Humans as models of human disease: Mice are a convenient model for exploring the functions of cellular signaling pathways. Occasionally, however, an “experiment of nature” highlights the perils of overreliance on mice. RIPK1 is a well studied protein kinase that regulates cell death. Mice deficient in RIPK1 die soon after birth because of the protein's widespread role in multiple tissues and organs. Cuchet-Lourenço et al. studied patients with inherited immunodeficiency of unknown cause (see the Perspective by Pasparakis and Kelliher). They identified inactivating mutations in the RIPK1 gene in four individuals. Unlike what has been seen in mice, the deleterious effects of RIPK1 loss in humans were confined to the immune system, a finding with potential therapeutic implications. Science , this issue p. 810 ; see also p. 756

Quorum sensing (QS) regulates bacterial functions like virulence and biofilm formation, mediated by proteins such as LasI and QscR in Pseudomonas aeruginosa. This study investigates the structural dynamics of LasI and QscR proteins in complex with Sulfamerazine and Sulfaperin, using AiiA lactonase as a negative control, through molecular dynamics (MD) simulations to identify potential QS modulators. Molecular docking and MD simulations assessed binding affinity and structural dynamics, analyzing parameters like docking scores, root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), solvent-accessible surface area (SASA), radius of gyration (Rg), principal component analysis (PCA), and covariance analysis. Sulfamerazine exhibited the highest binding affinity for LasI based on docking scores, indicating strong ligand-protein interactions. MD simulations revealed stability in the LasI-Sulfamerazine complex, with lower RMSD compared to LasI-Sulfaperin and QscR complexes. RMSF analysis indicated greater flexibility in ligand-binding regions of LasI-Sulfaperin and QscR complexes, suggesting weaker binding. SASA showed a decrease in solvent-accessible surface area for the LasI-Sulfamerazine complex, supporting a compact structure. Rg values confirmed this, with the LasI-Sulfamerazine complex being more compact (~2.00 nm) than QscR-ligand complexes (2.10–2.30 nm). PCA revealed significant conformational changes in the LasI-Sulfamerazine complex, with PC1 explaining 57.26% variance. Covariance analysis indicated stronger residue coupling in the LasI-Sulfamerazine complex, suggesting higher rigidity, while LasI-Sulfaperin and QscR complexes exhibited flexible dynamics. AiiA lactonase was used as a negative control due to its established quorum quenching activity, which hydrolyzes AHL molecules and disrupts QS signaling. Unlike LasI and QscR, AiiA does not rely on small molecule binding for activation. However, a known LasI or QscR inhibitor would have served as a more appropriate positive control, which will be considered in future studies. These findings suggest the LasI-Sulfamerazine complex’s stability and rigidity make Sulfamerazine a promising QS modulator. Computational analyses highlight its potential to disrupt bacterial communication. Further experimental validation is needed to confirm its therapeutic implications.

Recent outbreaks caused by hMPXV, especially hMPXV lineages/sub-lineages, represent public health threats necessitating stringent prophylactic measures to ameliorate their colossal impact. The current study annotated the EEV form of hMPXV’s target proteins to formulate a reverse vaccinology-dependent hMPXV multiepitope vaccine. Epitope determination, followed by vaccine formulation, was undertaken. The promising formulation was validated for its potential to trigger immune responses immunoinformatically. The MPXV-1-Beta formulation was characterised as a promising candidate based on antigenicity score, physicochemical properties, solubility score, ProSA Z-score, and Ramachandran plot. Docking, normal mode analysis, and molecular dynamic simulation of MPXV-1-Beta with TLRs and MHCs authenticated rigid docking and its efficacy in enhancing immune receptor activation under physiological conditions. MPXV-1-Beta was discerned to trigger a sustained immune response (IR) with a broader average population coverage of 97.526, SD = 12.44. The proposed MPXV-1-Beta candidate showed significant potential. The findings of this study provide a preliminary framework for developing an efficacious hMPXV vaccine; however, extensive in vitro, in vivo, and clinical evaluations are required to substantiate the computational insights.