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Killer‐cell immunoglobulin‐like receptor (KIR) interactions with HLA class I have crucial roles in modulating NK cell function in response to viral infections. To explore the correlation between KIR/HLA and susceptibility to SARS‐CoV‐2 infection, we analysed polymorphism of KIR genes, haplotypes, HLA allotypes, and the interplay between KIR and HLA in individuals diagnosed with COVID‐19. Compared to a population control group, we observed a significantly increased frequency of KIR3DL3*00802 in the COVID‐19 group. When encoded by the HLA‐B gene, the frequency of HLA‐Bw4, a ligand for KIR3DL1, was at lower frequency in the COVID‐19 group. Additionally, significantly elevated frequencies of KIR‐Bx3, KIR3DL3*00301, 3DL3*048, and C1+HLA‐C were identified in the COVID‐19 group before multiple test correction, suggesting associations with susceptibility to SARS‐CoV‐2 infection. Our findings indicate that the KIR3DL3*00802 allele may be a high‐risk factor for SARS‐CoV‐2 infection, while Bw4 encoded by HLA‐B gene may confer protective effects against the infection. [ABSTRACT FROM AUTHOR]

Ferroptosis therapy has emerged as a promising strategy for cancer treatment due to its unique cell death mechanism and tumor targeting. However, for colorectal cancer (CRC), the tumor cells exhibit ferroptosis resistance, and the reason remains a debate. To enhance the ferroptosis activity for CRC treatment, herein, we loaded a Co single-atom nanozyme on the Fe-based zeolitic imidazolate framework (ZIF) via atomic layer deposition. The synthesized materials performed better anti-HT29 tumor activity in vitro and in vivo than Fe-based ZIFs and showed excellent biosecurity. Based on bioinformatics analysis, Western blot, and immunohistochemical analyses, it was found that the catalyst not only increased the reactive oxygen species by consuming glutathione via the GPX4 pathway but also downregulated the JAK1-STAT3 signal pathway, which benefited to reduce the ferroptosis resistance. This work provides an innovative strategy for CRC treatment and highlights the function of single-atom nanozymes in reducing the ferroptosis resistance. [ABSTRACT FROM AUTHOR]

Epsilon toxin (ETX), a potential agent of biological and toxic warfare, causes the death of many ruminants and threatens human health. It is crucial to understand the toxic mechanism of such a highly lethal and rapid course toxin. In this study, we detected the effects of ETX on the proteome and phosphoproteome of MDCK cells after 10 min and 30 min. A total of 44 differentially expressed proteins (DEPs) and 588 differentially phosphorylated proteins (DPPs) were screened in the 10 min group, while 73 DEPs and 489 DPPs were screened in the 30 min group. ETX-induced proteins and phosphorylated proteins were mainly located in the nucleus, cytoplasm, and mitochondria, and their enrichment pathways were related to transcription and translation, virus infection, and intercellular junction. Meanwhile, the protein–protein interaction network screened out several hub proteins, including SRSF1/2/6/7/11, SF3B1/2, NOP14/56, ANLN, GTPBP4, THOC2, and RRP1B. Almost all of these proteins were present in the spliceosome pathway, indicating that the spliceosome pathway is involved in ETX-induced cell death. Next, we used RNAi lentiviruses and inhibitors of several key proteins to verify whether these proteins play a critical role. The results confirmed that SRSF1, SF3B2, and THOC2 were the key proteins involved in the cytotoxic effect of ETX. In addition, we found that the common upstream kinase of these key proteins was SRPK1, and a reduction in the level of SRPK1 could also reduce ETX-induced cell death. This result was consistent with the phosphorylated proteomics analysis. In summary, our study demonstrated that ETX induces phosphorylation of SRSF1, SF3B2, THOC2, and SRPK1 proteins on the spliceosome pathway, which inhibits normal splicing of mRNA and leads to cell death. [ABSTRACT FROM AUTHOR]

Food poisoning caused by Staphylococcal enterotoxins (SEs) is prevalent globally, making efficient detection of these toxins very important. Traditionally, liquid chromatography–mass spectrometry required immunosorbent enrichment by magnetic bead-coupled antibodies obtained by animal-specific immunization. However, this method is time-consuming and costly. In this study, two recombinant protein capture molecules were designed based on the principle of toxins binding to Major Histocompatibility Complex (MHCII) and T cell receptor (TCR) molecules. The two capture molecules are called MHCII and MHCII-D10. The design of the MHCII and TCR-D10 was achieved through searching for the binding site protein sequence of Staphylococcal enterotoxins in the relevant literature, and MHCII-D10 was to link MHCII sequence with TCR-D10 sequence using linker (G4S)3 linking peptide. These capture molecules were shown to effectively bind to seven types of toxins and to capture SEs in various matrices. The digestion time, ratio, and temperature were further optimized, reducing the overall digestion time to just 2 h. The specificity, linearity, sensitivity, precision (RSD%), and recovery of the two methods were verified by liquid chromatography–mass spectrometry. When the MHCII and MHCII-D10 captured the toxins, the limit of quantification (LOD) in the 1 × PBS, plasma, and milk matrices ranged from 1.5625 to 100 fmol/µL, with the recovery rate ranging from 18.4% to 96%. The design of these capture molecules eliminates the need for animal-specific immunization, simplifying the pre-detection process and avoiding ethical concerns. This development holds significant promise for clinical diagnosis and reference. [ABSTRACT FROM AUTHOR]