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The adrenomedullin receptor is a complex molecule that comprises the calcitonin-receptor-like receptor (CRLR) and the receptor-activity-modifying protein (RAMP). RAMP1 is a vasodilation factor, and RAMP1-deficient mice (RAMP1(−/−)) exhibit inflammatory responses with a significant transient increase in serum calcitonin-gene-related peptide levels and proinflammatory cytokines when compared with RAMP1(+/+) mice. The purpose of the present study was to investigate the relationships between essential hypertension (EH) and RAMP1gene single-nucleotide polymorphisms (SNPs) or haplotypes in a Japanese population via a case–control study. Based on a database search of the National Center of Biotechnology Information website and the HapMap project, we chose six RAMP1gene SNPs and performed an association study involving 263 patients with EH and 267 age-matched normotensive (NT) subjects. There was no significant difference between the EH and NT groups with regard to overall distribution of genotypes or SNP alleles. However, the haplotype-based case–control analysis revealed that there was a significant difference between the EH and NT groups with regard to overall distribution of the allele combinations at three SNPs—rs3754701–rs3769048–rs10199956—(P=0.002). The T-A-T haplotype was significantly more common in the EH group (10.3%) than in the NT control group (6.1%) (P=0.047). These results suggested that this T-A-T RAMP1gene haplotype might have utility as a genetic marker for EH and that the RAMP1gene or a neighbouring gene may be associated with increased susceptibility to EH.

The Nemuro Belt is a tectonic belt in the Paleo‐Kuril Arc system, the NW Pacific region. The Paleo‐Kuril Arc has been interpreted as an intraoceanic arc system between the Izanagi and Pacific Plates during the Late Cretaceous, suggesting that the boundary between these plates was a trench. However, this study shows it was a volcanic arc that developed atop a continental margin. To determine the nature of this arc during the Late Cretaceous, U‐Pb ages of detrital zircons from the Nemuro and Urahoro Groups in the Paleo‐Kuril Arc were analyzed. Our results identify two distinct types of detrital zircon U‐Pb age distributions. The first (Type 1) is characterized by multimodal age distributions with peaks ranging from ca. 1.8 Ga to 78 Ma. The other (Type 2) exhibits a unimodal age distribution with a peak at 60‐52 Ma. These different age distributions indicate a provenance transition occurred between the Late Cretaceous and Paleogene. Precambrian zircons in Type 1 sandstones indicate that the Paleo‐Kuril Arc was part of a continental plate, presumably the Okhotsk Block, in NE Asia during the Late Cretaceous. In contrast, Type 2 sandstones were supplied only from the magmatic arc region that the Izanagi‐Pacific Ridge subduction could have activated. This provenance transition suggests the initially continental arc became separated from its continental source at the beginning of the Paleogene. Understanding the origin of the Paleo‐Kuril Arc is important for the plate tectonic history of the NW Pacific region. It is closely related to controversy regarding subduction of the oceanic ridge that may have existed between the Izanagi and Pacific Plates. This study aims at testing the hypothesis that the Paleo‐Kuril Arc system developed as an intraoceanic arc along the boundary between two oceanic plates. Detrital zircon U‐Pb age distributions from sandstones of the Nemuro and Urahoro Groups of the Paleo‐Kuril Arc terrain are examined. If the Paleo‐Kuril Arc was a volcanic arc formed between oceanic plates associated sandstones should not contain craton‐derived detrital zircon grains of Precambrian age. Detrital zircons of Precambrian age are common in Upper Cretaceous sandstones of the Nemuro Group, suggesting that the Paleo‐Kuril Arc developed as a continental arc system rather than an intraoceanic arc system. A new model in which a continental Paleo‐Kuril Arc emerged initially at the southern end of the Okhotsk Block during the Late Cretaceous and later split from continental cratons due to southward translation of this terrain is proposed. Detrital zircon ages indicate that the Paleo‐Kuril Arc developed as a continental rather than intraoceanic arcPrecambrian‐Cretaceous zircons in Cretaceous sandstones indicate continental craton provenancePaleogene sandstones contain few pre‐Cretaceous zircon grains, suggest a significant shift in provenance Detrital zircon ages indicate that the Paleo‐Kuril Arc developed as a continental rather than intraoceanic arc Precambrian‐Cretaceous zircons in Cretaceous sandstones indicate continental craton provenance Paleogene sandstones contain few pre‐Cretaceous zircon grains, suggest a significant shift in provenance

A nationwide neonatal sreening program for phenylketonuria (PKU), maple syrup urine disease (MSUD), homocystinuria, histidinemia and galactosemia was started in Japan in 1977. The total number of infants screened had reached 6,311,754 by March, 1982. A follow-up study revealed the incidence of the disease in Japan: 1/108,823 for PKU; 1/450,840 for hyperphenylalaninemia (HPA); 1/1,577,939 for biopterin deficiency; 1/525,980 for MSUD; 1/1,051,959 for homocystinuria; 1/8,371 for histidinemia, and 1/788,969 for galactosemia type 1. The incidences of PKU, HPA, homocystinuria, and galactosemia (type 1) were found to be markedly low in Japan as compared with those in Caucasian countries. There was no great difference in the incidence of MSUD between both. On the other hand, the incidence of histidinemia was higher in Japan.

The epithelial lining of the respiratory tract of urodeles has been shown to harbor an innervated system of neuroepithelial endocrine (NEE) cells. Even between phylogenetically closely related species, large differences have been reported in the appearance and chemical coding of the NEE system. Although urodeles are well suited for the purpose, none of the prior studies have provided an immunocytochemical survey of the NEE system in all parts of the respiratory tract. In the present study, many bioactive substances and a general marker were immunocytochemically demonstrated in serial sections of the entire respiratory tract of the Tokyo salamander, Hynobius nebulosus tokyoensis, a species in which neuroepithelial bodies (NEBs) were previously characterized at the electron microscopic level. In the current study, serotonin-immunoreactive solitary NEE cells were observed in variable numbers in the larynx, in all parts of the trachea, and in areas of the lungs covered with ciliomucous epithelium. Serotonin-containing NEBs, however, were detected in small cranial areas of the lung only. Solitary NEE cells were seen in the trachea and lungs of H. nebulosus tokyoensis by immunocytochemical staining for somatostatin, calcitonin, calcitonin gene-related peptide, and bombesin, but the number, localization, and appearance of the labeled NEE cells differed considerably. Only calcitonin-like immunoreactivity was also noted in some NEB-like cell clusters in the cranial parts of the lungs. Unlike many other vertebrates, neuron specific enolase was found to be a poor marker for the NEE system in the salamander species used in this investigation. It may be concluded that the NEE system of H. nebulosus tokyoensis contains at least five different bioactive substances. The different markers, however, demonstrate the presence of NEE cells with obvious differences in respect to appearance and topographical distribution. The necessity is emphasized of reliable methods for adequate sampling of all regions of the respiratory tract in comparative histological studies of the NEE system.

About 15 serial passages of wild type mumps virus (Sasazaki strain) in the amnion sac of chick embryo (CE) yielded a CE-adapted strain which was poorly replicative and did not form plaques in Vero cells where the wild strain grew well. In the course of this limited replication of the CE-adapted strain in Vero cells, we have analysed the viral protein and RNA synthesis. It was found that protein synthesis took place very efficiently at least early in infection by 12 h. The subsequent rate of synthesis remained, however, at a low level without showing the progressively increasing synthesis observed with the wild strain. Furthermore, 50S genomic RNA was synthesized early in the limited infection, but the subsequent synthesis was markedly suppressed. In addition, the other virus-specific RNA species could not be detected throughout. Thus the amplified RNA synthesis observed in the permissive CE cells and in the wild strain-infection of Vero cells seemed not to occur in the limited replication. Neither interferon nor DI (defective interfering) RNA was involved in the limited virus growth. When Vero cells were infected with the wild strain 6 to 8 h before inoculation of CE-adapted strain, growth restriction was overcome and the yield of the latter virus was greatly enhanced by a factor more than 103. These results suggest that through adaptation to CE, mumps virus may be altered in such a way that there is a restriction, probably at a step (s) involved in amplification of the viral RNA synthesis in Vero cells and that the restriction may be overcome by the simultaneous genome expression of the prototype wild strain.

We have developed a strategy for making synthetic peptide vaccines, in which a peptide, HA127-133, derived from the hemagglutinin (HA) of A/Aichi/2/68(H3N2) influenza virus (Aichi/68) is introduced into the Ab binding component consisting of 43-46 and 54-58 residues of a pigeon cytochrome c analogue peptide, 46F50V54A. Indeed, this hybrid peptide, 46F/HA127-133/54A, induced impressive T-cell responses and antibody production neutralizing infectivity of Aichi/68 in vitro. In a subsequent study we found that 46F/HA127-133/54A(18mer) peptide antigen, which had been prepared by substitution at the central five residues of 46F50V54A with HA127-133, generated T-cell responses and neutralizing antibody responses as well. On the basis of these prior findings, in the present study we analyzed immunopotency of 46F/HA127-133/54A(18mer) in vivo administered in several ways to I-Ab mice. We show herein that this peptide vaccine loaded in multilamellar liposomes without adjuvant protects the mice against infection with Aichi/68 within 2 weeks after final immunization. Further, this peptide vaccine was shown to be effective in preventing infection with a naturally occurring antigenic variant, A/Texas/1/77(H3N2), carrying the same sequence at 127-133 of the HA as Aichi/68 virus. Since this part of the HA is relatively conserved among H3 subtype influenza viruses, our peptide vaccine may become the basis for a new strategy to prepare effective vaccines that will overcome the ineffectiveness of classical vaccines attributable to antigenic drift of influenza viruses.

We have determined the H-2 class II allele-specific amino acid motif of the agretope (the site of contact between the peptide antigen and the major histocompatibility complex) for a synthetic peptide composed of residues 43-58 of pigeon cytochrome c (p43-58). Residues 46 and 54 functioned as the agretope, and residues 50 and 52 functioned as the epitope (the site for contact between the peptide antigen and the T-cell antigen receptor). In general, agretopes and epitopes function independently. Thus, substitution of amino acids in the epitope does not significantly affect binding of the peptide antigen to a class II molecule. On the basis of these findings, synthetic peptide vaccines against influenza Aichi (H3N2) virus were prepared by introducing seven residues of the influenza virus hemagglutinin into the frame component residues 43-46 and 54-58 of p43-58 analogues including the agretopes for Ak or Ab previously determined on the p43-58 segment. These peptide vaccines induced both helper T-cell responses and production of antibodies that were specific for influenza Aichi hemagglutinin but not for the major histocompatibility complex binding frame in mice bearing Ak or Ab. The antibodies produced neutralize the infectivity of influenza Aichi in vitro. The present findings should provide a basis for preparing potent peptide vaccines that function without producing side effects.

1. A method was devised for the determination of the specific radioactivity of the acetyl moiety of acetylcholine synthesized from various 14C-labelled substrates. 2. The precursor for the acetyl moiety of acetylcholine was studied in slices of striatum and cerebral cortex from rat and guinea-pig brain. Incorporation of radioactivity into acetylcholine was determined after incubating the slices in the presence of [2-14C]acetate, [14C]bicarbonate, [1,5-14C]citrate, dl-[1- or 5-14C]glutamate or [1- or 2-14C]pyruvate. 3. After incubation for 1h, acetylcholine was accumulated significantly in both striatum slices (4.1nmol/mg of protein) and cerebral-cortex slices (0.57nmol/mg of protein) from the rat. Final concentrations were about 11 and 5 times respectively the initial values. 4. With slices from rat striatum, rat cerebral cortex and guinea-pig cerebral cortex, the specific radioactivity of acetylcholine derived from [2-14C]pyruvate was very high, reaching approx. 30, 20 and 6% respectively of the initial specific radioactivity of added pyruvate in the medium. With the striatum slices this high value was reached after incubation for 15min. Incorporation of radioactivity from [2-14C]acetate was only 1.25, 5.3 and 19.7% of that from [2-14C]pyruvate in rat striatum, rat cerebral-cortex and guinea-pig cerebral-cortex slices respectively. A small but definite incorporation was found from [5-14C]glutamate. No incorporation was found from the other substrates. The findings suggest that pyruvate is the most important precursor for the synthesis of the acetyl moiety of acetylcholine in brain slices. 5. The specific radioactivity of acetylcholine relative to that of citrate when [2-14C]pyruvate was used compared with that obtained when [2-14C]acetate was used. A marked difference was found in all slices, suggesting metabolic compartmentation of the acetyl-CoA pool.

The specific activity of citric acid of the lobster nerve which was incubated in Ringer-bicarbonate solution containing 14C-bicarbonate was determined. The specific activity of citric acid was higher than that of malic acid by a factor of 2.5. The citric acid obtained from the lobster nerve was degraded with an improved method which is described in this paper. The ratio of the radio-activity of C-6 to C-1 of citric acid was 1:1. Aspartic acid obtained from the lobster nerve was also degraded, and the ratio of the radioactivity of C4 to C1 was almost 10:1.

The extent of CO2 fixation in the sciatic nerve of the rabbit was determined. The specific activitiy of citric acid was higher than that of glutamic, aspartic, and malic acids, and the specific activity of citric acid obtained from the 2 hour incubation nerve was close to 1/3 of that of the CO2 in the medium. The ratio of the radioactivity of the C-6 to C-1 of citrate was about 2:1 in intact nerves and about 1:1 in damaged nerves, and the ratio of the radioactivitiy of C-4 to C-1 of aspartate was approximately 1:1 in both cases. These results suggest that in the sciatic nerve of the rabbit: 1) the dicarboxylic acid “shuttle” was active, 2) the extent of the carboxylation at the oxalosuccinic acid level was 1/2 or more of that at the oxaloacetic acid level, and 3) the CO2 fixation by the carboxylation of a-ketoglutaric acid might have some relationship to nerve function. The significance of CO2 fixation, and the possible relationship between the carboxylation of a-ketoglutaric acid and the concentrations of citric acid, acetyl-CoA and acetylcholine, and the control of the rate of tricarboxylic acid cycle were discussed.

The separation on a Dowex-1-acetate column of glutamic, aspartic, lactic, succinic, and malic acids was described. The “citric acid” (citric, cisaconitic and isocitric acids), fumaric, and oxaloacetic acids were separated.

The accuracy of slit-ray position measurement on an image plane of a TV camera is improved to the order of one-hundredth of pixel spacing by a regression analysis and an error analysis. Also, the effectiveness of the method is confirmed by means of shape measurement experiments.

Optical properties have been investigated in titanium doped sapphire, prepared under oxidized condition. Charge-transfer transitions to 3d states of tetravalent Ti4+ from 2p ones of O2[?] are found to be located below the fundamental absorption edge of Al2O3. The photo-excitation for this band leads to the intense blue emission, the spectrum of which is quite different from the luminescence of the d-d transitions in trivalent Ti3+. The UV-irradiation also leads to an absorption peak below the charge-transfer band, resulted from that the photo-excited electrons in part form color centers. The post-annealing at higher temperatures above 300degC completely destroys the color centers. The blue photoluminescence is found to be greatly suppressed by the UV-irradiation and is recovered by the post-annealing. This fact indicates that the color centers prevent the blue emission.