Increased stress response and beta-phenylethylamine in MAOB-deficient mice.

MAOA and MAOB are key iso-enzymes that degrade biogenic and dietary amines. MAOA preferentially oxidizes serotonin (5-hydroxytryptamine, or 5-HT) and norepinephrine (NE), whereas MAOB preferentially oxidizes beta-phenylethylamine (PEA). Both forms can oxidize dopamine (DA). A mutation in MAOA results in a clinical phenotype characterized by borderline mental retardation and impaired impulse control. X-chromosomal deletions which include MAOB were found in patients suffering from atypical Norrie's disease, which is characterized by blindness and impaired hearing. Reduced MAOB activity has been found in type-II alcoholism and in cigarette smokers. Because most alcoholics smoke, the effects of alcohol on MAOB activity remain to be determined. Here we show that targetted inactivation of MAOB in mice increases levels of PEA but not those of 5-HT, NE and DA, demonstrating a primary role for MAOB in the metabolism of PEA. PEA has been implicated in modulating mood and affect. Indeed, MAOB-deficient mice showed an increased reactivity to stress. In addition, mutant mice were resistant to the neurodegenerative effects of MPTP, a toxin that induces a condition reminiscent of Parkinson's disease.

Activated volcanism of Mount Fuji by the 2011 Japanese large earthquakes.

The relation between earthquakes and volcanic eruptions, each of which is manifested by large-scale tectonic plate and mantle motions, has been widely discussed. Mount Fuji, in Japan, last erupted in 1707, paired with a magnitude (M)-9-class earthquake 49 days prior. Motivated by this pairing, previous studies investigated its effect on Mount Fuji after both the 2011 M9 Tohoku megaquake and a triggered M5.9 Shizuoka earthquake 4 days later at the foot of the volcano, but reported no potential to erupt. More than 300 years have already passed since the 1707 eruption, and even though consequences to society caused by the next eruption are already being considered, the implications for future volcanism remain uncertain. This study shows how volcanic low-frequency earthquakes (LFEs) in the deep part of the volcano revealed unrecognized activation after the Shizuoka earthquake. Our analyses also show that despite an increase in the rate of occurrence of LFEs, these did not return to pre-earthquake levels, indicating a change in the magma system. Our results demonstrate that the volcanism of Mount Fuji was reactivated by the Shizuoka earthquake, implying that this volcano is sufficiently sensitive to external events that are considered to be enough to trigger eruptions.

Search for antihelium with the BESS-Polar spectrometer.

In two long-duration balloon flights over Antarctica, the Balloon-borne Experiment with a Superconducting Spectrometer (BESS) collaboration has searched for antihelium in the cosmic radiation with the highest sensitivity reported. BESS-Polar I flew in 2004, observing for 8.5 days. BESS-Polar II flew in 2007-2008, observing for 24.5 days. No antihelium candidate was found in BESS-Polar I data among 8.4×10(6) |Z|=2 nuclei from 1.0 to 20 GV or in BESS-Polar II data among 4.0×10(7) |Z|=2 nuclei from 1.0 to 14 GV. Assuming antihelium to have the same spectral shape as helium, a 95% confidence upper limit to the possible abundance of antihelium relative to helium of 6.9×10(-8)} was determined combining all BESS data, including the two BESS-Polar flights. With no assumed antihelium spectrum and a weighted average of the lowest antihelium efficiencies for each flight, an upper limit of 1.0×10(-7) from 1.6 to 14 GV was determined for the combined BESS-Polar data. Under both antihelium spectral assumptions, these are the lowest limits obtained to date.

Drug delivery observation of hydrophobe ferrofluid and magnetite nanoparticals by SPring-8 synchrotron radiation.

In this study, the composite magnetic nanoparticles of coated SiO nano film with about 8 nm size and high saturation magnetization value, were synthesized by liquid phase precipitation method. The magnetic nanoparticles can be dispersed in various liquid media, widely known as magnetic fluids or ferrofluids with both magnetic and liquid properties. The materials been collected great interests and more and more attentions to focus into Drug Delivery System (DDS) as a new technology in this paper. We use the composite nanoparticles to disperse H2O and inject the solutions into rat's in-vivo organs. And, in the experiments by using a strong photon beam of SPring-8 Synchrotron Radiation facility, the distribution stat and the effects of magnetic field as well as drug delivery behaviour of nanoparticles in the rat' kidney are verified by the in-vivo observations.

The taste system of the channel catfish: from biophysics to behavior.

Catfish, described as 'swimming tongues', are unique experimental models for studies of taste reception because of the extensive distribution of taste buds over their external body surface and within their oropharyngeal cavity. Both the extraordinary numbers of taste buds and their high sensitivity to amino acids have made it possible to perform in the same species: biochemical and biophysical studies of stimulus recognition and signal transduction; electrophysiological recordings of taste activity from receptor cells, afferent nerve fibers and CNS relays; and behavioral studies of taste-controlled food search, biting and mastication. The close correspondence of results obtained with these diverse experimental approaches has provided critical information concerning vertebrate gustation.

New species of Hercostomus Loew, 1857 (Dolichopodidae, Diptera) from Japan.

Six new species of the genus Hercostomus Loew, 1857, are described from Japan: Hercostomus acutiformis Negrobov, Kumazawa & Tago sp. nov., H. falcilis Negrobov, Kumazawa & Tago sp. nov., H. flavipalpus Negrobov, Kumazawa, Tago & Sato sp. nov., H. nigricollaris Negrobov, Kumazawa & Tago sp. nov., H. spathulatus Negrobov, Kumazawa, Tago & Sato sp. nov., H. spinitibialis Negrobov, Kumazawa & Tago sp. nov. Hercostomus flaveolus Negrobov & Chalaya, 1987 is newly recorded from Japan, and Hercostomus arcticus Yang, 1996 is newly synonymized with Hercostomus flaveolus (syn. nov.). The holotype of Hercostomus flaviventris Smirnov & Negrobov, 1979 is redescribed. Hercostomus ussurianus Stackelberg is transferred to the genus Gymnopternus Loew, 1857 (stat. nov.). A key to the eleven recognized species of Japanese Hercostomus is provided.

Measurements of cosmic-ray proton and helium spectra from the BESS-Polar long-duration balloon flights over Antarctica.

The BESS-Polar Collaboration measured the energy spectra of cosmic-ray protons and helium during two long-duration balloon flights over Antarctica in December 2004 and December 2007, at substantially different levels of solar modulation. Proton and helium spectra probe the origin and propagation history of cosmic rays in the galaxy, and are essential to calculations of the expected spectra of cosmic-ray antiprotons, positrons, and electrons from interactions of primary cosmic-ray nuclei with the interstellar gas, and to calculations of atmospheric muons and neutrinos. We report absolute spectra at the top of the atmosphere for cosmic-ray protons in the kinetic energy range 0.2-160 GeV and helium nuclei 0.15-80 GeV/nucleon. The corresponding magnetic rigidity ranges are 0.6-160 GV for protons and 1.1-160 GV for helium. These spectra are compared to measurements from previous BESS flights and from ATIC-2, PAMELA, and AMS-02. We also report the ratio of the proton and helium fluxes from 1.1 GV to 160 GV and compare to ratios from PAMELA and AMS-02.

Contribution of electrostatic and hydrophobic interactions of bitter substances with taste receptor membranes to generation of receptor potentials.

The effects of changed ionic environments on the frog taste nerve responses to the bitter substances were examined. The responses to quinine and strychnine carrying a positive charge were suppressed by an increase in ionic strength of stimulating solutions. It was concluded that electrostatic interaction of these positive bitter substances with the receptor membranes greatly contributes to the adsorption of the substances on the membranes and that this interaction was suppressed by an increase in ionic strength. The responses to neutral bitter substances (caffeine and theophylline) were unchanged by an increase in salt concentration. The zeta potential of the mouse neuroblastoma (N-18 clone), which was depolarized by various bitter substances similarly to a taste cell, was measured in the presence of the bitter substances. The zeta potential was a little changed by quinine and practically unchanged by strychnine, caffeine and theophylline. The membrane fluidity of the N-18 cell monitored with 2-(9-anthroyloxy)stearic acid was changed in response to the bitter substances, while the fluidity monitored with 12-(9-anthroyloxy)stearic acid or 1,6-diphenyl-1,3,5-hexatriene was unchanged. This suggested that the bitter substances are adsorbed on the hydrophobic region near the surface and induce a conformational change at the region. The depolarization by the bitter substances seems to stem from changes in the "boundary potential" at the region near the surface within the membrane interior.

Trace levels of pyrroloquinoline quinone in human and rat samples detected by gas chromatography/mass spectrometry.

A detailed procedure for the assay of free pyrroloquinoline quinone (PQQ) in human and rat samples by gas chromatography/mass spectrometry (GC/MS) has been established with stable-isotopic PQQ as internal standard. PQQ was extracted from the samples, after addition of the internal standard, with butanol under acid conditions and with Sep-Pak C18 cartridges. After derivatization of PQQ with phenyltrimethylammonium hydroxide, molecular peaks at m/z 448 and 462 were used for detection of PQQ and [U-13C]PQQ by selected ion monitoring, respectively. Trace amounts of free PQQ were detected in eight organs, plasma and urine of the human, and in three organs of the rat. The PQQ level was highest in the human spleen (5.9 +/- 3.4 ng/g tissue, followed by the pancreas and lung, and it was below detection limits for human brain and heart. Trace levels of PQQ were also found in rat small intestine, liver and testis. Our data are far below those measured by the redox cycling method of Gallop's group for human plasma, adrenal and urine.

Large enhancement of canine taste responses to sugars by salts.

The effects of changed ionic environments on the canine taste responses to sugars were examined by recording the activity of the chorda tympani nerve. a) The responses to various sugars were greatly enhanced by the presence of salts having monovalent cations such as Na+, K+, choline+, or Tris+. The responses to sugars were suppressed by high concentrations of salts. (b) The presence of 100 mM NaCl in fructose solution did not affect the maximal response and changed the Hill constant for the concentration-response relationship from 1.3 to 2.4. (c) CaCl2 greatly enhanced the response to fructose, while MgCl2 exhibited practically no effect. The presence of 20 mM CaCl2 in fructose solution changed the Hill constant from 1.2 to 2.4. (d) CaCl2 suppressed the responses to 0.5 M sugars except for fructose and sucrose and enhanced the responses to all sugars examined at 1 M. In the glucose response, the slope of the concentration-response curve was increased by the presence of CaCl2. Here the curve in the absence of CaCl2 intersected with that in the presence of CaCl2, indicating that CaCl2 suppressed the response to glucose of low concentrations and enhanced that of high concentrations. (e) The enhancement of the sugar responses by salts was not simply explained in terms of ionic permeability at the apical membranes of taste cells. The enhanced and suppressed effects of salts on the sugar responses were interpreted in terms of the cooperativity between receptor molecules for sugars.

Excitation of marginal and substantia gelatinosa neurons in the primate spinal cord: indications of their place in dorsal horn functional organization.

Electrophysiological recordings were made from superficial parts of the spinal dorsal horn in monkeys, using dye-filled micropipette electrodes to permit iontophoretic marking of the recording sites for subsequent histological recovery. Focal field potentials and unitary activity evoked by dorsal root volleys including slowly-conducting components (both myelinated and unmyelinated) were found in the posteromarginal zone and the substantia gelatinosa (SG). Unitary potentials identified as being of the type recorded from cellular regions were separated into categories according to which group of slowly-conducting fibers and which kinds of cutaneous stimulation evoked the discharge. Recording locations for units excited by volleys in myelinated fibers conducting under 35 m/sec, by the types of skin stimulation activating either high-threshold mechanoreceptors (nociceptors) or cooling thermoreceptors, and giving no evidence of suprathreshold C-fiber excitation were centered on the posteromarginal zone. In contrast, recording loci for units exhibiting a strong C-fiber excitation and responses to cutaneous stimulation known to effectively excite C-fiber polymodal nociceptors or C-mechanoreceptors were centered in the SG. There appeared varying degrees of convergence of primary afferent input to the neuronal units, although most showed substantial specificity in their afferent excitation. On the bases of these results and consideration of existing morphological data, it is proposed that the marginal zone is a major synaptic termination region for the afferent fibers from high-threshold mechanoreceptors, cooling thermoreceptors, and perhaps other receptors with fine myelinated peripheral fibers. The SG, on the other hand, is suggested to be the terminal region for all types of unmyelinated primary afferent sensory neurons, and to have the complex role of integrating and distributing this input.

Spinal termination patterns of canine identified A-delta and C spermatic polymodal receptors traced by intracellular labeling with Phaseolus vulgaris-leucoagglutinin.

The spinal projection patterns of spermatic polymodal receptors were studied by intracellular labeling of functionally identified canine dorsal root ganglion (DRG) neurons with Phaseolus vulgaris-leucoagglutinin (PHA-L). The processes of 2 C-fiber and 1 A-delta-fiber spermatic polymodal receptor neurons were labeled well enough to trace their central terminations. The labeled C-fiber DRG neurons were of medium size (mean diameter 36.8 and 40.7 microns). On entering the spinal cord, axons of the C-polyclonal receptors divided into rostral and caudal main branches that extended over 3 spinal segments (20 and 25 mm, respectively), and issued a total of 16 and 15 collaterals, respectively. The majority of collaterals ran in or along the lateral surface, but both neurons had 1 or 2 collaterals or terminal branches running through the middle, or along the medial surface of the dorsal horn. Terminal swellings and en passant enlargements were observed mainly in laminae I, V, and VII. Some C-fiber terminations appeared in lamina II and the adjacent lateral column. The A-delta polymodal receptor had a termination pattern similar to that of the C-fiber units with the exception of a shorter distance over which its 13 identified collaterals were issued (10 mm), and continuation of the rostral main branch into Lissauer's tract (traced for 3.6 mm) after all branches appeared. Two terminal branches were found running just above the central canal in another A-delta neuron in which termination could be only partially traced.(ABSTRACT TRUNCATED AT 250 WORDS)

Thermally potentiated responses to algesic substances of visceral nociceptors.

Using spermatic nerve preparations from testis superior, the effects of temperature rise on chemical responses were studied in vitro, within both subthreshold and suprathreshold ranges for testicular polymodal receptors, one type of visceral nociceptor. In the range of temperature subthreshold for polymodal receptors, the responses to algesic substances tested were greater at higher temperatures. The mean discharge rates induced by various concentrations of bradykinin (BK, 9 X 10(-9)-9 X 10(-6) M), were significantly greater at 36 degrees C than at 30 degrees C. Responses to hypertonic saline, tested in the temperature range, 34-43 degrees C, showed similar temperature-dependent increases, and Q10 values between 2.3 and 4.2. In the units exhibiting 'heat sensitization' with repeated testing of suprathreshold temperature rises, the response to hypertonic saline (616 mM) at 34 degrees C also increased. Although calor in the inflamed tissues is in itself not high enough to cause excitation of 'pain receptors,' temperature-dependent augmentation of chemical responses of the polymodal receptor might partly explain peripheral hyperalgesic behaviour observable in inflamed tissue on the basis of sensory receptor activity.

Schizophrenia, monoamine oxidase activity, and cigarette smoking.

Reduced monoamine oxidase activity has been proposed as a marker for vulnerability to schizophrenia. Reduced monamine oxidase activity has also been shown to occur in cigarette smokers. This study compared monamine oxidase activity level in a matched group of patients with schizophrenia who smoked with a group who did not. Lower levels of monoamine oxidase activity were found in the smokers and this is the likely explanation for the low levels hypothesized as a marker for schizophrenia.

Indole derivatives as a new class of steroid 5 alpha-reductase inhibitors.

A series of indole derivatives with varied substituents on the alpha, beta-unsaturated double bond were synthesized and evaluated for their ability to inhibit rat prostatic 5 alpha-reductase. Compounds possessing an ethyl substituent at the beta-position of the double bond showed potent inhibitory activity. Among them, (Z)-4-{2-[[3-[1-(4,4'-difluorobenzhydryl)indol-5-yl]-2-pentenoy l]- amino]phenoxy}butyric acid (16, KF20405) showed the maximum potency with an IC50 value of 0.48 +/- 0.086 nM, which was 20-fold higher potency than 1 (MK-906). Compound 16 effectively inhibited DHT production 4 h after a 3 mg/kg oral administration. Several potent indole derivatives, 1 and 2 ((+/-)-ONO-3805), were tested versus rat and human isozymes. Nonsteroidal inhibitors such as indole derivatives and 2 were 2-3 orders of magnitude less potent for human type 2 isozyme than steroidal inhibitor 1 and expressed a significant species deference for these isozymes.

(E)-4-(2-[[3-(indol-5-yl)-1-oxo-2-butenyl]amino]phenoxy)butyric acid derivatives: a new class of steroid 5 alpha-reductase inhibitors in the rat prostate. 1.

A series of (E)-4-(2-[[3-(indol-5-yl)-1-oxo-2-butenyl]amino]phenoxy)butyric acid derivatives was prepared, and the derivatives were demonstrated to be potent inhibitors of steroid 5 alpha-reductase in the rat prostate. The structure-activity relationships were as follows. An alpha-branched alkyl or benzyl substituent of proper size at position 1 of the indole is crucial for optimal enzyme inhibitory activity. N-Methylation of the amide NH resulted in complete loss of activity. Thus, coplanarity of the benzene ring and amide moiety is essential for such activity. Among the compounds prepared, (E)-4-(2-[[3-[1-[bis(4-fluorophenyl)methyl]indol-5-yl]-1-oxo-2- butenyl]-amino]phenoxy)butyric acid (57, KF18678) was one of the most potent compounds (rat prostate 5 alpha-reductase IC50 = 3.3 nM).

Synthesis and antiulcer activity of 5,11-dihydro[1]benzoxepino[3,4-b]pyridines.

A series of substituted 5,11-dihydro[1]benzoxepino[3,4-b]pyridines was synthesized and evaluated for antiulcer activity in water immersion/restrained stress ulcer assay in rats. Structure-activity relationships are described. Most of the tested compounds exhibited low affinity to the muscarinic acetylcholine receptor. The molecular features for the best activities are the 2-(diethylamino)ethylenediamine group at the 5-position of the oxepin ring and an oxepin skeleton rather than a thiepin or a pyran skeleton. Methyl and chlorine substitution on the benzene ring reduced the activity. Compound 11, 5-[[2-(diethylamino)ethyl]amino]-5,11-dihydro[1]benzoxepino [3,4-b]pyridine trihydrochloride was selected for further evaluation. Synthesis and antiulcer activity of optically active 11 is described. There were no statistically significant differences between (+)-, (-)-, and (+/-)-11. Compound 11 showed weak antisecretory activity in pylorus-ligated rats. It is now under clinical evaluation as KW 5805.

Synthesis and antiarrhythmic activity of 5,11-dihydro[1]benzoxepino[3,4-b]pyridines.

During further modification of the new antiulcer agent 5 (KW-5805), a 5,11-dihydro[1]benzoxepino[3,4-b]pyridine derivative, we found that some new derivatives had antiarrhythmic activity. So we continued synthesis and evaluation of a series of 5-substituted 5,11-dihydro[1]benzoxepino[3,4-b]pyridines for antiarrhythmic activity in chloroform-induced ventricular arrhythmias in mice and in ouabain-induced ventricular arrhythmias in dogs. In chloroform-induced ventricular arrhythmias, the 7-methoxy group played an important role in activity and the type of terminal side chain at position 5 had not obvious effect on potency. On the other hand, in ouabain-induced ventricular arrhythmias, the structure-activity relationship was highly specific and only four compounds, 9, 30, 34, and 35, were effective. Compound 9,5-[[2-(diethylamino)ethyl]amino]-7-methoxy-5,11-dihydro[1] benzoxepino[3,4-b]pyridine 1.5-fumarate, which exhibited low affinity for muscarinic acetylcholine receptors and a high ED100(mydriasis)/ED50(antiarrhythmic activity) ratio, was selected for further development and clinical evaluation as KW-3407. The synthesis and antiarrhythmic activity of optically active 9 is described. The order of potency of antiarrhythmic activity in ouabain-induced ventricular arrhythmias in dogs was (-)-9, (+/-)-9, and (+)-9.

Inhibitors of acyl-CoA:cholesterol acyltransferase. 1. Synthesis and hypocholesterolemic activity of dibenz[b,e]oxepin-11-carboxanilides.

A series of N-phenyl-6,11-dihydrodibenz[b,e]oxepin-11-carboxamides and related derivatives were prepared on the basis of structures of the reported inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). These compounds were tested for their ability to inhibit ACAT (liver microsomes from cholesterol-fed rabbits) in vitro and to decrease serum total cholesterol in cholesterol-fed golden hamsters in vivo. The structure-activity relationships in vitro were as follows. Substitution at positions 2 and 6 in the anilide resulted in potent inhibitory activity, and the potency increased with increasing size of the substituents, with maximum potency being obtained with a 2,6-diisopropyl substitution. The position of the substituent on the dibenz[b,e]oxepin ring system influenced the activity, and substitution at position 2 was critical for potent activity. The electronic effect of the substituent at position 2 does not influence activity, but bulkiness seems to be a significant factor. The lipophilicity of the compounds also plays an important role in determining ACAT inhibitory activity. Among the compounds tested, 2-bromo-N-(2,6-diisopropylphenyl)-6,11-dihydrodibenz-[b,e]++ +oxepin-11- carboxamide (33, KF17828) showed significant in vitro activity (rabbit liver microsomes IC50 = 23 nM) and the most potent in vivo activity (complete reduction in elevated serum total cholesterol levels at a dose of 10 mg/kg in hamsters).

Synthesis and antiallergic activity of 11-(aminoalkylidene)-6,11-dihydrodibenz[b,e]oxepin derivatives.

A new series of 11-substituted 6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid derivatives was synthesized and demonstrated to be orally active antiallergic agents. These compounds are structurally related to 1 (KW-4994), which we had reported previously to be a new antiallergic agent. Most compounds synthesized exhibited potent inhibitory effects on 48-h homologous passive cutaneous anaphylaxis (PCA) in rats and on IgG1-mediated bronchoconstriction in guinea pigs. Additionally, compounds possessing a terminal carboxyl group at the 2-position of the dibenz[b,e]oxepin ring system exhibited inhibitory effects on specific [3H]pyrilamine binding to guinea pig cerebellum histamine H1 receptors, whereas these demonstrated negligible effects on specific [3H]QNB binding to rat striatum muscarinic acetylcholine M1 receptors. Structure-activity relationship studies revealed that the following key elements were required for enhanced antiallergic activities: (1) a 3-(dimethylamino)propylidene group as the side chain at the 11-position, (2) a terminal carboxyl moiety at the 2-position, and (3) a dibenzoxepin ring system. Among the compounds synthesized, (Z)-11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenz [b,e]oxepin-2-acetic acid hydrochloride (16) was selected for further evaluation. It had an ED50 value of 0.049 mg/kg po in the PCA test in rats and an ID50 value of 0.030 mg/kg po in inhibiting anaphylactic bronchoconstriction in guinea pigs. Furthermore, it had a Ki value of 16 +/- 0.35 nM for the histamine H1 receptor, while it exhibited negligible CNS side effects up to a dose of 600 mg/kg po. Compound 16 is now under clinical evaluation as KW-4679.