Highlights d 54 antibodies have neutralizing IC 50 values in the range of 3.3-81 ng/mL d Neutralization by 47D1 is achieved without direct blocking of RBD-ACE2 binding d 47D1 binds only to one side of the receptor binding surface on the RBD d Convergent epitope targeting in neutralizing antibody responses to SARS-CoV-2
In recent times, co-delivery of therapeutics has emerged as a promising strategy for treating dreadful diseases such as cancer.Materials and methodsIn this study, we developed a novel nanocarrier based on bacterial magnetosomes (BMs) that co-loaded with siRNA and doxorubicin (DOX) using polyethyleneimine (PEI) as a cross-linker (BMs/DP/siRNA). The delivery efficiency of siRNA as well as the pH-responsive release of DOX, and synergistic efficacy of these therapeutics in vitro were systematically investigated.ResultsThe structure of DOX–PEI (DP) conjugates that synthesized via hydrazone bond formation was confirmed by 1H nuclear magnetic resonance (NMR). The in vitro release experiments showed that the DP conjugate (DOX-loading efficiency – 5.77%±0.08%) exhibited the long-term release behavior. Furthermore, the optimal BMs/DP/siRNA particle size of 107.2 nm and the zeta potential value of 31.1±1.0 mV facilitated enhanced cellular internalization efficiency. Moreover, the agarose gel electrophoresis showed that the co-delivery system could protect siRNA from degradation in serum and RNase A. In addition, the cytotoxicity assay showed that BMs/DP/siRNA could achieve an excellent synergistic effect compared to that of siRNA delivery alone. The acridine orange (AO)/ethidium bromide (EB) double staining assay also showed that BMs/DP/siRNA complex could induce cells in a stage of late apoptosis and nanocomplex located in the proximity of the nucleus.ConclusionThe combination of gene and chemotherapeutic drug using BMs is highly efficient, and the BMs/DP/siRNA would be a promising therapeutic strategy for the future therapeutics.
The equivocality of dose-response relationships has, in practice, hampered the application of biomarkers as a means to evaluate environmental risk, yet this important issue has not yet been fully recognized or explored. This paper evaluates the potential of antioxidant enzymes in the ciliated protozoan Euplotes vannus for use as biomarkers. Dose-response dynamics, together with both the enzyme activity and the gene expression of the antioxidant enzymes, superoxide dismutase, and glutathione peroxidase, were investigated when E. vannus were exposed to graded doses of nitrofurazone for several discrete durations. Mathematical models were explored to characterize the dose-response profiles and, specifically, to identify any equivocality in terms of endpoint. Significant differences were found in both enzyme activity and messenger RNA (mRNA) expression in the E. vannus treated with nitrofurazone, and the interactions between exposure dosage and duration were significant. Correlations between enzyme activity, mRNA expression, and nitrofurazone dose varied with exposure duration. Particularly, the dose-responses showed different dynamics depending on either endpoint or exposure duration. Our findings suggest that both the enzyme activity and the gene expression of the tested antioxidant enzymes can be used as biomarkers for ecotoxicological assessment on the premise of ascertaining appropriate dosage scope, exposure duration, endpoint, etc., which can be achieved by using dose-response dynamics.
Early-activated CD8 + T cells increase both aerobic glycolysis and mitochondrial oxidative phosphorylation (OXPHOS). However, whether and how the augmentation of OXPHOS regulates differentiation of effector CD8 + T cell remains unclear. Here, we found that C1qbp was intrinsically required for such differentiation in antiviral and antitumor immune responses. Activated C1qbp-deficient CD8 + T cells failed to increase mitochondrial respiratory capacities, resulting in diminished acetyl-coenzyme A as well as elevated fumarate and 2-hydroxyglutarate. Consequently, hypoacetylation of H3K27 and hypermethylation of H3K27 and CpG sites were associated with transcriptional down-regulation of effector signature genes. The effector differentiation of C1qbp-sufficient or C1qbp-deficient CD8 + T cells was reversed by fumarate or a combination of histone deacetylase inhibitor and acetate. Therefore, these findings identify C1qbp as a pivotal positive regulator in the differentiation of effector CD8 + T cells and highlight a metabolic-epigenetic axis in this process.
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