Entry inhibitors as arenavirus antivirals.

Arenaviruses belonging to the Arenaviridae family, genus mammarenavirus, are enveloped, single-stranded RNA viruses primarily found in rodent species, that cause severe hemorrhagic fever in humans. With high mortality rates and limited treatment options, the search for effective antivirals is imperative. Current treatments, notably ribavirin and other nucleoside inhibitors, are only partially effective and have significant side effects. The high lethality and lack of treatment, coupled with the absence of vaccines for all but Junín virus, has led to the classification of these viruses as Category A pathogens by the Centers for Disease Control (CDC). This review focuses on entry inhibitors as potential therapeutics against mammarenaviruses, which include both New World and Old World arenaviruses. Various entry inhibition strategies, including small molecule inhibitors and neutralizing antibodies, have been explored through high throughput screening, genome-wide studies, and drug repurposing. Notable progress has been made in identifying molecules that target receptor binding, internalization, or fusion steps. Despite promising preclinical results, the translation of entry inhibitors to approved human therapeutics has faced challenges. Many have only been tested in in vitro or animal models, and a number of candidates showed efficacy only against specific arenaviruses, limiting their broader applicability. The widespread existence of arenaviruses in various rodent species and their potential for their zoonotic transmission also underscores the need for rapid development and deployment of successful pan-arenavirus therapeutics. The diverse pool of candidate molecules in the pipeline provides hope for the eventual discovery of a broadly effective arenavirus antiviral.

Optimization of Injection Source Settings for SNCR Numerical Simulation of Low-Water Content Biomass Boilers with Blending.

In order to control NOx emissions and meet China's ultralow emission standards, a numerical simulation based on the computational fluid dynamics (CFD) approach is performed for the optimization of the reductant injection volume, number of injection sources, distribution, and injection direction for the flue gas denitrification process of a circulating fluidized bed boiler (CFB) blended with low-water content biomass in a 168 MW unit of a thermal power plant. Using the target power plant boiler entity as a template, a simplified geometric model is established, 1:1, and the mass fractions of each flue gas component set by the inlet boundary conditions are O22, H2O11.6, CO216.2%, and NO0.05%(about 134 ppm), and the reduction reactions under different optimized conditions are numerically simulated using the SNCR model in ANSYS Fluent 2021 R1. The simulation results under each condition were analyzed. The results show that the optimal ammonia-to-nitrogen ratio should be taken as NSR = 1.25, the denitrification efficiencies of 81.00, 81.63, and 82.74% at the three outlets are high, and the ammonia escapes of 1.76, 2.08, and 9.42 mg/s are within a reasonable range; increasing the number of injection sources can significantly reduce the disturbance of the flue gas flow field by reductant injection; the direction of injection is parallel to the direction of the flue gas flow, and the line of the injection source is orthogonal to the direction of the flue gas flow, which is conducive to the mixing of the reductant and flue gas; the optimized boiler denitrification efficiency reaches 74.2%, meeting the ultralow emission requirements of nitrogen oxides and ammonia escape.

Study on the emission characteristics of VOCs under the condition of biomass blending combustion.

In order to understand the emission characteristics of volatile organic compounds (VOCs) in the flue gas under the mixed combustion of biomass, the study on the emission characteristics of VOCs in the flue gas was carried out on a 58 MW circulating fluidized bed (CFB) unit. The results show that the co-firing of biomass can significantly reduce the emissions of VOCs and NOx and SO2. Changes in blended fuel particle size and combustion temperature reduce VOCs emissions. The most obvious change in the emission reduction of VOCs is reflected in the increase of the biomass mixing ratio from 20 % to 30 %. Biomass contains less S and N elements is the reason for the reduction of NOx and SO2 emissions. The emission of pollutants such as VOCs was the lowest when the biomass blending ratio was 40 %. Based on the actual operation of the power plant, 30 % is the optimal mixing ratio. The analysis showed that the amount of VOCs components had a strong positive correlation with the proportion of biomass in the fuel. The emission of VOCs under the condition of biomass blending has different characteristics from coal-fired boilers and biomass boilers. Under the two different mixing ratios, benzene series accounted for the largest proportion of VOCs emissions, reaching 44.38 % (20 %) and 33.75 % (40 %), respectively. The emission of benzene series is dominated by benzene and toluene, the emission of alkanes is dominated by n-hexane, and the emission of esters is dominated by ethyl acetate. The ozone formation potential (OFP) was analyzed by the maximum incremental reactivity method. The contribution of ozone generation potential at 20 % and 40 % mixing ratios was mainly from benzene series, which contributed 69.88 % and 70.24 %, respectively, and alkanes. contribution can also account for 25.76 % and 17.75 %.

Signal-regulatory protein alpha is an anti-viral entry factor targeting viruses using endocytic pathways.

Signal-regulatory protein alpha (SIRPA) is a well-known inhibitor of phagocytosis when it complexes with CD47 expressed on target cells. Here we show that SIRPA decreased in vitro infection by a number of pathogenic viruses, including New World and Old World arenaviruses, Zika virus, vesicular stomatitis virus and pseudoviruses bearing the Machupo virus, Ebola virus and SARS-CoV-2 glycoproteins, but not HSV-1, MLV or mNoV. Moreover, mice with targeted mutation of the Sirpa gene that renders it non-functional were more susceptible to infection with the New World arenaviruses Junín virus vaccine strain Candid 1 and Tacaribe virus, but not MLV or mNoV. All SIRPA-inhibited viruses have in common the requirement for trafficking to a low pH endosomal compartment. This was clearly demonstrated with SARS-CoV-2 pseudovirus, which was only inhibited by SIRPA in cells in which it required trafficking to the endosome. Similar to its role in phagocytosis inhibition, SIRPA decreased virus internalization but not binding to cell surface receptors. We also found that increasing SIRPA levels via treatment with IL-4 led to even greater anti-viral activity. These data suggest that enhancing SIRPA's activity could be a target for anti-viral therapies.

The Renin-Angiotensin-Aldosterone System (RAAS) Is One of the Effectors by Which Vascular Endothelial Growth Factor (VEGF)/Anti-VEGF Controls the Endothelial Cell Barrier.

Leakage of retinal blood vessels, which is an essential element of diabetic retinopathy, is driven by chronic elevation of vascular endothelial growth factor (VEGF). VEGF quickly relaxes the endothelial cell barrier by triggering signaling events that post-translationally modify pre-existing components of intercellular junctions. VEGF also changes expression of genes that are known to regulate barrier function. Our goal was to identify effectors by which VEGF and anti-VEGF control the endothelial cell barrier in cells that were chronically exposed to VEGF (hours instead of minutes). The duration of VEGF exposure influenced both barrier relaxation and anti-VEGF-mediated closure. Most VEGF-induced changes in gene expression were not reversed by anti-VEGF. Those that were constitute VEGF effectors that are targets of anti-VEGF. Pursuit of such candidates revealed that VEGF used multiple, nonredundant effectors to relax the barrier in cells that were chronically exposed to VEGF. One such effector was angiotensin-converting enzyme, which is a member of the renin-angiotensin-aldosterone system (RAAS). Pharmacologically antagonizing either the angiotensin-converting enzyme or the receptor for angiotensin II attenuated VEGF-mediated relaxation of the barrier. Finally, activating the RAAS reduced the efficacy of anti-VEGF. These discoveries provide a plausible mechanistic explanation for the long-standing appreciation that RAAS inhibitors are beneficial for patients with diabetic retinopathy and suggest that antagonizing the RAAS improves patients' responsiveness to anti-VEGF.