to be a maximum value of approximately 3×10−6 S/cm at 30°C and at 40 wt%. Dynamic mechanical measurements for neat- and IL-MPS composites revealed that the addition of fillers improves storage modulus of PEO-based electrolytes at room temperature. The addition of IL-MPS was able to realize the improvement in both ionic conductivity and storage modulus.

Woodceramics has been studied as an Ecomaterial, and is expected to have applications in a wide variety of fields. In this report, thermogravimetry and differential thermal analysis of Woodceramics with changing concentration of oxygen was conducted. Experiments in chemical reaction kinetics were also performed in order to clarify the thermo-physical and thermo-chemical properties of Woodceramics in the presence of oxygen. The experimental results show that both mass loss curves and differential heat curves are dependent on the concentration of oxygen. In addition, the reaction rate law of the thermal degradation of Woodceramics with change in concentration of oxygen is reported to verify the suitability of the method.

We compared effects of α-galactosylceramide (α-GalCer) and its 3α- or 3β-galactosylated derivatives on the proliferation of murine spleen cells. The 3α-galactosylated α-GalCer showed stongger proliferative response than the parental α-GalCer, but the 3β-galactosylated α-GalCer possessed weaker activity than the α-GalCer. In addition, α-Gal-3-Cer did not show immunostimulatory activity.

Uno, A., N. Takeda, A. Horii, M. Morita, Y. Yamamoto, A. Yamatodani and T. Kubo. Histamine release from the hypothalamus induced by gravity change in rats and space motion sickness. Physiol Behav 61(6) 883–887, 1997.—Freely moving rats were exposed to 2 g hypergravity in an animal centrifuge device to produce motion sickness. Histamine release from the anterior hypothalamus of the rats was measured in vivo with a microdialysis technique. After a 2-h load of 2 g hypergravity, rats ate kaolin. Because pica, eating a nonnutritive substance such as kaolin, is a behavioral index of motion sickness in rats, this finding indicates that the rats suffered from motion sickness. During 2 g hypergravity for 2-h, histamine release from the hypothalamus was transiently increased. In contrast, neither the transient increase of histamine release nor the kaolin consumption were induced by 2 g hypergravity in bilaterally labyrinthectomized rats. Pretreatment with α -fluoromethylhistidine, an inhibitor of histamine-synthesizing enzyme, decreased both the basal and hypergravity-induced releases of histamine from the hypothalamus and suppressed the kaolin consumption induced by hypergravity. Taken together, these findings suggest that the vestibular information of changes in gravity activate the histaminergic neuron system, resulting in the development of motion sickness. More prolonged stimulation, a 4-h load of 2 g hypergravity, induced significant increase of kaolin consumption on postdays 1–3, though rats ate kaolin on postdays 1–2 after 2 g hypergravity for 2 h. During 2 g hypergravity for 4 h, the initial transient increase of histamine release was followed by the gradual increase of histamine release after the end of centrifugation. It is suggested that rats adapted to the hypergravity environment after centrifugation for 4 h, but not 2 h, so that the change in gravity from 2 g to 1 g became a provocative stimulation. We, therefore, concluded that motion sickness in rats induced by a negative change in gravity can be used as a simulation of space motion sickness, which is induced by exposure to microgravity. Histaminergic activation in the development of motion sickness induced by negative change in gravity might be an underlying mechanism of space motion sickness.

We examined the life-span-prolonging effects of five kinds of α-Galactosylceramides (α-GalCers) on mice irradiated with lethal dose (9 Gy) of X ray, and found that they show strong radioprotective activities even when they are administered to mice after the irradiation. These results suggest that α-GalCers are useful as radioprotective agents.

Agelasphin-9b, (2S,3S,4R)-1-O-(alpha-D-galactopyranosyl)-16-methyl-2- [N-((R)-2- hydroxytetracosanoyl)-amino]- 1,3,4-heptadecanetriol, is a potent antitumor agent isolated from the marine sponge Agelas mauritianus. Various analogues of agelasphin-9b (a lead compound) were synthesized, and the relationship between their structures and biological activities was examined using several assay systems. From the results, KRN7000, (2S,3S,4R)-1-O-(alpha-D- galactopyranosyl)-2-(N-hexacosanoylamino)-1,3,4-octadecanetriol , was selected as a candidate for clinical application.

To examine antitumor activities of monoglycosylceramide, we synthesized α-, β-galactosylceramides and α-, β-glucosylceramides which have the same ceramide portion, and four kinds of diastereomers of the ceramide portion in an α-galactosylceramide.

A novel method, a combination of a micro–injection and in situ hybridization cytochemistry, was developed for the examination of gene expression in Erysiphe graminis f. sp. hordei. In view of its high cellular content, hence high probability of hybridization with corresponding probes, cytoplasmic rRNA was chosen as the target and hybridized with a micro–injected photobiotin–labelled nucleic acid probe. The rDNA sequence was isolated from a genomic library of the fungus by the, use of cDNA derived from 28S RNA of Fusarium oxysporum f. sp. lycopersici, and the complementry RNA strand was synthesized in vitro for a probe. Since neither intact nor fixed conidial cells took up FITC–labelled albumin, the photo, biotin–conjugated RNA probe was introduced into cytoplasm of conidiospores by a pricking method. Positive hybridization was visualized by the colour–generating reaction catalyzed by biotinylated enzyme (alkaline phosphatase) which was first bound to the hybridized photobiotinlabelled probe. Specific hybridization was detected in cytoplasm of more than 80% of pricked conidiospores. A similar result was obtained when a probe was introduced into appressoria and haustoria formed on/in barley coleoptile epidermal cells. Hybridization was also observed in these structures when a double–stranded rDNA probe was introduced by pricking.

New glycosphingolipids, named agelasphins ( 1-8 ), have been isolated by antitumor and immunostimulatory bioassay-guided purification from an extract of a marine sponge, Agelas mauritianus . Strongly active agents in agelasphins had characteristic α-galactosylceramide structures, the isolation of which from natural products has not previously been reported. The absolute configurations of agelasphins were elucidated by the total synthesis.

Agelasphin-9b, one of the α-galactosylceramides from an Okinawan marine sponge, was synthesized, and the absolute stereochemistry was determined.

CCR4, an evolutionarily conserved member of the CCR4-NOT complex, is the main cytoplasmic deadenylase. It contains a C-terminal nuclease domain with homology to the endonuclease-exonuclease-phosphatase (EEP) family of enzymes. We have determined the high-resolution three-dimensional structure of the nuclease domain of CNOT6L, a human homologue of CCR4, by X-ray crystallography using the single-wavelength anomalous dispersion method. This first structure of a deadenylase belonging to the EEP family adopts a complete alpha/beta sandwich fold typical of hydrolases with highly conserved active site residues similar to APE1. The active site of CNOT6L should recognize the RNA substrate through its negatively charged surface. In vitro deadenylase assays confirm the critical active site residues and show that the nuclease domain of CNOT6L exhibits full Mg(2+)-dependent deadenylase activity with strict poly(A) RNA substrate specificity. To understand the structural basis for poly(A) RNA substrate binding, crystal structures of the CNOT6L nuclease domain have also been determined in complex with AMP and poly(A) DNA. The resulting structures suggest a molecular deadenylase mechanism involving a pentacovalent phosphate transition.

Long-term potentiation (LTP), the increase in synaptic strength evoked by high-frequency stimulation, is often considered to be a cellular model for learning and memory. The validity of this model depends on the assumptions that physiological stimuli can induce LTP in vivo and that the resulting synaptic modifications correlate with behavioural changes. However, modifiable synapses are generally embedded deep in complex circuits. In contrast, the goldfish Mauthner (M)-cell and its afferent synapses are easily accessible for electrophysiological studies, and firing of this neuron is sufficient to trigger fast escape behaviour in response to sudden stimuli1,2. We have previously shown that tetanic stimulation can induce LTP of the feedforward inhibitory synapses that control the excitability of the M-cell3,4. Here we report that natural sensory stimulation can induce potentiation of this inhibitory connection that resembles the LTP induced by afferent tetanization. Furthermore, comparable acoustic stimulation produced a parallel decrease in the probability of the sound-evoked escape reflex. Thus we demonstrate for the first time, to our knowledge, a behavioural role for the long-term synaptic strengthening of inhibitory synapses.

We compared the immunostimulatory effects of chemically synthesized alpha-galactosylceramides (alpha-GalCers), alpha-glucosylceramides (alpha-GluCers), 6"-monoglycosylated alpha-GalCer and 6"- or 4"-monoglycosylated alpha-GluCer and made the following observations: (1) the length of the fatty acid side chain in the ceramide portions greatly affects the immunostimulatory effects of alpha-GalCers and alpha-GluCers; (2) the configuration of the 4"-hydroxyl group of the inner pyranose moiety plays an important role in the immunostimulatory effects of monoglycosylated alpha-D-pyranosylceramides; (3) the free 4"-hydroxyl group of the inner pyranose of monoglycosylated alpha-D-pyranosylceramides plays a more important role in their immunostimulatory effects than the free 6"-hydroxyl group.

The two-dimensional govering equations including an exothermic chemical reaction, a heat convection a buoyancy effect and a diffusion for the spontaneous combustion of coal storage are derived from the thermophysical and thermochemical considerations. The oxidative pyrolysis of coal is assumed to be represented by a two-step chemical reaction. These governing equations are approximated by using the difference equations of Crank and Nicholson's implicit finite-difference method, and are solved numerically by the computer. The spontaneous combustion time of coal storage is predicted by the calculated results. Furthermore, the lowest spontaneous combustion time of coal storage is also calculated numerically on the adiabatic condition.

The title compound, one of the stereoisomers of physiologically interesting indolizidine alkaloid swainsonine, has been synthesized from the known methyl 3-azido-4,6-O-benzylidene-3-deoxy-α-D-altropyranoside.

The molecular structure of an anhydrous zinc 8-quinolinolate obtained by sublimation has been determined by means of X-ray diffraction. The complex forms triclinic crystals; a=11.858(1), b=13.019(2), c=10.834(1) A, α=106.56(1), β=109.00(1), and γ=74.14(1)°, space group P\bar1 (No. 2) with one [Zn(C9H6NO)2]4 molecule. The structure was solved by the heavy atom method and refined by the block-diagonal least-squares procedure to R=0.043 for 3320 non-zero reflections. The molecule is centrosymmetric and tetrameric; four [Zn(C9H6NO)2] units being connected by oxygen atoms of 8-quinolinolate ligands. Two types of bridging oxygen atoms were found. Two crystallographically independent zinc atoms take different geometries, hexa-, and pentacoordinations.

Thermogravimetry of coal has been carried out by changing the oxygen concentration of the heating atmosphere, and the effect of oxygen in the concentration of 1-60% flow gas has been discussed based on the thermogravimetric curves. The kinetic parameters of exothermic oxidizing reaction of coal in the thermogravimetric, which has one of the critical effects on the spontaneous combustion of coal storage have been discussed, and also the available parameters have been evaluated.

(−)-8a-epi-Swainsonine (4), one of the stereocongeners of physiologically interesting indolizidine alkaloid (−)-swainsonine (1), has been synthesized starting from known methyl 3-azido-4,6-O-benzylidene-3-deoxy-α-D-altropyranoside. The α-D-mannosidase inhibitory activity of 4 was compared with natural 1.

The isothermal thermogravimetric analysis of coal has been carried out by changing the oxygen concentration of the heating atmosphere at the temperature range of 400, 450, 500 and 600°C. The effect of oxygen concentrations of 1 - 50% of the flow gas is discussed based on the weight loss curves and the IR spectra. The kinetic parameters of the exothermic oxidizing reactions of coal in the isothermal thermogravimetric analysis have been evaluated.

A method to measure circulating blood volume continuously on a conscious rat was developed using the dilution method of 51Cr-labelled red cell and changes in blood volume after drinking and food intake were monitored. In splenectomized rats, the blood volume showed a transient decrease of 0.1-0.2 ml/100 g body wt. about 30 min after food intake, while increasing by 0.1-0.4 ml/100 g body wt. after water ingestion. Thus, blood volume showed fluctuations following water and food intake ranging from 2-8% of the circulating blood volume.

Rats were rotated about two parallel axes to produce motion sickness, and the histamine levels in their hypothalamus and pons-medulla oblongata were measured. Rotation for 60 min induced kaolin intake, which is a behavioral index of motion sickness in rats, and increased the histamine levels in the hypothalamus and pons-medulla oblongata, the highest levels occurring after 15 min of rotation. In bilaterally labyrinthectomized rats, no rise in histamine level was observed. alpha-Fluoromethylhistidine (alpha-FMH), which depletes the neural component of histamine in the brain, suppressed kaolin intake induced by rotation. These findings demonstrated that the histaminergic neuron system contributes to development of motion sickness, and suggested that alpha-FMH may be effective as an anti-motion sickness drug.

Three kinds of neurotransmitters (histamine, acetylcholine, and catecholamine) are thought to be important in the neural processes of motion sickness because antihistaminics, scopolamine, and amphetamine are effective in preventing motion sickness. In this study, we examined the neurochemical and neuropharmacologic features of motion sickness in rats. Based on our results, we propose the following hypotheses for the neurochemical mechanisms of motion sickness: (1) the histaminergic neuron system is involved in the signs and symptoms of motion sickness, including vomiting; (2) the acetylcholinergic neuron system is involved in the processes of habituation to motion sickness, including neural store mechanisms; and (3) the catecholaminergic neuron system in the brain stem is not related to the development of motion sickness.