E7766, a Macrocycle-Bridged Stimulator of Interferon Genes (STING) Agonist with Potent Pan-Genotypic Activity

A strategy for creating potent and pan-genotypic stimulator of interferon genes (STING) agonists is described. Locking a bioactive U-shaped conformation of cyclic dinucleotides by introducing a transannular macrocyclic bridge between the nucleic acid bases leads to a topologically novel macrocycle-bridged STING agonist (MBSA). In addition to substantially enhanced potency, the newly designed MBSAs, exemplified by clinical candidate E7766 , exhibit broad pan-genotypic activity in all major human STING variants. E7766 is shown to have potent antitumor activity with long lasting immune memory response in a mouse liver metastatic tumor model. Two complementary stereoselective synthetic routes to E7766 are also described.     

Reduced Claudin-12 Expression Predicts Poor Prognosis in Cervical Cancer

Background: Within the claudin (CLDN) family, CLDN12 mRNA expression is altered in various types of cancer, but its clinicopathological relevance has yet to be established due to the absence of specific antibodies (Abs) with broad applications. Methods: We generated a monoclonal Ab (mAb) against human/mouse CLDN12 and verified its specificity. By performing immunohistochemical staining and semiquantification, we evaluated the relationship between CLDN12 expression and clinicopathological parameters in tissues from 138 cases of cervical cancer. Results: Western blot and immunohistochemical analyses revealed that the established mAb selectively recognized the CLDN12 protein. Twenty six of the 138 cases (18.8%) showed low CLDN12 expression, and the disease-specific survival (DSS) and recurrence-free survival rates were significantly decreased compared with those in the high CLDN12 expression group. We also demonstrated, via univariable and multivariable analyses, that the low CLDN12 expression represents a significant prognostic factor for the DSS of cervical cancer patients (HR 3.412, p = 0.002 and HR 2.615, p = 0.029, respectively). Conclusions: It can be concluded that a reduced CLDN12 expression predicts a poor outcome for cervical cancer. The novel anti-CLDN12 mAb could be a valuable tool to evaluate the biological relevance of the CLDN12 expression in diverse cancer types and other diseases.     

Well‐defined,environment‐friendly synthesis of polypeptides based on phosgene‐free transformation of amino acids into urethane derivatives and their applications

In this study, both naturally occurring and artificial amino acids were successfully transformed into the corresponding urethane derivatives using diphenyl carbonate. The urethanes thus prepared could be efficiently cyclized into amino acid N‐carboxyanhydrides (NCAs) without the requirement of phosgene. In addition, the presence of primary amines converted the urethane derivatives into NCAs and initiated the ring‐opening polymerization of the in situ formed NCAs, allowing for the well‐defined synthesis of polypeptides. These polypeptides contained initiating ends functionalized by an amine‐derived residue and propagating ends bearing the reactive amino group. By precise control of the structures of the polypeptides, various polypeptide conjugates such as block copolymers and graft copolymers were successfully synthesized as designed, and their applications in antifouling coatings against proteins, drug delivery systems and biosensors were demonstrated. © 2019 Society of Chemical Industry     

Gas‐phase removal of indoor volatile organic compounds and airborne microorganisms over mono‐ and bimetal‐modified (Pt,Cu, Ag) titanium(IV) oxide nanocomposites

The photocatalytic deactivation of volatile organic compounds and mold fungi using TiO₂ modified with mono‐ and bimetallic (Pt, Cu, Ag) particles is reported in this study. The mono‐ and bimetal‐modified (Pt, Cu, Ag) titanium(IV) oxide photocatalysts were prepared by chemical reduction method and characterized using XRD, XPS, DR/UV‐Vis, BET, and TEM analysis. The effect of incident light, type and content of mono‐ and bimetallic nanoparticles deposited on titanium(IV) oxide was studied. Photocatalytic activity of as‐prepared nanocomposites was examined in the gas phase using LEDs array. High photocatalytic activity of Ag/Pt‐TiO₂ and Cu/Pt‐TiO₂ in the reaction of toluene degradation resulted from improved efficiency of interfacial charge transfer process, which was consistent with the fluorescence quenching effect revealed by photoluminescence (PL) emission spectra. The photocatalytic deactivation of Penicillium chrysogenum, a pathogenic fungi present in the indoor environment, especially in a damp or water‐damaged building using mono‐ and bimetal‐modified (Pt, Cu, Ag) titanium(IV) oxide was evaluated for the first time. TiO₂ modified with mono‐ and bimetallic NPs of Ag/Pt, Cu, and Ag deposited on TiO₂ exhibited improved fungicidal activity under LEDs illumination than pure TiO₂.     

Evaluation of the Anti-Proliferative Activity of Rare Aldohexoses against MOLT-4F and DU-145 Human Cancer Cell Line and Structure-Activity Relationship of D-Idose

D-Allose (D-All), a C-3 epimer of D-glucose (D-Glc), is a naturally rare monosaccharide, which shows anti-proliferative activity against several human cancer cell lines. Unlike conventional anticancer drugs, D-All targets glucose metabolism and is non-toxic to normal cells. Therefore, it has attracted attention as a unique “seed” compound for anticancer agents. However, the anti-proliferative activities of the other rare aldohexoses have not been examined yet. In this study, we evaluated the anti-proliferative activity of rare aldohexoses against human leukemia MOLT-4F and human prostate cancer DU-145 cell lines. We found that D-All and D-idose (D-Ido) at 5 mM inhibited cell proliferation of MOLT-4F cells by 46 % and 60 %, respectively. On the other hand, the rare aldohexoses at 5 mM did not show specific anti-proliferative activity against DU-145 cells. To explore the structure–activity relationship of D-Ido, we evaluated the anti-proliferative activity of D-sorbose (D-Sor), 6-deoxy-D-Ido, and L-xylose (L-Xyl) against MOLT-4F cells and found that D-Sor, 6-deoxy-D-Ido, and L-Xyl showed no inhibitory activity at 5 mM, suggesting that the aldose structure and the C-6 hydroxy group of D-Ido are important for its activity. Cellular glucose uptake assay and western blotting analysis of thioredoxin-interacting protein (TXNIP) expression suggested that the anti-proliferative activity of D-Ido is induced by inhibition of glucose uptake via TXNIP-independent pathway.     

A molten metal jet impingement on a flat spreading surface

ABSTRACT

In the event of a severe accident, past experiences such as Three Mile Island and Fukushima Daichi have shown that the reactor core of a light-water nuclear reactor, if not properly safeguarded, could go through a meltdown. This will be followed by the formation of a corium, a mix of molten fuel elements, and liquid metals from the Reactor Pressure Vessel (RPV). In the worst-case scenario, a melt through from the RPV can occur and lead to the spreading of the corium, in the form of a molten element’s jet impinging on a flat concrete structure of the Primary Containment Vessel (PCV). To enhance the decommissioning and the safety procedure, scope of the present article is to deepen the understanding of the phenomena involved in the mentioned scenario, mainly jet-instability and molten material spreading. In the present study, experiments were carried out, by using corium simulant materials such as Copper and Tin, to investigate the link between the instability of the gravity-driven molten metal jet and the impinging followed by its spreading over a flat area.     

Surface treatment of titanium dioxide nanopowder using rotary electrode dielectric barrier discharge reactor

Titanium dioxide (TiO2) nanopowder (P-25;Degussa AG) was treated using dielectric barrier discharge (DBD) in a rotary electrode DBD (RE-DBD) reactor.Its electrical and optical characteristics were investigated during RE-DBD generation.The treated TiO2 nanopowder properties and structures were analyzed using x-ray diffraction (XRD) and Fourier-transform infrared spectroscopy (FTIR).After RE-DBD treatment,XRD measurements indicated that the anatase peak theta positions shifted from 25.3° to 25.1°,which can be attributed to the substitution of new functional groups in the TiO2 lattice.The FTIR results show that hydroxyl groups (OH) at 3400 cm-1 increased considerably.The mechanism used to modify the TiO2 nanopowder surface by air DBD treatment was confirmed from optical emission spectrum measurements.Reactive species,such as OH radical,ozone and atomic oxygen can play key roles in hydroxyl formation on the TiO2 nanopowder surface.     

Feasibility of using U to reconstruct close-in fallout deposition from the Hiroshima atomic bomb

The first results on the feasibility of using ²³⁶U to reconstruct the level and spatial distribution of close-in fallout deposition from the Hiroshima A-bomb are reported, coupled with the use of global fallout ¹³⁷Cs and ^239 + 240Pu. The results for global fallout ²³⁶U in soil samples (0-30 cm) from Ishikawa prefecture showed that the deposition density of ²³⁶U from the global fallout can be accurately evaluated using AMS. All deposited ²³⁶U, ¹³⁷Cs and ^239 + 240Pu appeared to have been recovered using 30-cm cores. It was also noted from the depth profiles for ²³⁶U/^239 + 240Pu and ²³⁶U/¹³⁷Cs ratios that the downward behavior of ²³⁶U in the soil was apparently similar to that of ^239 + 240Pu, while the ¹³⁷Cs was liable to be retained in upper layers compared with ²³⁶U and ^239 + 240Pu. The accumulated levels were 1.78 × 10¹³ atoms m^− 2 for ²³⁶U, 4340 Bq m^− 2 for ¹³⁷Cs and 141 Bq m^− 2 for ^239 + 240Pu. The ratios of ²³⁶U/¹³⁷Cs and ²³⁶U/^239 + 240Pu were (4.10 ± 0.12) × 10⁹ and (1.26 ± 0.04) × 10¹¹ atoms Bq^− 1, respectively. Results of ²³⁶U, ¹³⁷Cs and ^239 + 240Pu measurements for the seven soil cores (0-30 cm) from Hiroshima were discussed on the basis of ratios of ²³⁶U/¹³⁷Cs and ²³⁶U/^239 + 240Pu by comparing with those from the background area in Ishikawa, indicating that the global fallout dominates the current level of ²³⁶U accumulation in soil in the Black-rain area around Hiroshima after the Hiroshima bomb, and the contribution of the close-in fallout ²³⁶U produced by the Hiroshima A-bomb seems difficult to observe.     

Investigation report of geotechnical disaster on river area due to typhoon landfall three times on Okhotsk region,Hokkaido, Japan

For one week from August 17 to 23, 2016, three consecutive typhoons made landfall in Hokkaido for the first time on record. These typhoons and the front they stimulated brought record-breaking torrential rain over the eastern part of Hokkaido. To investigate the damage to grounds and rivers resulting from this rainfall, the Japan Society of Civil Engineers (JSCE) and the Japanese Geotechnical Society (JGS) formed a disaster research group to conduct an investigation. This report provides the results of the investigation into damage to the grounds of areas along the Tokoro River of the Okhotsk region, Hokkaido, that suffered from this tremendous and diverse disaster. Specifically, the report describes the situation of the levees which were broken and eroded by the overflowing water, the shape of the levee bodies, the levee body soil properties examined by observation of the sections, as well as the occurrence of sand boiling and air blows. The washout of road embankments as well as damage to road bridge mounting fills and abutment backfills were also investigated. The investigation has demonstrated the need to clarify the resistance of the abutment backfills and levee bodies to flowing water as well as the geotechnical predominant factors in order to clarify the mechanisms behind erosion and washout, the need to review new measures that allow for the scale of sand boiling and resultant changes in levee body stability, and the fact that the existing embankments were able to temporarily suppress the flooding water which had spilled over from the river. Furthermore, although it has been identified that the findings of a study on an embankment washout associated with a tsunami can be applied to measures taken against the overflowing water, it has also been found necessary to clarify the predominant geotechnical factors using model tests and to use a more sophisticated analytical approach to establish a geotechnical stability review as soon as possible in order to prevent the levees and embankments from being eroded and washed out due to overflowing water.     

Characterization of the Oxide Scale Formed on T12 Water Wall Tube After Long-term Service in Supercritical Power Plant

Oxidation of Metals - Oxide scale control is one of the critical maintenance issues in fossil fuel power plant. Hence, the water treatment of the feed water has been changed from all-volatile...