Three-component, one-pot tandem Sonogashira/Suzuki–Miyaura coupling reactions and derivatization for the synthesis of a library of ceramide-transport protein inhibitors that were designed in silico

We have developed a one-pot, tandem Sonogashira/Suzuki–Miyaura coupling reaction, which is unknown synthetically, and applied it for the synthesis of a library of potential natural ligand nonmimetic inhibitors of the lipid-transfer protein, ceramide-transport protein (CERT). The characteristic feature of this reaction is that the two-step coupling reaction proceeds smoothly with only 5 mol% of palladium catalyst. Furthermore, the location of the formed carbon–carbon bond would be strictly defined because of the difference in reactivity. Therefore, many derivatives could be synthesized in high yields without the formation of regioisomeric byproducts by the same procedure. We also performed a semi-gram scale synthesis of several derivatives to provide the bioactive assey. After synthesizing as many as 113 derivatives, we identified a nonnatural mimetic inhibitor with activity comparable to that of the known inhibitor (1R,3S)-HPA-12

Performance of the TPC with Micro Pixel Chamber Readout: micro-TPC

Micro-TPC, a time projection chamber(TPC) with micro pixel chamber($\mu$-PIC) readout was developed for the detection of the three-dimensional fine(sub-m illimeter) tracks of charged particles. We developed a two-dimensional position sensitive gaseous detector, or the $\mu$-PIC, with the detection area of 10$\times$10 cm${}^{2}$ and 65536 anode electrodes of 400 $\mu$m pitch. We achieved the gas gain of over 10000 without any other multipliers. With the pipe-line readout system specially developed for the $\mu$-PIC, we detected X-rays at the rate as high as 7.7 Mcps. We attached a drift cage with an 8 cm drift length to the $\mu$-PIC and developed a micro-TPC. We measured the basic performances of the micro-TPC and took three-dimensional tracks of electrons. We also developed a prototype of the MeV gamma-ray imaging detector which is a hybrid of the micro-TPC and NaI(Tl) scintillators and confirmed its concept by reconstructing the obtained data.Comment: 6 pages 16 figures, submitted for IEEE/TNS 200

Competitiveness of the Chinese Manufacturers in the Digital Appliances Industry: Limits of Combination Capabilities for Product Development of Modular Products (Japanese)

Chinese firms have rapidly become more competitive in the digital appliances industry. For example, they lead the world market in DVD players. Chinese manufacturers have also launched many new desktop PC and digital camera products. Since these are modular products, they can be developed simply by procuring components and assembling them. However, the international competitiveness of these products varies widely. No rapid increase in Chinese competitiveness has been seen in laptops or digital cameras, for instance. Even though these products are all modular, the capability to realize efficient combination of components is not, by itself, enough to make a firm competitive. The purpose of this paper is to reexamine product development capabilities in modular products and to present a theoretical framework regarding the true nature of product development capability in modular appliances, focusing on the competitiveness of Chinese firms in digital appliances. It is often argued that the combination capability is sufficient to develop competitive modular products but the paper suggests that this argument only applies to a limited range of products.

Chlamydial Infection-Dependent Synthesis of Sphingomyelin as a Novel Anti-Chlamydial Target of Ceramide Mimetic Compounds

The obligate intracellular bacterium Chlamydia trachomatis is the major causative agent of bacterial sexually transmitted diseases worldwide. In infected cells, the ceramide transport protein (CERT) is recruited to inclusions, where C. trachomatis replicates using host-synthesized ceramide. The ceramide is converted to sphingomyelin (SM) by a chlamydial infection-dependent SM synthesis (cidSM-synthesis) pathway, which occurs even in the absence of the SM synthases (SMS)-1 and -2 of host cells. The ceramide mimetic compound (1R,3S)-HPA-12 and the nonmimetic compound E16A, both of which are potent inhibitors of CERT, repressed the proliferation of C. trachomatis in HeLa cells. Unexpectedly, (1R,3R)-HPA-12, a ceramide mimetic compound that lacks CERT inhibitory activity, also exhibited potent anti-chlamydial activity. Using endogenous SMS-knockout mutant HeLa cells, we revealed that (1R,3R)-HPA-12 mildly inhibited cidSM-synthesis. In addition, LC-MS analysis revealed that (1R,3R)-HPA-12 is converted to a phosphocholine-conjugated metabolite in an infection-dependent manner. Imaging analysis with a fluorescent analog of ceramide suggested that cidSM-synthesis occurs in the bacterial bodies and/or inclusions. Collectively, these results suggested that (1R,3R)-HPA-12 exerts its anti-chlamydia activity not only as an inhibitor of cidSM-synthesis, but also via putative toxic effects of its phosphocholine adduct, which is most likely produced by the cidSM-synthesis route

Performance of a micro-TPC for a time-resolved neutron PSD

We report on the performance of a micro-TPC with a micro pixel chamber($\mu$-PIC) readout for a time-resolved neutron position-sensitive detector(PSD). Three-dimensional tracks and the Bragg curves of protons with energies of around 1 MeV were clearly detected by the micro-TPC. More than 95% of gamma-rays of 511 keV were found to be discriminated by simple analysis. Simulation studies showed that the total track length of proton and triton emitted from the $\rm {}^{3}He$(n,p(573 keV))$\rm {}^{3}H(191 keV)$ reaction is about 1.2 cm, and that both particles have large energy losses ($\rm > 200 keV/cm$) in 1 atm Ar+$\rm C_{2}H_{6}(10$+${}^{3}$He($< 1$). These values suit the current performance of the micro-TPC, and we conclude that a time-resolved neutron PSD with spatial resolution of sub-millimeters shall be developed as an application of the micro-TPC.Comment: 13 pages, 10 figures, to appear in NIM