The CAR mRNA-Interaction Surface is a Zipper Extension of the Ribosome A Site

The ribosome CAR interaction surface behaves like an extension of the decoding center A site and has H-bond interactions with the +1 codon that is next in line to enter the A site. Through molecular dynamics simulations, we investigated the codon sequence specificity of this CAR-mRNA interaction and discovered a strong preference for GCN codons, suggesting that there may be a sequence-dependent layer of translational regulation dependent on the CAR interaction surface. Dissection of the CAR-mRNA interaction through nucleotide substitution experiments showed that the first nucleotide of the +1 codon dominates over the second nucleotide position, consistent with an energetically favorable zipper-like activity that emanates from the A site through the CAR-mRNA interface. The +1 codon/CAR interaction is also affected by the identity of nucleotide 3 of +1 GCN codons which influences the stacking of G and C. Clustering analysis suggests that the A site decoding center adopts different neighborhood substates that depend on the identity of the +1 codon.

The High Transmission of SARS-CoV-2 Omicron (B.1.1.529) Variant is Not Only Due to Its hACE2 binding: A Free Energy of Perturbation Study

The mutations in the spike protein of SARS-CoV-2 Omicron variant (B.1.1.529 lineage) gave rise to questions, but the data on the mechanism of action at the molecular level is limited. In this study, we present the Free energy of perturbation (FEP) data about the RBD-hACE2 binding of this new variant.We identified two groups of mutations located close to the most contributing substitutions Q498R and Q493R, which altered significantly the RBD-hACE2 interactions. The Q498R, Y505H and G496S mutations, in addition to N501Y, highly increased the binding to hACE2. They enhanced the binding by 98, 14 and 13 folds, respectively, which transforms the S1-RBD to a picomolar binder. However, in contrast to the case in mice the Q493R/K mutations, in a combination with K417N and T478K, dramatically reduced the S1 RBD binding by over 100 folds. The N440K, G446S and T478K substitutions had lesser contribution. Thus, the total effect of these nine mutations located on the interaction surface of RBD-hACE2 turns out to be similar to that observed in the Alpha variant. In a special circumstances it could be further altered by the E484A and S477N mutations and even lower binding capacity is likely to be detected. Finally, we provide a structural basis of the observed changes in the interactions.These data may explain only partially the observed in South Africa extremely high Omicron spread and is in support to the hypothesis for multiple mechanisms of actions involved in the transmission.Graphical abstract

NLRP3 phosphorylation in its LRR domain critically regulates inflammasome assembly

NLRP3 controls the secretion of inflammatory cytokines IL-1β/18 and pyroptosis by assembling the inflammasome. Upon coordinated priming and activation stimuli, NLRP3 recruits NEK7 within hetero-oligomers that nucleate ASC and caspase-1 filaments, but the apical molecular mechanisms underlying inflammasome assembly remain elusive. Here we show that NEK7 recruitment to NLRP3 is controlled by the phosphorylation status of NLRP3 S803 located within the interaction surface, in which NLRP3 S803 is phosphorylated upon priming and later dephosphorylated upon activation. Phosphomimetic substitutions of S803 abolish NEK7 recruitment and inflammasome activity in macrophages in vitro and in vivo. In addition, NLRP3-NEK7 binding is also essential for NLRP3 deubiquitination by BRCC3 and subsequently inflammasome assembly, with NLRP3 phosphomimetic mutants showing enhanced ubiquitination and degradation than wildtype NLRP3. Finally, we identify CSNK1A1 as the kinase targeting NLRP3 S803. Our findings thus reveal NLRP3 S803 phosphorylation status as a druggable apical molecular mechanism controlling inflammasome assembly.

Practice-Oriented Validation of Embedded Beam Formulations in Geotechnical Engineering

The numerical analysis of many geotechnical problems involves a high number of structural elements, leading to extensive modelling and computational effort. Due to its exceptional ability to circumvent these obstacles, the embedded beam element (EB), though originally intended for the modelling of micropiles, has become increasingly popular in computational geotechnics. Recent research effort has paved the way to the embedded beam element with interaction surface (EB-I), an extension of the EB. The EB-I renders soil–structure interaction along an interaction surface rather than the centreline, making it theoretically applicable to any engineering application where beam-type elements interact with solid elements. At present, in-depth knowledge about relative merits, compared to the EB, is still in demand. Subsequently, numerical analysis are carried out using both embedded beam formulations to model deep foundation elements. The credibility of predicted results is assessed based on a comprehensive comparison with the well-established standard FE approach. In all cases considered, the EB-I proves clearly superior in terms of mesh sensitivity, mobilization of skin-resistance, and predicted soil displacements. Special care must be taken when using embedded beam formulations for the modelling of composite structures.

Analysis of Nanoindentation Test Results of Asphalt Mixture with Different Gradations

Nanoindentation has been applied in the field of asphalt mixtures, but, at the nano-scale, changes in the composition of the mixture and material properties can have a significant impact on the results. Therefore, it is necessary to investigate the feasibility of nanoindentation tests on different types of asphalt mixtures with different gradations and the influence of material properties and test methods on nanoindentation results. In this paper, the nanoindentation test results on three kinds of asphalt mixture (AC-13, SMA-13, and OGFC-13) with different aggregate gradations were investigated. The load-displacement curves and moduli obtained from the nanoindentation tests were analyzed. In addition, nanoindentation tests were carried out before and after polishing with different ratios of filler and asphalt (RFA) (0.8–1.6). On this basis, the morphology of asphalt specimens with different RFAs is observed by scanning electron microscopy (SEM) imaging. The results indicate that using the nanoindentation test to characterize the mechanical behavior of asphalt mixture, the confidence level of the dense-graded mixture is low, and non-dense-graded mixtures are used as much as possible. Moreover, results illustrate that the nanoindentation modulus tends to increase as the RFA increases. and the SEM chart shows that the higher the mineral powder content in the mastic, the more complex the bitumen and mineral powder interaction surface, confirming the influence of mineral powder content on the nanoindentation test results. Furthermore, the effect of polishing is almost insignificant.

Behavior of Sliding Angle as Function of Temperature Difference between Droplet and Superhydrophobic Coating for Aircraft Ice Protection Systems

A hybrid anti-/de-icing system combining a superhydrophobic coating and an electrothermal heater is an area of active research for aircraft icing prevention. The heater increases the temperature of the interaction surface between impinging droplets and an aircraft surface. One scientific question that has not been studied in great detail is whether the temperatures of the droplet and the surface or the temperature difference between the two dominate the anti-/de-icing performance. Herein, this scientific question is experimentally studied based on the mobility of a water droplet over a superhydrophobic coating. The mobility is characterized by the sliding angle between the droplet and the coating surface. It was found that the temperature difference between the droplet and the coating surface has a higher impact on the sliding angle than their individual temperatures.

Efficient Removal of Cd (II) From Aqueous Solution By Chitosan Modified Kiwi Branch Biochar

A novel chitosan-modified kiwi branch biochar (CHKB) was successfully fabricated as cut-price modified biochar to remove Cd (II) from wastewater. Characterization experiments with SEM-EDS, FTIR and XPS suggested that CHKB had more cations and surface functional groups compared with the original kiwi biochar (KB). The adsorption experiment results of Cd (II) on CHKB showed that the adsorption isotherms can be described best by the Langmuir model and that the pseudo-second-order model fits the Cd (II) adsorption kinetics well, indicating that the process was monolayer and controlled by chemisorption. CHKB exhibited the Langmuir maximum adsorption capacity of Cd (II) (126.58 mg g-1), however, that of KB is only 4.26 mg g-1. The adsorption ability of CHKB was improved by the increase of the surface area and abundant surface functional groups (-OH, -NH, C=O and so on). And the cation exchange, electrostatic interaction, surface complexation and precipitation were main mechanisms in the sorption of Cd (II) on CHKB. In addition, CHKB can be regenerated and reused for Cd (II) sorption by the eluent of EDTA-2Na. Excellent adsorption performance, low-cost, and environmental-friendly made CHKB become the fantastic adsorbent to remove Cd (II) in wastewater.

Mapping the interaction surface of scorpion β-toxins with an insect sodium channel

The interaction of insect-selective scorpion depressant β-toxins (LqhIT2 and Lqh-dprIT3 from Leiurus quinquestriatus hebraeus) with the Blattella germanica sodium channel, BgNav1-1a, was investigated using site-directed mutagenesis, electrophysiological analyses, and structural modeling. Focusing on the pharmacologically-defined binding site-4 of scorpion β-toxins at the voltage-sensing domain II (VSD-II), we found that charge neutralization of D802 in VSD-II greatly enhanced the channel sensitivity to Lqh-dprIT3. This was consistent with the high sensitivity of the splice variant BgNav2-1, bearing G802, to Lqh-dprIT3, and low sensitivity of BgNav2-1 mutant, G802D, to the toxin. Further mutational and electrophysiological analyses revealed that the sensitivity of the WT = D802E < D802G < D802A < D802K channel mutants to Lqh-dprIT3 correlated with the depolarizing shifts of activation in toxin-free channels. However, the sensitivity of single mutants involving IIS4 basic residues (K4E = WT << R1E < R2E < R3E) or double mutants (D802K = K4E/D802K = R3E/D802K > R2E/D802K > R1E/D802K > WT) did not correlate with the activation shifts. Using the cryo-EM structure of the Periplaneta americana channel, NavPaS, as template and the crystal structure of LqhIT2, we constructed structural models of LqhIT2 and Lqh-dprIT3-c in complex with BgNav1-1a. These models along with the mutational analysis suggest that depressant toxins approach the salt-bridge between R1 and D802 at VSD-II to form contacts with linkers IIS1-S2, IIS3-S4, IIIP5-P1 and IIIP2-S6. Elimination of this salt-bridge enables deeper penetration of the toxin into a VSD-II gorge to form new contacts with the channel, leading to increased channel sensitivity to Lqh-dprIT3.

Exploring antibody repurposing for COVID-19: beyond presumed roles of therapeutic antibodies

The urgent need for a treatment of COVID-19 has left researchers with limited choice of either developing an effective vaccine or identifying approved/investigational drugs developed for other medical conditions for potential repurposing, thus bypassing long clinical trials. In this work, we compared the sequences of experimentally verified SARS-CoV-2 neutralizing antibodies and sequentially/structurally similar commercialized therapeutic monoclonal antibodies. We have identified three therapeutic antibodies, Tremelimumab, Ipilimumab and Afasevikumab. Interestingly, these antibodies target CTLA4 and IL17A, levels of which have been shown to be elevated during severe SARS-CoV-2 infection. The candidate antibodies were evaluated further for epitope restriction, interaction energy and interaction surface to gauge their repurposability to tackle SARS-CoV-2 infection. Our work provides candidate antibody scaffolds with dual activities of plausible viral neutralization and immunosuppression. Further, these candidate antibodies can also be explored in diagnostic test kits for SARS-CoV-2 infection. We opine that this in silico workflow to screen and analyze antibodies for repurposing would have widespread applications.

Graphene-Based Coronal Hybrids for Enhanced Energy Storage

Functional materials with designer morphologies are anticipated to be the next generation materials for energy storage applications. In this manuscript, we have developed a holistic approach to enhance the surface area and hence the properties of nanostructures by synthesizing coronal nanohybrids of graphene. These nanohybrids provide distinctive advantages in terms of performance and stability over vertically stacked nanocomposites reported in literature. Various double hydroxide materials self-assembled as coronal lamellae on graphene shells have been synthesized and systematically studied. These coronal nanohybrids result in about a threefold increase in energy storage capacity as compared to their traditionally synthesized nanocomposite counterparts. The 3D graphene-based nanofibrils in the synthesized coronal nanohybrids provide mechanical support and connect the nodes of the double hydroxide lattices to inhibit restacking. Complex morphologies such as coronal nanostructures increase the interaction surface of the nanostructure significantly. Such an approach is also expected to bring a paradigm shift in development of functional materials for various applications such as sensors, energy storage, and catalysis.