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The monolayer properties of some single-chain polyprenyl phosphates (phytanyl, phytyl, and geranylgeranyl phosphates), which we regard as hypothetical primitive membrane lipids, were investigated at the air−water interface by surface pressure−area (π−A) isotherm measurements. The molecular area/pressure at various pH conditions dependence revealed the acid dissociation constants (pKa values) of the phosphate. The pKa values thus obtained at the air−water interface (pKa1 = 7.1 and pKa2 = 9.4 for phytanyl phosphate) were significantly shifted to higher pH than those observed in the bilayer state in water (pKa1 = 2.9 and pKa2 = 7.8). The difference in pKa values leads to a stability of the phosphate as both monolayer and bilayer states in a pH range of 2−6. In addition, the presence of ions such as sodium, magnesium, calcium, and lanthanum in the subphase significantly altered the stability of the polyprenyl phosphate monolayers, as shown by the determination of monolayer collapse and compression/expansion hysteresis. Although sodium ions in the subphase showed only a weak effect on the stabilization of the monolayer, addition of magnesium ions or of a small amount of calcium ions significantly suppressed the dissolution of the monolayer into the subphase and increased its mechanical stability against collapse. In contrast, the presence of larger amounts of calcium or of lanthanum ions induced collapse of the monolayers. Based on these experimental facts, a plausible scenario for the formation of primitive cell membrane by transformation of a monolayer to vesicle structures is proposed.

Although it has been reported that chronic obstructive pulmonary disease (COPD) is frequently associated with systemic immune disturbances, negative impact of these disturbances on the increased prevalence of acute respiratory tract infections (aRTIs) has remained unclear. We evaluated circulating levels of interferon-@c (IFN-@c), soluble interleukin-2 receptor (sIL-2R), neopterin, and soluble intercellular adhesion molecule-1 (sICAM-1) in 35 clinically stable patients with COPD and in 22 age-matched healthy controls, since these molecules are considered to reflect the in vivo status of systemic cell-mediated immunity (CMI). We found that circulating levels of sIL-2R (1.52+/-1.25 vs. 0.97+/-0.48ng/ml; P<0.05), neopterin (7.23+/-4.24 vs. 4.95+/-1.52nmol/l; P<0.05), and sICAM-1 (665+/-302 vs. 328+/-164ng/ml; P<0.0001), but not IFN-@c (7.55+/-4.72 vs. 6.65+/-1.13pg/ml; P=NS) were significantly higher in patients with COPD than in the controls. Importantly, follow-up study for 12 months demonstrated that patients in subgroup with relatively higher circulating levels of sIL-2R (2.20+/-1.44ng/ml, n=18) had significantly higher risk of developing aRTIs (P=0.0204) than those in subgroup with relatively lower circulating levels of sIL-2R (0.80+/-0.23ng/ml, n=17). These results may suggest that impaired systemic CMI observed in COPD patients is associated with the increased susceptibility to aRTIs in these patients.

Survivin, a protein that inhibits apoptosis, is expressed in a variety of tumour cells. We detected survivin-specific mRNA and protein in normal placental tissues, two human choriocarcinoma cell lines (JEG-3 and BeWo), and a trophoblastic cell line (tPA30-1) by reverse transcription-polymerase chain reaction (RT-PCR), Northern blotting, and Western blotting. Immunohistochemically, survivin was localized to normal villous cytotrophoblasts, normal extravillous trophoblasts, cytotrophoblasts in hydatidiform mole, and choriocarcinoma cells. Antisense oligonucleotides for survivin dose-dependently induced apoptosis in two choriocarcinoma cell lines (JEG-3 and BeWo) and a trophoblastic cell line (tPA30-1), while sense oligonucleotides showed little effect. These findings suggest that survivin antagonizes apoptosis in cytotrophoblasts, extravillous trophoblasts, and choriocarcinoma cells.

Abstract: A series of N-acetyl-L-glutamic acid oligopeptide benzyl esters with exact residue numbers 4, 6, and 12 has been synthesized by a stepwise procedure. For these oligopeptide–dioxane binary systems, the behavior of the liquid-crystalline phases has been examined␣by the use of 2H NMR, and the results indicate that highly ordered aggregates formed by these oligopeptides in dioxane are in an alignment similar to that in a nematic mesophase.

Fas- and tumour necrosis factor (TNF) receptor-mediated apoptosis are known to be two principal apoptotic mechanisms in humans. Although there are several distinctions between these two systems, in vitrostudies have demonstrated similar hypoxic activation and a functional relationship. Since patients with chronic obstructive pulmonary disease (COPD) show chronic hypoxaemia and the activation of the TNF- αsystem, we investigated whether these pathophysiological changes influence the Fas–Fas ligand system. We measured the circulating soluble Fas ligand (sFas-L) level, an inducer of apoptosis, and the soluble Fas receptor (sFas) level, an inhibitor of apoptosis, in 34 COPD patients and 35 age-matched healthy controls. In addition, we investigated the relationships between the levels of sFas-L or sFas and clinical variables including the TNF- αsystem; circulating TNF- αand soluble TNF-receptor (sTNF-Rs: sTNF-R55 and R75) levels, in the COPD patients. Although circulating TNF- α, sTNF-R55 and R75 levels were significantly higher in the COPD patients than in the healthy controls, serum level of sFas-L (Fisher's exact probability test;P=0·26) and plasma level of sFas [COPD patients vs.controls; mean (SD); 3·74 (0·63) vs.3·67 (0·48) ng/ml;P=0·89) were not increased in the COPD patients. There was no significant correlation between the levels of sFas-L or sFas and clinical variables in COPD patients. These results suggest that the Fas–Fas ligand system does not independently play an important role in the pathophysiology of patients with COPD.

Abstract: Bremsstrahlung photons associated with the α-decay of210Po were measured in α-γ coincidence measurements with Si and Ge detectors. Emission probabilities of the bremsstrahlung deduced for210Po were 10−11∼10−12/keV/sr/decay for 100≤E γ≤600 keV. It was found that the bremsstrahlung yields are much smaller than those predicted by a Coulomb acceleration model. This suggests that α-particles also emit photons inside the barrier. The bremsstrahlung spectrum was compared with a quasi-classical calculation in which the bremsstrahlung emission in tunneling motion of α-particles is taken into account. It is shown that the data can be interpreted as a consequence of destructive interference of radiative amplitudes outside the Coulomb barrier with those in tunneling.

Background: We newly synthesized YF476 ((R)‐1‐[2,3‐dihydro‐2‐oxo‐1‐pivaloylmethyl‐5‐(2′‐pyridyl)‐1H‐1,4‐benzodiazepin‐3‐yl]‐3‐(3‐methylamino‐phenyl)urea) as a gastrin/cholecystokinin‐B (CCK‐B) receptor antagonist. We investigated the pharmacological profile of YF476 in vitroand in vivo.

(R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo-5-phenyl-1H-1,4- benzodiazepin-3-yl]-3-(3-methylphenyl)urea (YM022) is an extremely potent and highly selective gastrin/cholecystokinin (CCK)-B receptor antagonist. We compared the gastrin/CCK-B receptor-blocking properties of this compound with those of the racemate (mixture of YM022 and its S-form), its enantiomer (S-form), L-365, 260 and Cl-988 in vitro and in vivo. YM022 replaced specific binding of [125I]CCK-8 to rat brain gastrin/CCK-B receptors in a stereoselective and competitive manner. The Ki value of YM022 for gastrin/CCK-B receptors in brain were estimated to be 0.068 nM. The racemate, the S-form of YM022, L-365,260 and Cl-988 also replaced gastrin/CCK-B receptor binding, with Ki values of 0.11, 140, 19 and 6.3 nM, respectively. The affinity of YM022 for gastrin/CCK-B receptor was more than 2 orders of magnitude higher than that for rat pancreatic CCK-A receptor and various other receptors, such as benzodiazepine. In vivo, intravenous (i.v.) administration of YM022 inhibited pentagastrin-induced gastric acid secretion in anesthetized rats, with an ED50 value of 0.0078 mumol/kg. Inhibition by the S-form of YM022 was only 33.8% even at the relatively high dose of 1 mumol/kg i.v. L-365,260 (1-10 mumol/kg i.v.) and Cl-988 (0.3-3 mumol/kg i.v.) also antagonized acid secretion induced by pentagastrin, with ED50 values of 4.23 and 1.01 mumol/kg, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

We evaluated the effect of YM022 [(R)-1-[2,3-dihydro-1-(2'- methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3- (3-methylphenyl)urea], a potent and selective gastrin/cholecystokinin-B receptor antagonist, on gastric acid secretion and gastric and duodenal lesions in rats. Oral YM022 (0.1-10 mumol/kg), famotidine (0.3-30 mumol/kg) and omeprazole (3-100 mumol/kg) dose-dependently suppressed acid secretion in pylorusligated rats with ED50 values of 0.83, 1.63 and 10.9 mumol/kg, respectively. YM022 (1-10 mumol/kg p.o.), famotidine (1-10 mumol/kg p.o.) and omeprazole (10-100 mumol/kg p.o.) prevented indomethacin-induced gastric lesions in a dose-related manner. The potency of YM022 was comparable to that of famotidine and was 8 times greater than that of omeprazole. YM022 and famotidine partially inhibited gastric damage induced by water-immersion and restraint stress, whereas omeprazole abolished these lesions. In an acidified ethanol-induced gastric injury model, all three drugs inhibited the formation of erosions. The YM022 dosage required in this model was much greater than that required in the inhibition of gastric acid. The inhibitory effect of YM022 was partially reversed by indomethacin, indicating the involvement of a prostaglandin-mediated pathway. YM022 (3-100 mumol/kg p.o.), famotidine (1-30 mumol/kg p.o.) and omeprazole (3-100 mumol/kg p.o.) inhibited mepirizole-induced duodenal ulcers. On the basis of ED50 values, YM022 was 5 times less potent than famotidine and as potent as omeprazole against mepirizole-induced duodenal ulcers. These results suggest that YM022 possesses antisecretory and antiulcer activities that are as potent as those of famotidine in rats and that YM022 represents a useful therapeutic agent in the treatment of peptic ulcer disease.

The possibility that 5-hydroxytryptamine (serotonin; 5-HT) mediates bowel dysfunction caused by stress was evaluated in rats and mice treated with 5-HT or thyrotropin-releasing hormone (TRH) injection and in rats subjected to stress. Restraint stress at room temperature (23 degrees C) significantly increased fecal pellet output without the formation of gastrointestinal mucosal lesions in free-feeding rats, and caused diarrhea in 90 to 100% of animals within 3 hr in food-deprived rats. Oral YM060, ondansetron, granisetron, atropine and diazepam and s.c. tetrodotoxin inhibited these stress-induced changes in bowel function in fed and fasted rats. ED50 values were 1.1 (0.2-6.6) and 2.5 (1.1-5.7) micrograms/kg for YM060, 483 (338-691) and 354 (262-477) micrograms/kg for ondansetron, 208 (111-393) and 142 (48.9-414) micrograms/kg for granisetron, 811 (639-1,030) and 847 (641-1,118) micrograms/kg for atropine, 3,099 (1,499-6,405) and 5,396 (4,768-6,106) micrograms/kg for diazepam and 1.9 (1.7-2.1) and 3.3 (1.6-6.5) micrograms/kg for tetrodotoxin, respectively. Methysergide inhibited stress-induced diarrhea with an ED50 value of 724 (384-1,366) micrograms/kg s.c., whereas it had partial effect on stress-induced increases in fecal pellet output. Exogenous 5-HT increased fecal pellet output in rats and caused diarrhea in mice.(ABSTRACT TRUNCATED AT 250 WORDS)

YM060 [(R)-5-[(1-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimida zol e hydrochloride], is structurally independent of other 5-HT3 receptor antagonists. We investigated in vivo 5-HT3 receptor blocking activity of YM060 and compared results with those of its enantiomer (S-form), ondansetron (GR38032F), granisetron (BRL43694), ICS205-930 [(3 alpha-tropanyl)-1H-indole-3-carboxylic acid ester], LY277359 [endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1] oct-3-yl)-7-benzofuran-carboxamide-(Z)-2-butenedioate (1:1)], Y25130 [(+-)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-4-methyl-3-oxo-3,4- dihydro-2H-1,4-benzoxazine-8-carboxamide hydrochloride] and zacopride [(R,S)4-amino-N-[1-azabicyclo (2.2.2)oct-3-yl]-5-chloro-2-methoxybenzamide(E)-2-butenedioat e]. YM060 injected i.v. dose-dependently inhibited the reduction in heart rate induced by 5-HT (30 micrograms/kg i.v.) in rats (von Bezold-Jarisch reflex) with an ED50 value of 0.036 (0.031-0.041) micrograms/kg (n = 3-5). Based on these values, YM060 was 53, 18, 23, 16, 11 and 4 times as potent as ondansetron, granisetron, ICS205-930, LY277359, Y25130 and zacopride, respectively. The S-form of YM060 also inhibited 5-HT-induced bradycardia, but with a potency approximately 250 times less than that of YM060 (R-form). YM060 dosed p.o. also inhibited 5-HT-induced bradycardia with an ED50 value of 0.59 (0.44-0.80) micrograms/kg (n = 3-5), indicating the drug to be 387, 66, 97, 6 and 16 times more potent than ondansetron, granisetron, ICS205-930, LY277359 and Y25130, respectively, but 2 times less potent than zacopride. Bioavailability of YM060 based on the p.o.-to-i.v. ED50 ratio (p.o./i.v. = 16) was lower than those of zacopride (2) and LY277359 (6), similar to that of Y25130 (22) and better than those of ondansetron (109), granisetron (60) and ICS205-930 (71).(ABSTRACT TRUNCATED AT 250 WORDS)

(R)-5-[(1-Methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride (YM060) is a structurally novel, extremely potent, and highly selective serotonin (5HT)3 receptor antagonist. Its 5HT3 receptor blocking properties were compared with those of its enantiomer (S-form), granisetron and ondansetron, in the isolated distal colon of the guinea pig. YM060 competitively antagonized 5HT- and 2-methyl-5HT-induced contraction of the colon, with pA2 values of 8.71 +/- 0.09 (n = 12) and 8.69 +/- 0.06 (n = 9), respectively. Its antagonistic activity was approximately 200, 5 and 50 times more potent than those of the S-form (pA2 = 6.33 +/- 0.06, n = 9 against 5HT; 6.47 +/- 0.1, n = 9 against 2-methyl-5HT), granisetron (pA2 = 8.03 +/- 0.07, n = 9; 8.02 +/- 0.04, n = 9), and ondansetron (pA2 = 7.02 +/- 0.08, n = 9; 6.98 +/- 0.02, n = 9), respectively. Each pA2 value was constant and the isomeric activity ratio (R-form/S-form) was constant irrespective of the agonist used, suggesting that each drug acted on the same 5HT3 receptor. YM060 failed to antagonize contractions induced by 5HT in the saphenous vein of the dog (5HT1-like receptor) or in the aorta of the rabbit (5HT2 receptor. YM060 has a low affinity for alpha-1 (rabbit aorta; pA2 = 5.08 +/- 0.07, n = 8) and alpha-2 (guinea pig ileum; pA2 = 5.61 +/- 0.09, n = 11) adrenergic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract: Low-lying excited levels of231Th fed through α-decay of235U were investigated by using α-γ and γ-γ coincidence technique. From the analyses for co-relating energy levels and transition intensities, we found that the most favorable transition from 205.3 keV ([631]7/2) level that is fed by the most dominant α transition from235U is 19.6 keV transition (205.3 keV [631]7/2−→185.7 keV [631]5/2−). We also found that the transition probability of 109.2 keV, 205.3 keV [631]7/2−→96.1 keV [633]9/2+, was corrected to be weak. These findings can explain why the 185.7 keV γ-ray is so strongly observed, 0.57 photons/ga, in the γ-spectrum associated with the α-decay of235U. The decay scheme of231Th levels previously reported has been modified according to the present analysis.

The morpholines (VIII) mentioned in the title are synthesized from the epoxides (I) via two pathways shown in the reaction scheme.