No abstract

Niemann-Pick type C disease (NPC), an autosomal recessive lysosomal storage disorder, is an inherited disease characterized by the accumulation of intracellular unesterified cholesterol. A solubilizing agent of lipophilic compounds, 2-hydroxypropyl-β-cyclodextrin (HPBCD), is an attractive drug candidate against NPC disease. However, establishment of the optimum dosage of HPBCD remains to be determined. In this study, we evaluated the effective dosage of HPBCD in NPC model (Npc1 / ) mice, and determined serum HPBCD concentrations. Subcutaneous injection of 1000-4000 mg/kg HPBCD improved the lifespan of Npc1 / mice. In addition, liver injury and cholesterol sequestration were significantly prevented by 4000 mg/kg HPBCD in Npc1 / mice. Serum HPBCD concentrations, when treated at the effective dosages (1000-4000 mg/kg), were approximately 1200-2500 µg/mL at 0.5 h after subcutaneous injection, and blood HPBCD concentrations were immediately eliminated in Npc1 / mice. Furthermore, we examined serum HPBCD concentrations when treated at 40000 mg (approximately 2500 mg/kg) in a patient with NPC. We observed that the effective concentration in the in vivo study using Npc1 / mice was similar to that in the patient. In the patient, systemic clearance and the volume of distribution of HPBCD were in accordance with the glomerular filtration rate and extracellular fluid volume, respectively. These results could provide useful information for developing the optimal dosage regimen for HPBCD therapy when administered intravenously to NPC patients.

No abstract

Polyethylene glycol (PEG) modification (PEGylation) is one of the best approaches to improve the stabilities and blood half-lives of protein drugs; however, PEGylation dramatically reduces the bioactivities of protein drugs. Here, we present "self-assembly PEGylation retaining activity" (SPRA) technology via a host-guest interaction between PEGylated β-cyclodextrin (PEG-β-CyD) and adamantane-appended (Ad) proteins. PEG-β-CyD formed stable complexes with Ad-insulin and Ad-lysozyme to yield SPRA-insulin and SPRA-lysozyme, respectively. Both SPRA-proteins showed high stability against heat and trypsin digest, comparable with that of covalently PEGylated protein equivalents. Importantly, the SPRA-lysozyme possessed ca. 100% lytic activity, whereas the activity of the covalently PEGylated lysozyme was ca. 23%. Additionally, SPRA-insulin provided a prolonged and peakless blood glucose profile when compared with insulin glargine. It also showed no loss of activity. In contrast, the covalently PEGylated insulin showed a negligible hypoglycemic effect. These findings indicate that SPRA technology has potential as a generic method, surpassing conventional PEGylation methods for proteins.

cDNAs encoding an enzyme with UDP-glucose:cyclo-DOPA 5-O-glucosyltransferase activity were isolated from four o'clocks and feather cockscombs. Phylogenetic analysis of the amino acid sequences deduced from the cDNAs show that they represent a single subclade distinct from those of other phenylpropanoid and flavonoid glucosyltransferases. Changes in the amount of transcripts of the cDNA in four o'clocks correlated with the accumulation of betanin during flower development. The cDNAs isolated here were candidates for the gene of the enzyme involved in another pathway of betacyanin biosynthesis via glucosylation at the cyclo-DOPA step rather than at the betanidin step.

No abstract

We find that the true ground state of the dipolar spin ice system under [110]-magnetic fields is the "Q = X" structure, which is consistent with both experiments and Monte Carlo simulations. We then perform a Monte Carlo simulation to confirm that there exists a first order phase transition under the [110]-field. In particular this result indicates the existence of the first order phase transition to the "Q = X" phase in the field above 0.35 T for Dy2Ti2O7. We also show the magnetic fieldtemperature phase diagram to summarize the ordered states of this system.

Akamatsu et al.(2006) proposed a new transportation demand management scheme called "tradable bottleneck permits" (TBP), and proved its efficiency properties for a single bottleneck model. This paper explores the properties of a TBP system for general networks. An equilibrium model is first constructed to describe the states under the TBP system. It is proved that equilibrium resource allocation is efficient in the sense that the total transportation cost in a network is minimized. Theoretical relationships between TBP and congestion pricing (CP) are also discussed. It is demonstrated that TBP has definite advantages over CP when demand information is not perfect, whereas both TBP and CP are equivalent for the perfect information case. Finally, it is shown that the "self-financing principle" also holds for the TBP system. Key Words : bottleneck congestion, dynamic traffic assignment, time-space network, tradable permit, ITSRecent advances in information and communication technology (ICT) have led to rapid changes in the "virtual" world represented by the Internet. The increasing capabilities and decreasing cost of ICT is now becoming the impetus for changing the "real" world. The effects of ICT on transportation systems are no exception. The broadly defined "Intelligent Transportation Systems (ITS)" that exploits ICT has a large potential for dramatically improving efficiency of road transportation systems if the systems are implemented together with appropriate transportation demand management (TDM) schemes.As an example of such futuristic TDM schemes making the most of ICT/ITS, Akamatsu, Sato andNguyen (2006), andAkamatsu (2007a) proposed the "tradable bottleneck permit system." Their proposed scheme is designed for resolving the problem of congestion during the morning rush hour at a single bottleneck, and consists of the following two parts: a) the road manager issues a right that allows a permit holder to pass through the bottleneck at a pre-specified time period ("bottleneck permits"), b) a new trading market is established for bottleneck permits differentiated by a pre-specified time Note here that both parts a) and b) of this scheme are feasible for implementation from a technical point of view, even at the present time. The system for handling part a) may be constructed as an application of the dedicated short range communication (DSRC) system that is used in the current electric toll collection (ETC) system; the trading markets in part b) also can be realized inexpensively by using Internet auction markets. It is, therefore, reasonable to assume that implementing this scheme will become technically easier when we take into account the future advances of ICT/ITS.