• Curran Simmons posted an update 4 hours, 31 minutes ago

    The influenza virus hemagglutinin (HA) is an attractive target for antiviral therapy due to its essential role in mediating virus entry into the host cell. We here report the identification of a class of N-benzyl-4,4,-disubstituted piperidines as influenza A virus fusion inhibitors with specific activity against the H1N1 subtype. Using the highly efficient one-step Ugi four-component reaction, diverse library of piperidine-based analogues was synthesized and evaluated to explore the structure-activity relationships (SAR). Mechanistic studies, including resistance selection with the most active compound (2) demonstrated that it acts as an inhibitor of the low pH-induced HA-mediated membrane fusion process. Computational studies identified an as yet unrecognized fusion inhibitor binding site, which is located at the bottom of the HA2 stem in close proximity to the fusion peptide. A direct π-stacking interaction between the N-benzylpiperidine moiety of 2 and F9HA2 of the fusion peptide, reinforced with an additional π-stacking interaction with Y119HA2, and a salt bridge of the protonated piperidine nitrogen with E120HA2, were identified as important interactions to mediate ligand binding. This site rationalized the observed SAR and provided a structural explanation for the H1N1-specific activity of our inhibitors. IACS-13909 manufacturer Furthermore, the HA1-S326V mutation resulting in resistance to 2 is close to the proposed new binding pocket. Our findings point to the N-benzyl-4,4,-disubstituted piperidines as an interesting class of influenza virus inhibitors, representing the first example of fusion peptide binders with great potential for anti-influenza drug development. Air quality models have been used in health studies to provide spatial and temporal information of various air pollutants. Model resolution is an important factor affecting the accuracy of exposure assessment using model predictions. In this study, the WRF/CMAQ model system was applied to quantitatively estimate the impacts of the model resolution on the predictions of air quality and associated health exposure in Nanjing, China in 2016. Air quality was simulated with a grid resolution of 1, 4, 12, and 36 km respectively. Predictions with 1 or 4 km resolution are slightly better for particulate matter with an aerodynamic diameter ≤2.5 μm (PM2.5) and its compositions and predictions with 12 km are slightly better for daily 8-h maximum ozone (O3-8 h). Model resolution does not significantly improve predictions for PM2.5 and O3-8 h in Nanjing, however, the spatial distributions of PM2.5 and O3-8 h are better captured with finer resolutions. Population weighted concentrations (PWCs) of PM2.5 with different model resolutions are similar to the average of observations, but PWCs of O3-8 h with all resolutions are obviously larger than the observations, indicating that the current sites may well represent the population exposure to PM2.5, but under-estimate the exposure to O3. Model resolution results in about 6% in the estimated premature mortality due to exposure to PM2.5 but more than 20% difference in premature mortality due to exposure to O3. Future studies are needed to evaluate the impacts of the resolution on the exposure of PM2.5 compositions in the city scale when PM2.5 composition measurements available at multiple sites. Anodic oxidation process is considered as an effective solution for the treatment of refractory effluents. Its performance is strongly depending on the stability of the anodes used during the process. For this reason, we aim to enhance the stability of the SS/PbO2 anodes electrodeposited by pulsed current while studying their performance for the anodic oxidation of methylene blue and industrial textile wastewater. The basic idea deals with the possibility to replace the expensive alternatives used for reinforcing the steadiness of the anodes during the anodic oxidation by a simple method based on coupling electrochemical oxidation with biosorption by vegetable material (Luffa cylindrica). The performance of the coupling process was optimized based on its performance in colored and industrial wastewater depollution. Results confirmed the efficiency of the coupling process where 98.7 and 80.02% of methylene blue were removed, respectively, after 60 and 120 min for alternating and direct current. Otherwise, 62.84 and 46.87% of methylene blue were removed by anodic oxidation, respectively, after 120 and 180 min for alternating and direct current. The % COD obtained for the anodic oxidation and the coupling process reached 57.45, 33.61, 91.32 and 75.48% respectively for alternating and direct current. The use of alternating current for both processes has enhanced the speed and the efficiency. Atomic absorption analysis has confirmed that the rates obtained of Pb2+ complied with those allowed by the Standards. LC/MS analysis allowed the identification of by-products generated and the germination tests proved the reuse of the treated water. In this study, we investigated the accumulation and transport patterns of six phthalic acid esters (PAEs) in two leafy vegetables under hydroponic conditions. The tested PAEs included dibutyl phthalate (DBP), diethyl phthalate (DEP), diallyl phthalate (DAP), diisobutyl phthalate (DIBP), dimethyl phthalate (DMP) and benzyl butyl phthalate (BBP), and the tested vegetables included Gaogengbai and Ziyoucai. The results revealed that the six PAEs were taken up by vegetables from the solution, although their accumulation and distribution varied among PAEs. The ability of concentrating PAEs into the roots followed the order of BBP > DBP > DIBP > DAP > DEP > DMP, whereas the ability of concentrating PAEs in plant shoots had the opposite order. By analysing the fractionation of the six PAEs in vegetable roots, DMP had the largest proportion in terms of apoplastic movement, while BBP had the largest proportion in terms of symplastic movement. Correlation analyses revealed that the differences among the accumulation and distribution behaviours of the six PAEs in plant tissues were not only related to their physicochemical parameters, such as alkyl chain length and the octanol/water partition coefficient (logKow), but also related to the proportion of apoplastic and symplastic movement in the plant roots. In addition, PAEs were more readily accumulated in the Gaogengbai roots than in the Ziyoucai roots; however, the opposite trend was observed for the shoots.