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With specific and inherent mRNA cleaving activity, small interfering RNA (siRNA) has been deemed promising therapeutics to reduce the exacerbation rate of asthma by inhibiting the expression and release of proinflammatory cytokines from airway epithelial cells (AECs). To exert the therapeutic effects of siRNA drugs, nano-formulations with high efficiency and safety are required to deliver these nucleic acids to the target cells. Herein, we exploited novel inhaled lipid nanoparticles (LNPs) targeting intercellular adhesion molecule-1 (ICAM-1) receptors on the apical side of AECs. This delivery system is meant to enhance the specific delivery efficiency of siRNA in AECs to prevent the expression of proinflammatory cytokines in AECs and the concomitant symptoms in parallel. A cyclic peptide that resembles part of the capsid protein of rhinovirus and binds to ICAM-1 receptors was initially conjugated with cholesterol and subsequently assembled with ionizable cationic lipids to form the LNPs (Pep-LNPs) loaded with siRNA against thymic stromal lymphopoietin (TSLP siRNA). The obtained Pep-LNPs were subjected to thorough characterization and evaluations in vitro and in vivo. Pep-LNPs significantly enhanced cellular uptake and gene silencing efficiency in human epithelial cells expressing ICAM-1 in vitro, exhibited AEC-specific delivery and improved the gene silencing effect in ovalbumin-challenged asthmatic mice after pulmonary administration. More importantly, Pep-LNPs remarkably downregulated the expression of TSLP in AECs, effectively alleviated inflammatory cell infiltration, and reduced the secretion of other proinflammatory cytokines, including IL-4 and IL-13, as well as mucus production in asthmatic mice. This study demonstrates that Pep-LNPs are safe and efficient to deliver siRNA drugs to asthmatic AECs and could potentially alleviate allergic asthma by inhibiting the overexpression of proinflammatory cytokines in the airway.

Summary Missense mutations may affect proteostasis by destabilizing or over-stabilizing protein complexes and changing the pathway flux. Predicting the effects of stabilizing mutations on protein-protein interactions is notoriously difficult because existing experimental sets are skewed toward mutations reducing protein-protein binding affinity and many computational methods fail to correctly evaluate their effects. To address this issue, we developed a method MutaBind2, which estimates the impacts of single as well as multiple mutations on protein-protein interactions. MutaBind2 employs only seven features, and the most important of them describe interactions of proteins with the solvent, evolutionary conservation of the site, and thermodynamic stability of the complex and each monomer. This approach shows a distinct improvement especially in evaluating the effects of mutations increasing binding affinity. MutaBind2 can be used for finding disease driver mutations, designing stable protein complexes, and discovering new protein-protein interaction inhibitors., Graphical Abstract, Highlights • A new method to predict binding affinity changes upon single and multiple mutations • Improved performance in evaluating the effects of mutations increasing binding affinity • Generation of the structural model of a mutant complex, Protein Folding; Bioinformatics; 3D Reconstruction of Protein

In this research effort, numerical simulation of two-dimensional magnetohydrodynamic (MHD) channel is performed and Hall effect is studied. The computational model consists of the Navier-Stokes (N-S) equations coupled with electrical-magnetic source terms, Maxwell equations and the generalized Ohm's law. Boundary conditions for the electrical potential equation considering Hall effect are derived. To start with, the MHD channel with single-pair electrodes is studied and flow of the electric current is in accordance with physical principle. Then the MHD channel with five-pair electrodes is numerically simulated. The results show that the electrical current concentrates on the downstream of the anode and the upstream of the cathode due to Hall effect, and the flow field becomes asymmetrical. At the current value of the magnetic interaction parameter, the electrical-magnetic force affects the flow remarkably, decreasing the outlet Mach number and increasing the outlet pressure; what's more, the flow structure in the channel becomes extremely complex. Performances of MHD channels with continual electrodes and segmented electrodes are compared. The results show that performance of the MHD channel with segmented electrodes is better than that with continual electrodes with the increase of Hall parameter.