Amyloid β (Aβ) plays a key role in the pathology of Alzheimer’s disease (

) and is toxic owing to its ability to aggregate into oligomers and fibrils. Aβ has high aggregative ability and potent toxicity due to the “toxic turn” at positions and 23. Furthermore, APP knock-in mice producing P-Aβ with the toxic turn exhibited -related phenotypes such as cognitive impairment, Aβ plaque accumulation, and tau hyperphosphorylation. In these mice, it is suggested that the activation of neuroinflammation and dysregulation of hypoxia-inducible factor (HIF) expression in the hippocampus contribute to the pathogenesis of -related phenotype. However, it remains unclear which cells are responsible for the dysregulation of HIF expression and the neuroinflammation which was induced by P-Aβ with the toxic turn. Here, we investigated the effects of chronic treatment with P-Aβ42 and lipopolysaccharides (LPS) on the inflammatory response in BV-2 microglia. Chronic treatment with P-Aβ42 and LPS increased nitric oxide production and the expression of interleukin- (IL-), whereas it reduced the expression of HIF-α and HIF-3α in BV-2 microglia. The reduction of HIF-α caused by P-Aβ42 and LPS was milder than that caused by LPS. Furthermore, chronic treatment with P-Aβ42 and LPS increased the nuclear translocation of nuclear factor-kappaB (NF-κB). P-Aβ42 could enhance the inflammatory response of microglia with abnormal HIF signaling and contribute to the progression of pathology.

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We screened the differentiation-inducing activities of 39 mushroom extracts from Akita prefecture, Japan, on the mouse osteoblastic cell line, MC3T3-. Sixteen phosphate buffered saline (PBS), 8 boiled PBS, 14 ethanol and 12 methanol extracts induced alkaline phosphatase (ALP) activities, an indicator of MC3T3- cell differentiation. The enzyme activities were markedly induced by extracts of Tricholoma auratum, and we isolated the active compound from methanol extracts of this mushroom. Physical data for the isolated active compound were identical to those for (,24R)-ergosta-7,-diene-3β,5α,-triol (). induced ALP activities of MC3T3- cells and promoted cell proliferation. To investigate the relationships between the chemical structure and differentiation-inducing activity of the compound, ALP-inducing activities of MC3T3- cells by , ergosterol (2), ergocalciferol (3), cholesta-3β,5α,-triol (4), 7-dehydrocholesterol (5) and cholecalciferol () were tested. The enzyme activities of MC3T3- cells were increased 3.0-fold by 10 μM and 2.4-fold by 10 μM 4. However, 2, 3, 5 and did not induce MC3T3- cell ALP activity at 0.—10 μM. These results suggested that the OH groups at C-5 and/or C- of and 4 played an important role in their differentiation-inducing activities on MC3T3- cells. Furthermore, suppressed induction of MC3T3- cell apoptosis by serum starvation.

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In the first part of the present work the interaction of glycophorin with dimyristoylphosphatidylcholine (DMPC) is studied by freeze fracture electron microscopy, densitometry, calorimetry, and 90° static light scattering. An exothermic lipid/protein interaction energy of W_P=190 kJ•mol-

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was found by application of the well known Van Laar relation for the displacement of the freezing point and the Gibbs-Duhem relationship. Secondly, the effects of Ca²⁺ on the lipid/protein interaction were studied. Following Ca²⁺ addition a remarkable decoupling of the interaction of the glycophorin head group with the bilayer surface was revealed by densitometry and gold-labeling electron microscopy. It is estimated that about 80% of lipid once disturbed by the adsorption of glycophorin head groups is decoupled after addition of Ca²⁺. Thirdly, the selective interaction of glycophorin with binary lipid mixtures was studied, including the mixtures of DMPC with dimyristoylphosphatidylserine (DMPS) and dilauroylphosphatidylcholine (DLPC), and the mixture of dipalmitoylphosphatidylcholine (DPPC) with DLPC.

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The acetone extracts from three samples of the hepatopancreas of the poisonous scallops obtained on the Okhotsk Coast of Hokkaido Island were fractionated into two parts, hexane soluble fraction (fraction H) and 85% aqueous ethanol soluble fraction (fraction ) by partition to two layers. The majortoxic components in the mouse assay of “diarrheic shellfish toxin” by intra-peritoneal injection were found to be free unsaturated fatty acids showed the following toxicity in MU per g, 18: n- 35, 18:2 n- , 18:3 n-3 167, 18:4 n-3 , 20:5 n-3 167, and : n-3 , respectively. Toxicity of the fraction Hin MUper g was much lower than that of the fraction . However, the toxicity of the fraction H per g of the hepatopancreas was about twice that of the fraction , since the fraction Hwas much more abundant than the fraction in the hepatopancreas. The method for the assay of the diarrhetic shellfish toxin must be reexamined by considering the toxic effect of the free unsaturated fatty acids.

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アトピー性皮膚炎 (以下, ) の犬60頭と癈痒を有する非犬53頭に皮内反応および血清特異IgE抗体測定 (以下, 血清検査) を実施した. 犬の皮内反応陽性率はノミ40.0%, チリダニ (以下, ダニ) 96.7%, 花粉18.2%, 血清検査陽性率はノミ13.3%, ダニ.3%, 花粉33.3%であった. 非犬の皮内反応陽性率はノミ15.%, ダニ5.7%, 花粉.7%, 血清検査陽性率はノミ.4%, ダニ23.7%, 花粉.7%であった. 犬におけるダニ陽性抗原の内訳は, 皮内反応がコナヒョウヒダニ (以下, Df) 85.2%, ヤケヒョウヒダニ (以下, Dp) 29.%, 血清検査がDf.3%, Dp.2%であった. 非犬におけるダニ陽性抗原の内訳は, 皮内反応がDf7.%, Dp0%, 血清検査がDf23.7%, Dp7.%であった. 本邦の犬に関与する抗原として, Dfを中心としたダニがきわめて重要であることが明らかになった.

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Chemical synthesis of (, 24R)- and (, 24S)-, 24-dihydroxy--vitamin D₃ has been achieved starting with the commercially available dinorcholenic acid acetate. Synthesis involved introduction of the -hydroxy group by a reduction of the , 2-epoxide generated by epoxidation of the , 4, -trien-3-one. The side chain on the steroid was then constructed by means of a Wittig reaction followed by introduction of the Δ⁷ bond by standard methods and its protection with -phenyl-, 2, 4-triazoline-3, 5-dione. Subsequent reduction of the hydroxy groups in the steroid side chain followed by reduction of the Diels-Alder addition products yielded the both 24-isomers. The 5, 7-dienes were irradiated and the corresponding vitamin D compounds isolated. Nuclear magnetic resonance was used to identify individual isomers. The (, 24S)-, 24-hydroxyvitamin D₃ compound bound equally well to the chick intestinal cytosol receptor as , 25-dihydroxyvitamin D₃, while the 24R-isomer was approximately ten times less active. In vivo, both isomers were less active than , 25-dihydroxyvitamin D₃ ; however, the 24S-isomer was considerably more active than the 24R-isomer approaching the activity of , 25-dihydroxyvitamin D₃.

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Background: Exenatide (EXE), a prototypical GLP-

R agonist, is known as glucoregulator, antiobesogenic and antidyslipidemic in hyperlipidic and hyperglucidic diet-induced obesity in rats (DIO). Objective: To evaluate bone effects of DIO and DIO treatment with EXE (DIO-). Methods: 72-75-day-old male rats had access only to (i) hyperlipidic food (5.2 kcal/g) and 30% sucrose solution for drinking (.2 kcal/mL), or (ii) received normocaloric diet (3 kcal/g) and were allowed to feed and to drink water

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libitum. 122-125-day-old rats with 20% overweight were selected from i as obese and those with normal weight were selected from ii as control (C) animals. Thus, obese animals remained untreated (DIO) or were treated with 10 μg EXE/kg sc (DIO-) daily, for 20 days. Plasma levels of insulin (INS), leptin (LEP), osteocalcin (OCN), carboxy-terminal telopeptide of type collagen (CTX-) (ng/mL), as well as calcitonin (CT) and procollagen type amino-terminal propeptide (PNP) (pg/mL) were measured by ELISA. Bone mineral density of femur (BMDF) (g/cm³) was measured by X-rays. Results: DIO exhibited similar INS (12.±., n=4) and CT (2.80±.05, n=4), higher LEP (0.33±0.04, n=5) and lower CTX- (0.48±0., n=3) than C. The treatment of DIO with EXE restored LEP (0.04±0.02, n=5), decreased CTX- (0.50±0., n=5) and increased CT (.87±0.72, n=5). The levels of OCN (.58±0.41, n=5), PNP (92.64±16.89, n=5) and BMDF (.±0.07, n=5) of C and those of DIO and DIO- were similar. Conclusions: Despite of increased LEP, decreased CTX- and normal OCN, PNP and BMDF reflect a relative normal balance in bone turnover in DIO. Mechanical overloading due to high body mass is known as a factor that promotes this normal condition. Given that EXE decreases 14% body mass of DIO, the present study suggests that normalization of LEP and increased CT and decreased CTX- are concomitant beneficial effects of EXE that contribute for maintaining bone turnover under decreased mechanical load in DIO.

Supported by FAPESP, CNPq and CAPES

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Aggregation of the 42-mer amloid β proptide (Aβ42) plays a pirotal role in the pathogenesis of Alzheimer's disease (). Aβ42 is physiologically produced from amyloid precursor protein by two proteases, while Aβ42 aggregates to form the toxic oligomer causing the cognitive impairment and synaptic loss in the presence of metals, oxidative stress, and abnormal lipid proteins. Although the imunotherapy targeting Aβ42 affrefates has been proved useful, the clinical trials are conductiong with caution because of severe adverse effects in some cases. We hypothesize these adverse effets could be due to excessive immunoreactions derived from the unintended removal of physiological Aβ42. Our recent studies of solid-state NMR and systematic proline replacement showed a toxic conformer of Aβ42 with a turn at Glu and Asp23 as well as a non-toxic one with a turn at positions Gly25 and Ser26 (Fig. ). Here we report a monoclonal antibody ofr the toxic Aβ42, in which P-Aβ10-35, a minimum moiety for neurotoxocity including the toxic turn at Glu and Asp23, was used as a hapten (Fig. ). The selected clone (11A) inhibited the neurotoxocity of Aβ42 and P-Aβ42 on PC12 cells estimated by MTT assay (Fig. 4). Immunohistochemical studies showed that not only extracellular but intracellular amyloid was stained in the brains of patients (Fig. 5). 11A recognized oligomers rather than the monomer of Aβ in Western blots using human tissues (Fig. ). These results suggest that 11A can detect Aβ42 assembles containing the toxic turn at Glu and Asp23 within cells. 11A might be applicable to anti-Aβ therapeutic approaches.

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The numerical values of the intervals betrween optieal levels are competed for the configurations *⁹4s, 5s, s and 7s of Cu⁺, according to the general expression of energy-levels derived in the previous paper The self-consistent field radial functions computed by Hartree adn Hartree are used fors, 2s, 2p, 3s, 3p and 3d. Those of 4s, 5s, .s and are ealenlated from Hartree Hartree's core-functions by the numerical integrations. The calculated results are shown in Table I.The agreement with experiment is satisfactory

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Glucosylceramide (-Cer) was isolated from the spermatozoa of the starfish, Asterias amurensis. The long-chain bases of the glycolipid consisted of dihydroxy (d18:2, d18:3, d19:3, and d:2), and trihydroxy (t:) types. Long-chain aldehydes derived from them were analyzed mainly by proton nuclear-magnetic resonance to determine the detailed structures. Two of the tri-unsaturated bases were identified as (, , )-2-amino-4, 8, 10-octadecatriene-, 3-diol (d18:3) and (, , )-2-amino--methyl-4, 8, 10-octa-decatriene-, 3-diol (d19:3), which is a novel base. Both d:2 and t: had a cis double bond at the C or C13 position. All fatty acids were 2-hydroxylated (C₁₄-C₂₅):Most of themwere saturated and unbranched. About 10% was mono-unsaturated and unbranched (-C₂₅), while saturated but branched (iso- and anteiso-types) C₁₅-C₁₈ acids were found as mi-nor components. The main fatty acids, which summed up to more than % of the fatty acids in the glucosylceramide, were n-14h: 0, n-15h:0, n-16h : 0, n-17h : 0, n-18h : 0, and n-24h:.

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BACKGROUND

Atopic dermatitis (

) and allergic contact dermatitis (ACD) are both forms of eczema and are common inflammatory skin diseases with a central role of T cell-derived IL- in their pathogenesis. Although prostaglandin 2 (PGE2) is known to promote inflammation, little is known about its role in processes related to and ACD development, including IL- upregulation.

OBJECTIVES

We set out to investigate whether PGE2 has a role in T cell-derived IL-

induction and development of ACD, which has augmented prevalence in patients with .

METHODS

T cell cultures and in vivo sensitization of mice with powerful haptens (oxazolone and dinitrofluorobenzene) were used to assess the role of PGE2 in IL-

production. The involvement of PGE2 receptors and their downstream signals was also examined. The specific effects of PGE2 during ACD pathogenesis were evaluated by using the oxazolone-induced ACD mouse model. Gene expression of PGE2 and IL- signaling pathways was also investigated by using genomic profiling in human lesional skin biopsies.

RESULTS

PGE2 promotes IL-

production from T cells through its receptors, prostanoid receptor 2 (EP2) and EP4. This is mediated by its downstream cAMP-PKA signaling and probably involves the transcription factor aryl hydrocarbon receptor (AHR). Selective deletion of EP4 in T cells prevents hapten-induced adaptive IL- production in vivo. Importantly, blockade of endogenous PGE2 production by a COX inhibitor indomethacin or deletion of EP4 in T cells limit atopic-like skin inflammation in the oxazolone-induced mouse ACD model. Moreover, both PGE2 and IL- pathway genes were coequally upregulated in human lesional skin but were down-regulated after treatment with betamethasone or ultraviolet B (UVB) radiation, both common therapies for .

CONCLUSIONS

Our results thus define a crucial role for PGE2 in promoting ACD by facilitating T cell-derived IL-

production.

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Transcutaneous carbon dioxide tension (tcPCO2) were continuously measured during open heart surgery for fifteen patients aging from 5 to 58.
The Hagihara transcutaneous CO2 electrode was used. This modified Severinghaus blood gas electrode consists of a PH-sensitive glass electrode and a silver-silver chloride reference electrode covered by a hydrophobic CO2 permeable membrane from which they are separated by a sodium bicarbonate electrolyte solution. The heating unit is also contained in this sensor-unit to dilate skin capillaries. Sensor temperature was maintained at 44°C throughout the study.
This sensor was attached at the thigh of the patient. During open heart surgeries, 117 arterial blood samples were taken for the determination of PaCO2. The regression curve between tcPCO2 and PaCO2 was
tcPCO2=.11×PaCO2+.5.
Using this formula, corrected tcPCO2 was calculated. During operation, at every thirty minutes the tcPCO2 and PaCO2 was determined and during . C. C., at every fifteen minutes, the determination was made.
The mean value of corrected tcPCO2 showed no statistical difference from that of PaCO2 throughout the study. Before . C. C., the corrected tcPCO2 ranged between 26.8 and 34.5 and the PaCO2 between 27.5 and 34.2 During . C. C., the corrected tcPCO2 ranged between 18. and ., PaCO2 between 17. and 21.5. After . C. C., the corrected tcPCO2 ranged between .2 and 37.4, PaCO2 between 24.8 and 33.8mmHg respectively.
This value of tcPCO2 with this machine proved to have a good coefficient with that of PaCO2 (r=0.).
In conclusion, this transcutaneous CO2 electrode is very useful for the monitoring of PaCO2 during open heart surgery.

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