Shingo Sakamoto

New RIKEN-RAL pulsed µCF facility and X-ray studies on DT-µCF

In November 1994, the construction of a new superconducting muon channel of the RIKEN-RAL muon facility at ISIS of Rutherford Appleton Laboratory was completed. Subsequently, important features, such as the highest instantaneous intensity with a single-pulse structure and a high purity have been confirmed. Along with the installation of advanced µCF experimental equipment, including a high-purity D-T mixture target system with an in situ3He removal capability and a 4 T confinement magnet, an advanced µCF experiment, e.g. a precise X-ray measurement on µ-α sticking in dtµ-µCF will be realized. An account of the commissioning experiments, a plan for the earliest phase of the µCF experiment and possible future directions are reported.

X-ray studies on muon transfer reactions from hydrogen to helium

We have experimentally studied the muon transfer reactions from hydrogen to helium in liquid hydrogen with helium impurity concentration around 100–1000 ppm. The X-ray from the decay of (d4Heμ) molecule was clearly observed in the D2-4He system, whereas the corresponding X-ray was very weak in other systems such as D2-3He and H2-4He. This is well explained by the particle decay mode of the muonic molecule.

Glucuronidation Converting Methyl 1-(3,4-Dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-trimethoxy-2-naphthoate (S-8921) to a Potent Apical Sodium-Dependent Bile Acid Transporter Inhibitor, Resulting in a Hypocholesterolemic Action

Methyl 1-(3,4-dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-trimethoxy-2-naphthoate (S-8921) is a novel inhibitor of the ileal apical sodium-dependent bile acid transporter (ASBT/SLC10A2) developed for the treatment of hypercholesterolemia. The present study investigated the hypocholesterolemic action of S-8921 glucuronide (S-8921G) in rats. The plasma concentration of S-8921G was higher than that of S-8921 after single oral administration of S-8921 in normal rats, and S-8921G was excreted into the bile (13% dose). Oral administration of either S-8921 or S-8921G reduced the serum total cholesterol, particularly nonhigh-density lipoprotein cholesterol, in hypercholesterolemic normal rats. In Gunn rats devoid of UDP glucuronosyltransferase-1A activity, S-8921G was undetectable both in the plasma and bile specimens, and only S-8921G administration significantly reduced the serum nonhigh-density lipoprotein cholesterol. An in vitro inhibition study showed that glucuronidation converts S-8921 to a 6000-fold more potent inhibitor of human ASBT (Ki = 18 nM versus 109 μM). S-8921G was detected both in the portal plasma and loop when S-8921 was administered into the loop of the rat jejunum, although the cumulative amount of S-8921G recovered in the bile was 5-fold greater than that in the loop. The uptake of S-8921G by freshly prepared rat hepatocytes was saturable, and sodium-dependent and -independent systems were involved. Organic anions, such as bromosulfophthalein, estrone 3-sulfate, and taurocholic acid, inhibited the uptake. These results suggest that UDP glucuronosyltransferase-1 isoforms play a critical role in the hypocholesterolemic action of S-8921 by converting S-8921 to a more potent ASBT inhibitor, and organic anion transporter(s) are also involved in its pharmacological action through the biliary excretion of S-8921G.

Identification of the Transporters Involved in the Hepatobiliary Transport and Intestinal Efflux of Methyl 1-(3,4-Dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-trimethoxy-2-naphthoate (S-8921) Glucuronide, a Pharmacologically Active Metabolite of S-8921

The glucuronide conjugate of methyl 1-(3,4-dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-trimethoxy-2-naphthoate (S-8921; S-8921G) is a 6000-fold more potent inhibitor of an ileal apical sodium-dependent bile acid transporter (SLC10A2) than S-8921 and is responsible for the hypocholesterolemic effect of S-8921 in rats. Because S-8921G is formed in the intestine and liver, the present study investigated the transporters involved in the secretion of S-8921G that govern its exposure to the target site and thereby play an important role in its pharmacological action. Organic anion transporting polypeptide (OATP) 1B1- and OATP1B3-expressing cells exhibited saturable accumulation of S-8921G with Km values (micromolar) of 1.9. The uptake of [14C]S-8921G by human cryopreserved hepatocytes was saturable and sodium-independent. Comparison of protein expression between the cDNA transfectants and hepatocytes suggests that the contribution of OATP1B1, OATP1B3, and Na+-taurocholate cotransporting polypeptide to the hepatic uptake of S-8921G is 63, 35, and 2.6%, respectively. The basal-to-apical transport of S-8921G was enhanced in Madin-Darby canine kidney cells expressing both OATP1B1 and multidrug resistance-associated protein (MRP) 2. In Mrp2-deficient mutant rats [Eisai hyperbilirubinemic rats (EHBR)], the biliary excretion clearance based on the plasma concentration was 20% of the normal value, whereas the pharmacokinetic parameters did not show any significant change in Bcrp-/- mice. Furthermore, the secretion clearance of S-8921G to the mucosal side was also significantly lower in everted jejunum sacs from EHBR (9.18 and 20.8 μl/min/g tissue). These results suggest that MRP2 is responsible for the secretion of S-8921G to the intestinal lumen and bile and that OATP1B1 and OATP1B3 account for the hepatic uptake. These transporters deliver S-8921G to the target site of its pharmacological action.

Efflux mechanism of taurocholate across the rat intestinal basolateral membrane.

We investigated the contribution of multidrug resistance associated protein 3 (Mrp3/ABCC3) to the transport of bile acids across the rat intestinal basolateral membrane using the everted sacs. The permeability-surface area (PS) products of taurocholate in the everted sacs of rat jejunum, ileum, and colon were determined in the absence or presence of inhibitors for Mrp3. The results were analyzed to determine the PS product for the uptake across the apical membrane (PS1) and that for the efflux across the basolateral membrane (PS3). The mucosal-to-serosal transport of taurocholate in the ileum was the highest. The concentration-dependent inhibitory effects by all inhibitors in the ileum were observed on both PS1 and PS3 for taurocholate. However, even in the presence of 1 mM of each inhibitor, the decrease of PS3 was low. Additionally, PS3 in the colon, where Mrp3 is expressed at a high level, was not inhibited by MK571 and taurolithocholate-3-sulfate. Unlike PS1, PS3 did not exhibit saturation at the concentration examined. These results suggest that Mrp3 makes only a minor contribution to the efflux of bile acids across the basolateral membrane. Ostalpha-Ostbeta heteromeric transporter is certainly one of the good candidates for such a transporter.

µCF experiments in thin deuterium films and progress towards slow µ− production

Muon-catalyzed fusion was investigated in thin solid deuterium films to determine the experimental feasibility of slow µ− production by detection of dd fusion protons as well as slow µ− collection utilizing a large-acceptance magnetic spectrometer. The spatial distribution of the fusion reaction in the film was extracted, and an optimum thickness for slow µ− emission was deduced. Collected 10 keV µ− were also successfully detected. However, the dd fusion yield being insufficient, we were not able to distinguish slow µ− via µCF from degraded µ−.

Measurement of X-rays from muon to alpha sticking and fusion neutrons in solid/liquid D-T mixtures of high tritium concentration

We measured the yields of K-series X-rays from (αμ)+ ion formed by muon to alpha sticking as well as the yields and the disappearance rates of fusion neutrons in 3He-free solid and liquid D-T mixtures. The effective sticking probability ωs obtained by neutron measurement is much smaller than any theoretical values so far published, while the discrepancy in αμ X-ray yield seems less significant.

X-ray measurement on muon to alpha sticking in muon catalyzed d-t fusion; present and future

Among a series of X-ray experiments on the muon catalyzed fusion (μCF) carried out by using pulsed muons at UTMSL/KEK, a direct knowledge of α-sticking probability (ωs) in μCF of high density D-T mixture with high T concentration has been obtained by measuring a characteristic muonic X-ray from the (αμ) atoms (central energy of 8.2 keV with a correct Doppler broadening). Combining with the recent X-ray measurements in (dμ) to3He and4He impurities, new insight is now obtained for the detailed background structure in the X-ray spectrum, suggesting the future direction for the X-ray measurements.

Impact of the 2011 Tsunami on Seagrass and Seaweed Beds in Otsuchi Bay, Sanriku Coast, Japan

The Sanriku Coast facing the Pacific Ocean is an important area for fishing and aquaculture. The Sanriku Coast was hit hard by the catastrophic tsunami event produced by the Great East Japan Earthquake on 11 March 2011. The tsunami destroyed not only infrastructures of coastal fisheries and aquacultures but also coastal ecosystems, such as the seagrass and seaweed beds vital for sustainable fisheries. This study surveyed the seagrass and seaweed beds in Otsuchi Bay, Iwate prefecture in June 2011 and found that the seaweed beds around the mouth and middle of the bay were not impacted by the tsunami, but that the seagrass beds in the bay head had been destroyed. However, observations verified the growth of seagrass seedlings germinated from seeds produced in previous years. This response of the seagrass demonstrates its resilience to huge tsunami events occurring in an interval of several decades. Huge seawall construction plan against tsunami threatens their recovery. The recovery program in Sanriku Coast must be established on a holistic approach including social and ecological aspects between land and the sea because coastal areas are ecotone and also “sociotone” between them.

Did huge tsunami on 11 March 2011 impact seagrass bed distributions in Shizugawa Bay, Sanriku Coast, Japan?

Seagrass beds play important roles for coastal ecosystems as an ecosystem engineer and also as a habitat for fish and mollusks as spawning, nursery and feeding grounds, and provide us important ecological services. On 11 March 2011, huge tsunami hit Sanriku Coast, Japan, after the big earthquakes occurred in Northwestern Pacific Ocean. Seagrass beds were distributed on sandy or muddy bottom in Shizugawa Bay, Sanriku Coast. Thus, remote sensing research was conducted to evaluate impact of the tsunami on seagrass bed in Shizugawa Bay, Sanriku Coast. GeoEye-1 multi-band imageries taken on 4 November 2009 and 22 February 2012 were analyzed to map seagrass beds before and after the tsunami, respectively. Analysis of the former imagery showed seagrass beds were distributed in sheltered bottom against waves along the coast corresponding to seagrass distributions obtained through inquiry to fishermen and references on seagrass bed distributions before the tsunami. Analysis of the latter imagery indicated that seagrass bed distributions on 22 February 2012 were less than on 4 November 2009. Seagrass beds in the bay head disappeared while some seagrass beds remained behind the points along the north coast. This was verified by the field survey conducted in October 2011 and May and October 2012. Since the tsunami waves propagated into the bay along the longitudinal axis of the bay without crossing both sides of the bay, they produced only big sea-level changes during the propagation along the both sides from the center to the bay mouth. Their energy is concentrated the bay head and removes seagrass with sand and mud substrates. On the other hand, the tsunami higher than 12 m could not completely destroy seagrass beds due to topographic effect protecting seagrass from strong force by the tsunami. Thus, all seagrass weren’t destroyed completely in Shizugawa Bay even by the hit of the huge tsunami.