The ␤-chemokine receptor CCR5 is considered to be an attractive target for inhibition of macrophagetropic (CCR5-using or R5) HIV-1 replication because individuals having a nonfunctional receptor (a homozygous 32-bp deletion in the CCR5 coding region) are apparently normal but resistant to infection with R5 HIV-1. In this study, we found that TAK-779, a nonpeptide compound with a small molecular weight (M r 531.13), antagonized the binding of RANTES (regulated on activation, normal T cell expressed and secreted) to CCR5-expressing Chinese hamster ovary cells and blocked CCR5-mediated Ca 2؉ signaling at nanomolar concentrations. The inhibition of ␤-chemokine receptors by TAK-779 appeared to be specific to CCR5 because the compound antagonized CCR2b to a lesser extent but did not affect CCR1, CCR3, or CCR4. Consequently, TAK-779 displayed highly potent and selective inhibition of R5 HIV-1 replication without showing any cytotoxicity to the host cells. The compound inhibited the replication of R5 HIV-1 clinical isolates as well as a laboratory strain at a concentration of 1.6-3.7 nM in peripheral blood mononuclear cells, though it was totally inactive against T-cell line-tropic (CXCR4-using or X4) HIV-1.

Recent studies in streams and ponds have demonstrated that the distribution and biomass of aquatic organisms can be estimated by detection and quantification of environmental DNA (eDNA). In more open systems such as seas, it is not evident whether eDNA can represent the distribution and biomass of aquatic organisms because various environmental factors (e.g., water flow) are expected to affect eDNA distribution and concentration. To test the relationships between the distribution of fish and eDNA, we conducted a grid survey in Maizuru Bay, Sea of Japan, and sampled surface and bottom waters while monitoring biomass of the Japanese jack mackerel (Trachurus japonicus) using echo sounder technology. A linear model showed a high R2 value (0.665) without outlier data points, and the association between estimated eDNA concentrations from the surface water samples and echo intensity was significantly positive, suggesting that the estimated spatial variation in eDNA concentration can reflect the local biomass of the jack mackerel. We also found that a best-fit model included echo intensity obtained within 10–150 m from water sampling sites, indicating that the estimated eDNA concentration most likely reflects fish biomass within 150 m in the bay. Although eDNA from a wholesale fish market partially affected eDNA concentration, we conclude that eDNA generally provides a ‘snapshot’ of fish distribution and biomass in a large area. Further studies in which dynamics of eDNA under field conditions (e.g., patterns of release, degradation, and diffusion of eDNA) are taken into account will provide a better estimate of fish distribution and biomass based on eDNA.

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The search for new small-molecule CCR5 antagonists by high-throughput screening (HTS) of the Takeda chemical library using [(125)I]RANTES and CHO/CCR5 cells led to the discovery of lead compounds (A, B) with a quaternary ammonium or phosphonium moiety, which were synthesized to investigate new MCP-1 receptor antagonists. A series of novel anilide derivatives 1 with a quaternary ammonium moiety were designed, synthesized, and tested for their CCR5 antagonistic activity. Through the optimization of lead compounds, we have found N,N-dimethyl-N-[4-[[[2-(4-methylphenyl)-6, 7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]tetrahydr o-2 H-pyran-4-aminium chloride (1r, TAK-779) as a highly potent and selective nonpeptide CCR5 antagonist with a IC(50) value of 1.4 nM in the binding assay. Compound 1r also inhibited the replication of macrophage (M)-tropic HIV-1 (Ba-L strain) in both MAGI-CCR5 cells and PBMCs with EC(50) values of 1.2 and 3.7 nM, respectively. The synthesis and structure-activity relationships of 1r and its related compounds are detailed.

Environmental DNA (eDNA) consists of DNA fragments shed from organisms into the environment, and can be used to identify species presence and abundance. This study aimed to reveal the dispersion and degradation processes of eDNA in the sea. Caged fish were set off the end of a pier in Maizuru Bay, the Sea of Japan, and their eDNA was traced at sampling stations located at the cage and 10, 30, 100, 300, 600 and 1000 m distances from the cage along two transect lines. Sea surface water was collected at each station at 0, 2, 4, 8, 24 and 48 h after setting the cage, and again after removing the cage. Quantitative PCR analyses using a species-specific primer and probe set revealed that the target DNA was detectable while the cage was present and for up to 1 h after removing the cage, but not at 2 h or later. Among the 57 amplified samples, 45 (79%) were collected within 30 m from the cage. These results suggest that eDNA can provide a snapshot of organisms present in a coastal marine environment.

The spatial distributions of radiocesium concentration in sea sediment to a core depth of 14 cm were investigated in the offshore region from the Fukushima Prefecture to the northern part of the Ibaraki Prefecture in February and July 2012, at a spatial resolution of 5 min of latitude and longitude. The concentrations in the area south of the Fukushima Dai-ichi Nuclear Power Plant (FDNPP) were generally higher than those in the area north of it. In the southern area, a band of especially high concentration with a width about 20 km was present in the region shallower than 100 m, and a narrow minimal concentration band was found along the 200-m isobaths. In more than half of all cases, the vertical core profiles of radiocesium concentration generally showed an exponential decreasing trend with depth. However, in the area north of the FDNPP, where the radiocesium concentrations tended to be very low, radiocesium concentrations that had similar or larger magnitude compared with those of the most-surface layer were often found in deeper layers. Relatively good correlations were found between radiocesium concentrations and grain sizes of the most-surface sediment. The vertical profile of radiocesium concentration also had a relationship with grain size. In other case, the radiocesium concentration in the sediment seems to have had a dependence on the radiocesium concentration in bottom seawater, suggesting that the quantity of radiocesium supplied and the grain size were major factors determining the spatial distribution pattern of the radiocesium concentration after the FDNPP accident.

intensive expression of muTAUT was observed in the gill and epithelium of the mantle, which were directly exposed to intensive osmotic changes of ambient seawater.

SMTP-7 (Stachybotrys microspora triprenyl phenol-7), a small molecule that promotes plasminogen activation through the modulation of plasminogen conformation, has excellent therapeutic activity against cerebral infarction in several rodent models. Detailed evaluations of SMTP-7 in a primate stroke model are needed for effective, safe drug development. Here we evaluated SMTP-7 in a monkey photochemical-induced thrombotic middle cerebral artery (MCA) occlusion model (n=6), in which MCA occlusion was followed by recanalization/reocclusion. SMTP-7 (10 mg/kg, intravenous infusion) significantly increased the postinfusion MCA recanalization rate (32.5-fold, P=0.043) and ameliorated the post-24-h neurologic deficit (by 29%, P=0.02), cerebral infarct (by 46%, P=0.033), and cerebral hemorrhage (by 51%, P=0.013) compared with the vehicle control animals. In normal monkeys, SMTP-7 did not affect general physiologic or hemostatic variables, including coagulation and platelet parameters. Investigations in rodent models of transient and permanent focal cerebral ischemia, as well as arterial thrombosis and bleeding tests, suggest a role for SMTP-7's regulated profibrinolytic action and neuroprotective properties in the monkey MCA occlusion model. In conclusion, SMTP-7 is effective in treating thrombotic stroke in monkeys. SMTP-7 is thus a promising candidate for the development of alternative therapy for ischemic stroke.