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Abstract Checkpoint kinase 1 (CHK1) is critical for cell survival under replication stress (RS). CHK1 inhibitors (CHK1i’s) in combination with chemotherapy have shown promising results in preclinical studies but have displayed minimal efficacy with substantial toxicity in clinical trials. To explore combinatorial strategies that can overcome these limitations, we perform an unbiased high-throughput screen in a non-small cell lung cancer (NSCLC) cell line and identify thioredoxin1 (Trx1), a major component of the mammalian antioxidant-system, as a determinant of CHK1i sensitivity. We establish a role for redox recycling of RRM1, the larger subunit of ribonucleotide reductase (RNR), and a depletion of the deoxynucleotide pool in this Trx1-mediated CHK1i sensitivity. Further, the TrxR inhibitor auranofin, an approved anti-rheumatoid arthritis drug, shows a synergistic interaction with CHK1i via interruption of the deoxynucleotide pool. Together, we show a pharmacological combination to treat NSCLC that relies on a redox regulatory link between the Trx system and mammalian RNR activity.

ABSTRACT In humans, sterile alpha motif (SAM) domain- and histidine–aspartic acid (HD) domain-containing protein 1 (SAMHD1) is a dNTPase enzyme that prevents HIV-1 infection in non-cycling cells, such as differentiated THP-1 cells and human primary macrophages. Although phosphorylation of threonine 592 (T592) in SAMHD1 is recognized as the primary regulator of the ability to prevent HIV-1 infection, the contributions of SAMHD1 acetylation to this ability remain unknown. Mass spectrometry analysis of SAMHD1 proteins derived from cycling and non-cycling THP-1 cells, primary cycling B cells, and primary macrophages revealed that SAMHD1 is preferentially acetylated at lysine residues 354, 494, and 580 (K354, K494, and K580). In non-cycling cells, SAMHD1 is preferentially acetylated at K580, suggesting that this post-translational modification may contribute to the ability of SAMHD1 to block HIV-1 infection. Consistent with this finding, we found that mutations in K580 disrupted the ability of SAMHD1 to block HIV-1 infection without affecting the ability of SAMHD1 to deplete cellular dNTP levels. Gene editing of SAMHD1 in macrophage-like cells revealed that an intact K580 is required for HIV-1 restriction. This finding suggests that K580 acetylation in SAMHD1 is essential for blocking HIV-1 infection. More importantly, we found that a larger proportion of SAMHD1 featuring K580 acetylation could be detected in human primary macrophages when compared to human primary monocytes. In agreement, we found that SAMHD1 is acetylated during the monocyte-to-macrophage differentiation process. This finding agrees with the idea that the blockade of HIV-1 infection in macrophages requires SAMHD1 acetylation.IMPORTANCEThe natural inhibitor of HIV-1, sterile alpha motif (SAM) domain- and histidine–aspartic acid (HD) domain-containing protein 1 (SAMHD1), plays a pivotal role in preventing HIV-1 infection of macrophages and dendritic cells, which are vital components of the immune system. This study unveils that SAMHD1 undergoes post-translational modifications, specifically acetylation at lysines 354, 494, and 580. Our research underscores the significance of these modifications, demonstrating that acetylation at residue K580 is indispensable for SAMHD1's efficacy in blocking HIV-1 infection. Notably, K580 is found in a critical regulatory domain of SAMHD1, highlighting acetylation as a novel layer of SAMHD1 regulation for HIV-1 restriction in humans. A comprehensive understanding of the regulation mechanisms governing this anti-HIV-1 protein is crucial for leveraging nature's defense mechanisms against HIV-1 and could pave the way for innovative therapeutic strategies.

Background: Disinfection of shared spaces has become essential to minimize the spread of various diseases. An efficient disinfection device that can simultaneously inactivate airborne bacteria and surface-adhered bacteria in an enclosed space is required.Aim: An air-passable plasma filter (APF) was developed and applied to a chamber model to evaluate the efficacy of zone disinfection.Methods: The 60 L chamber consisted of a nebulizer, circulation fans, temperature and humidity monitors, an air-sampling port with a sealed gate, airborne bacteria-trapping media, and a built-in fan for evaluation. After spraying each bacterial strain (Escherichia coli, Staphylococcus epidermidis, and Mycobacterium smegmatis) as a bioaerosol, airborne and surface-attached bacteria were quantified simultaneously to evaluate the zone-disinfection effect of APF.Findings: The operation of APF in the 60 L chamber showed a complete zone-disinfection effect for E. coli (10 min), S. epidermidis (10 min), and M. smegmatis (60 min) present in the air and on the walls at various locations. The time required to completely disinfect each of the airborne bacteria and surface-attached bacteria within the same space was different.Conclusion: APF has the potential to exhibit significant germicidal effects on various micro-organisms and can be an effective alternative for disinfection of enclosed spaces. [ABSTRACT FROM AUTHOR]

IntroductionEvaluating the anticancer property of Padina boergesenii mediated bimetallic nanoparticles.MethodsThe present study focuses on synthesizing Se-ZnO bimetallic nanoparticles from an aqueous algal extract of brown algae Padina boergesenii.Synthesized Se-ZnO NPs were characterized by UV, FTIR, SEM-EDS and HRTEM for confirmation along with the anticancer activity by MTT assay.ResultsThe UV gave an absorbance peak at 342 and 370 nm, and the FTIR showed functional groups involved in synthesizing Se-ZnO NPs. The TEM micrographs indicated the crystalline nature and confirmed the size of the Se-ZnO NPs to be at an average size of 26.14 nm. Anticancer efficacy against the MCF-7 breast and HepG2 (hepatoblastoma) cell lines were also demonstrated, attaining an IC50 value of 67.9 µg and 74.9 µg/ml respectively, which caused 50% cell death.DiscussionThis work aims to highlight an effective method for delivering bioactive compounds extracted from brown algae and emphasize its future therapeutic prospects. The potential of Selenium-Zinc oxide nanoparticles is of great interest due to the biocompatibility and low toxicity aspects of selenium combined with the cost-effectiveness and sustainability of zinc metal. The presence of bioactive compounds contributed to the stability of the nanoparticles and acted as capping properties.