Identification of 3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine Derivatives as Novel Selective Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase

Plasmodium falciparum’s resistance to available antimalarial drugs highlights the need for the development of novel drugs. Pyrimidine de novo biosynthesis is a validated drug target for the prevention and treatment of malaria infection. P. falciparum dihydroorotate dehydrogenase (PfDHODH) catalyzes the oxidation of dihydroorotate to orotate and utilize ubiquinone as an electron acceptor in the fourth step of pyrimidine de novo biosynthesis. PfDHODH is targeted by the inhibitor DSM265, which binds to a hydrophobic pocket located at the N-terminus where ubiquinone binds, which is known to be structurally divergent from the mammalian orthologue. In this study, we screened 40,400 compounds from the Kyoto University chemical library against recombinant PfDHODH. These studies led to the identification of 3,4-dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine and its derivatives as a new class of PfDHODH inhibitor. Moreover, the hit compounds identified in this study are selective for PfDHODH without inhibition of the human enzymes. Finally, this new scaffold of PfDHODH inhibitors showed growth inhibition activity against P. falciparum 3D7 with low toxicity to three human cell lines, providing a new starting point for antimalarial drug development.     

Application of a floc-forming genetically engineered microorganism to a sequencing batch reactor for phenolic wastewater treatment

For enhancing the survival of genetically engineered microorganisms (GEMs) in activated sludge processes, the use of a floc-forming bacterium as the host for a recombinant plasmid was proposed. The floc-forming and phenol-degrading GEM Sphingomonas paucimobilis 551 (pS10-45) was cultured to demonstrate this proposal. Although the maximum growth rate of the host strain S. paucimobilis 551 was low and the recombinant plasmid pS10-45 was unstable in the host, the resultant GEM S. paucimobilis 551 (pS10-45) was difficult to wash out together with the effluent, and it maintained population 3-4 times higher than the non-floc-forming GEM Escherichia coli HB101 (pS10-45) in a model activated sludge process operated in a sequencing batch mode. In the long run, the GEM-inoculated activated sludge process showed better phenol removal ability by the recombinant plasmid and better sludge settlement by the host strain.     

Antibacterial activity of essential oil vapor for histamine-producing bacteria

In this study, we evaluated the antibacterial activity of essential oil vapors against histamine-producing bacteria Morganella morganii NBRC3848 and Raultella planticola NBRC3317. We measured the minimum inhibitory dose (MID) of 14 essential oils towards these two strains. Allyl isothiocyanate (AIT) and salicylaldehyde (SA) vapors showed higher antibacterial activity than the other 12 essential oil vapors. Both AIT and SA vapors suppressed growth of total aerobic bacteria and histamine-producing bacteria in bigeye tuna and mackerel meat during storage at 12°C. These vapors also inhibited histamine accumulation in bigeye tuna meat and mackerel meat. Thus, application of AIT and SA vapors is effective for preventing increase of histamine-producing bacteria and histamine formation in fish meat.     

Design and performance of ultra-low-loss single-mode fiber cable in 1.5-µm wavelength region

The structural optimization of single-mode fiber for use in the 1.5-μm wavelength region is made with the aim of minimizing the total transmission-line loss over a repeater section. For example, the optimum ranges of the mode-field radius w0and effective cutoff wavelength λceare determined as 5.5 μmleq w_{0} leq 6.5 mum and 1.35μmleq lambda_{ce} leq 1.53 mum for high bit-rate transmission systems with a repeater spacing of 80 km. Based upon the design, ultra-low-loss single-mode fiber cables are fabricated. The average loss of 108 fibers in the cables is 0.19 dB/km at 1.55 μm. The total loss of a 216-km-long fiber link containing 107 splice points was 46.3 dB. Good loss stability at high temperatures as well as during the cable manufacturing processes, are achieved by the appropriate choices of coating materials and optimized fiber parameters.     

Detection of cytomegalovirus (CMV) antigen for rapid diagnosis and monitoring of CMV diseases in AIDS

Ten to forty percent of the patients with acquired immunodeficiency syndrome (AIDS) develop sight- or life-threatening cytomegalovirus (CMV) infections. In some patients with AIDS, CMV is detected in the bronchoalveolar lavage fluid (BALF), urine, and other specimens, even when there are no symptoms of CMV disease. An indicator of active CMV infection is needed to facilitate the diagnosis of CMV disease in patients with AIDS or HIV infection and the evaluation of the efficacy of subsequent treatment. The present study was conducted during the period from 1993 to 1994. The subjects consisted of three patients with AIDS and a confirmed diagnosis of CMV disease (one case of retinitis, one case of gastrointestinal disease and one case of pneumonia), and five HIV-positive patients in whom CMV associated disease was ruled out. Those patients were monitored occasionally for the following parameters of active CMV infection and disease: expression of CMV antigen in the nucleus of polymorphonuclear leukocyte (CMV antigenemia), as it was determined with a monoclonal antibody against a lower matrix protein (p65); infectious CMV detected by shell vial method; CMV DNA detected by PCR; anti-CMV antibody titer; and histological findings. CMV p65 antigen was detected in the leukocytes of both the peripheral blood and BALF during the early phase of CMV disease in three out of three cases of the CMV disease group, and this antigen became negative in two out of two cases who responded to the therapy. All the five patients in the CMV-related-disease-negative group were negative for CMV antigenemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Suitable definition of mode field diameter in view of splice loss evaluation

The definition of the mode field diameter is investigated theoretically and experimentally from a practical viewpoint of the splice loss estimation. The difference of mode field diameter defined by various definitions becomes larger as theV-value decreases. This tendency agrees with the experimental result. As a result, the definition of mode field diameter obtained from RMS width of far-field intensity is useful.     

Measurements of 220 GHz atmospheric opacity on Mt. Fuji with a radiometer/radome system

We measured atmospheric opacity at 220 GHz at the summit of Mt. Fuji (alt. 3776 m) about one year in order to explore a feasibility of submillimeter-wave astronomical observations. For this purpose, a 220 GHz radiometer system enclosed in a radome (51×51×62 cm³) has been developed. The 220 GHz opacity was lower than 0.06 for a significant fraction (～ 45 %) of time from November 1994 to March 1995. Diurnal variation of the opacity at the summit of Mt. Fuji is so small that continuous observation at submillimeter-wave is possible through day and night. Yearly variation of the opacity is studied from water vapor pressure data measured at the weather station for the past 3 years. To prevent accumulation of ice and snow on the Gore-Tex membrane in the radome, the outer membrane was supplied with a thermal flux of 0.63 kW m^?2 and the adjacent metal radome surfaces were supplied with a flux of ～0.9 kW m^?2. We evaluate from the 220 GHz transmission data that this heat flux is sufficient to keep the membrane on the radome free of ice and snow during 83 % of the time in 5 winter months. The summit of Mt. Fuji appears to be a promising site for submillimeter-wave observations.     

Estimation of creep crack growth rate in IN-100 based on the Q* parameter concept

Since the high-strength Ni-based superalloy, cast IN-100, is considered to be brittle at high temperatures, the stable creep crack growth region is limited. Therefore, technically, it is very difficult to perform creep tests and there are few experimental results on the creep crack growth behaviour of this material. We performed creep crack growth tests using Ni-based superalloy, cast IN-100, and derived the Q* parameter for this material, which characterizes the creep crack growth rate. Using this Q* parameter, we derived a law for the creep rupture life of this material.