Development of Novel Inhibitors for Histone Methyltransferase SET7/9 based on Cyproheptadine

The histone methyltransferase SET7/9 methylates not only histone but also non‐histone proteins as substrates, and therefore, SET7/9 inhibitors are considered candidates for the treatment of diseases. Previously, our group identified cyproheptadine, used clinically as a serotonin receptor antagonist and histamine receptor (H1) antagonist, as a novel scaffold of the SET7/9 inhibitor. In this work, we focused on dibenzosuberene as a substructure of cyproheptadine and synthesized derivatives with various functional groups. Among them, the compound bearing a 2‐hydroxy group showed the most potent activity. On the other hand, a 3‐hydroxy group or another hydrophilic functional group such as acetamide decreased the activity. Structural analysis clarified a rationale for the improved potency only by tightly restricted location and type of the hydrophilic group. In addition, a SET7/9 loop, which was only partially visible in the complex with cyproheptadine, became more clearly visible in the complex with 2‐hydroxycyproheptadine. These results are expected to be helpful for further structure‐based development of SET7/9 inhibitors.     

Unusual Two-Step Assembly of a Minimalistic Dipeptide-Based Functional Hypergelator

Self-assembled peptide hydrogels represent the realization of peptide nanotechnology into biomedical products. There is a continuous quest to identify the simplest building blocks and optimize their critical gelation concentration (CGC). Herein, a minimalistic, de novo dipeptide, Fmoc-Lys(Fmoc)-Asp, as an hydrogelator with the lowest CGC ever reported, almost fourfold lower as compared to that of a large hexadecapeptide previously described, is reported. The dipeptide self-assembles through an unusual and unprecedented two-step process as elucidated by solid-state NMR and molecular dynamics simulation. The hydrogel is cytocompatible and supports 2D/3D cell growth. Conductive composite gels composed of Fmoc-Lys(Fmoc)-Asp and a conductive polymer exhibit excellent DNA binding. Fmoc-Lys(Fmoc)-Asp exhibits the lowest CGC and highest mechanical properties when compared to a library of dipeptide analogues, thus validating the uniqueness of the molecular design which confers useful properties for various potential applications.     

Quantitative risk assessment using a Japanese hydrogen refueling station model

Although hydrogen refueling stations (HRSs) are becoming widespread across Japan and are essential for the operation of fuel cell vehicles, they present potential hazards. A large number of accidents such as explosions or fires have been reported, rendering it necessary to conduct a number of qualitative and quantitative risk assessments for HRSs. Current safety codes and technical standards related to Japanese HRSs have been established based on the results of a qualitative risk assessment and quantitative effectiveness validation of safety measures over ten years ago. In the last decade, there has been much development in the technologies of the components or facilities used in domestic HRSs and much operational experience as well as knowledge to use hydrogen in HRSs safely have been gained through years of commercial operation. The purpose of the present study is to conduct a quantitative risk assessment (QRA) of the latest HRS model representing Japanese HRSs with the most current information and to identify the most significant scenarios that pose the greatest risks to the physical surroundings in the HRS model. The results of the QRA show that the risk contours of 10^?3 and 10^?4 per year were confined within the HRS boundaries, whereas the risk contours of 10^?5 and 10^?6 per year are still present outside the HRS. Comparing the breakdown of the individual risks (IRs) at the risk ranking points, we conclude that the risk of jet fire demonstrates the highest contribution to the risks at all of the risk ranking points and outside the station. To reduce these risks and confine the risk contour of 10^?6 per year within the HRS boundaries, it is necessary to consider risk mitigation measures for jet fires.     

Effects of metal support interaction on dry reforming of methane over Ni/Ce-Al2O3 catalysts

Dry (CO₂) reforming of methane is conducted over two newly synthesized Ni20/Ce-γAl₂O₃ and Ni20/Ce-meso-Al₂O₃ catalysts. The x-ray diffraction (XRD) patterns indicated that Ni20/Ce-meso-Al₂O₃ exhibits a better dispersion of nickel, while Ni20/Ce-γAl₂O₃ has larger amounts of nickel crystallites. The temperature programmed desorption (TPD) kinetics analysis indicated that Ni20/Ce-meso-Al₂O₃ had a lesser metal-support interaction than the Ni20/Ce-γAl₂O₃. The thermal gravimetric analysis (TGA) indicated that the incorporation of ceria into the Al₂O₃ matrix helps to stabilize Ni20/Ce-meso-Al₂O₃ during dry reforming of methane. The temperature programmed reduction (TPR) indicated that the synthesized catalysts were sufficiently reducible below 750 °C. A fixed bed reactor evaluation (at 750 °C) showed that both catalysts can facilitate methane reforming to syngas with minimal coking throughout the 30 hours time-on-stream (TOS). However, Ni20/Ce-meso-Al₂O₃ is more promising in terms of prolonged stability for dry reforming applications. Moreover, the syngas yield for Ni20/Ce-γAl₂O₃ is close to equilibrium prediction during the first 1 hour of reaction time.     

Process design and techno‐economic analysis of ethyl levulinate production from carbon dioxide and 1,4‐butanediol as an alternative biofuel and fuel additive

Carbon dioxide capture, utilization, and storage (CCUS) is one of the promising negative emission technologies (NET). Within various CCUS routes available, CO₂ conversion into fuels is one of the attractive options. Currently, most of CO₂ conversion into fuels requires hydrogen, which is expensive and consume large energy to produce. Hence, a different route of producing fuel from CO₂ by utilizing 1,4‐butanediol as the raw material is proposed and evaluated in this study. This alternative route comprises production of levulinic acid from the reaction between CO₂ and 1,4‐butanediol and production of ethyl levulinate, an alternative biofuel and biofuel additive, via an esterification reaction of levulinic acid with ethanol. The process is designed and simulated according to the available data and evaluated in terms of its technical features. Because of the unavailability of reaction data for synthesis of levulinic acid from 1,4‐butanediol and CO₂, several assumptions were taken, which may implicate the accuracy of the studied design. This technical evaluation is followed by cost estimations and sensitivity analysis. Because of the free CO₂, the profitability of the plant depends strongly on the prices of the other chemicals and the price difference between 1,4‐butanediol (raw material) and ethyl levulinate (product). Monte Carlo simulation indicates that the proposed plant will always be profitable if the ethyl levulinate is slightly more expensive than the 1,4‐butanediol, highlighting that the process of producing ethyl levulinate from CO₂ is economically profitable. Future research should be directed towards a catalytic system that can effectively convert CO₂ into levulinic acid, by‐products produced from the two reaction steps, and reduce the excess ethanol used in the second reaction.     

Topic allocation method on edge servers for latency-sensitive notification service

The importance of real-time notification has been growing for social services and Intelligent Transporting System (ITS). As an advanced version of Pub/Sub systems, publish-process-subscribe systems, where published messages are spooled and processed on edge servers, have been proposed to achieve data-driven intelligent notifications. In this paper, we present a system that allows a topic to be managed on multiple edge servers so that messages are processed near the publishers, even when publishers spread over a wide area. Duplicating messages on geographically distributed servers could enable immediate notification to neighboring subscribers. However, the duplicated message spool may cause exhaustion of resources. We prepare a formal model of our publish-process-subscribe system and formulate the topic allocation as an optimization problem under the resource constraints of edge servers. As the optimization problem is NP-hard, we propose heuristics leveraging the locality and the pub/sub relationships observed between clients to use the edge server resources efficiently. Our performance evaluation shows that our method reduces the delay to deliver notifications and the effectiveness of the strategy exploiting the relationships between clients.     

Mercury contamination in the Yatsushiro Sea, south-western Japan: spatial variations of mercury in sediment

Mercury-contaminated effluent was discharged into Minamata Bay from a chemical plant over a 20-year period until 1965 (from 1958 to 1959, effluent was discharged into Minamata River), causing Minamata disease. In an effort to characterize the extent of the contamination in the Yatsushiro Sea, the vertical and horizontal distributions of mercury in sediment were investigated. Sediment was sampled at 62 locations in the southern part of the sea from 4 to 6 March 1996. In the lower layers of the long cores of sediment, the total amount of mercury was at a relatively uniform low concentration. We interpret these low values to represent the background concentration absent of anthropogenic influence. The background value thus estimated for the Yatsushiro Sea was 0.059 +/- 0.013 mg kg(-1) (mean +/- S.D., n = 51). The highest concentration in each sample ranged from 0.086 to 3.46 mg kg(-1) (mean, 0.57 mg kg(-1)). The higher values were obtained at stations near Minamata Bay and the Minamata River (the sources of the pollution). Concentrations decreased with distance from the source. An inspection of the vertical profiles of mercury concentration in cores suggested that the deposited mercury had not been fixed in sediment but had been transported, despite 30 years having past since the last discharge of contaminated effluent. At nine stations, extractable inorganic and organic mercury concentrations were determined differentially. Inorganic mercury is the predominant species in sediment and organic mercury comprising approximately 1% of the total.     

Revisiting the Mechanism of β-O-4 Bond Cleavage During Acidolysis of Lignin. Part 6: A Review

ABSTRACT

This paper reviews our results on the acidolysis of dimeric non-phenolic β-O-4-type lignin model compounds in aqueous 82% 1,4-dioxane containing an acid at 85°C. It was shown that the mechanism of a C₆-C₂-type model compound, 2-(2-methoxyphenoxy)-1-(3,4-dimethoxyphenyl)ethanol IX, is fairly different from that of a C₆-C₃ analogue, 2-(2-methoxyphenoxy)-1-(3,4-dimethoxyphenyl)propane-1,3-diol XX, suggesting the significance of the presence of the γ-hydroxymethyl group. It was confirmed that the hydride transfer mechanism exists as a reaction route of the benzyl-cation-type intermediates derived from both compounds, and the contribution of this mechanism is greater than expected in the acidolysis of compound XX. An enol ether compound, 2-(2-methoxyphenoxy)-3-(3,4-dimethoxyphenyl)prop-2-en-1-ol, was first detected in the acidolysis of compound XX using the DBr/D₂O/1,4-dioxane system. It was confirmed in the acidolysis of compound XX using HBr that the mechanism is different from that in the system using either HCl or H₂SO₄ and an unknown mechanism contributes to the reaction. This unknown mechanism surprisingly contributed more with decreasing concentration of HBr or Br^?, provided that Br^? still existed in the system.