Numerical Investigation of the Capture of Polydisperse Particles by Charged Droplets

The capture of particles by charged droplets was simulated by considering the electrostatic interactions of droplet-droplet and droplet-particle. The results indicate that the electrostatic repulsion between droplets leads to a dynamic accumulation mode of particles. However, the droplet spacing has an insignificant effect on the capture efficiency when the electrostatic deposition predominates. The increase of droplet charge remarkably improves the capture efficiency, in which the capture of fine particles accounts for the largest proportion. Compared to the droplet charge, the droplet size shows a limited improvement in the capture efficiency. Reducing the droplet velocity prolongs the capture time instead of enhancing the capture capacity per unit time, thereby improving capture efficiency.     

Coupling in situ experiments and modeling – Opportunities for data fusion,machine learning,and discovery of emergent behavior

This paper reviews recent studies, that not only includes both experiments and modeling components, but celebrates a close coupling between these techniques, in order to provide insights into the plasticity and failure of polycrystalline metals. Examples are provided of studies across multiple-scales, including, but not limited to, density functional theory combined with atom probe tomography, molecular dynamics combined with in situ transmission electron miscopy, discrete dislocation dynamics combined with nanopillars experiments, crystal plasticity combined with digital image correlation, and crystal plasticity combined with in situ high energy X-ray diffraction. The close synergy between in situ experiments and modeling provides new opportunities for model calibration, verification, and validation, by providing direct means of comparison, thus removing aspects of epistemic uncertainty in the approach. Further, data fusion between in situ experimental and model-based data, along with data driven approaches, provides a paradigm shift for determining the emergent behavior of deformation and failure, which is the foundation that underpins the mechanical behavior of polycrystalline materials.     

Tetrahydroindoles as Multipurpose Screening Compounds and Novel Sirtuin Inhibitors

Indoles are privileged structures in medicinal and bioorganic chemistry that are particularly well suited to serve as platforms for diversity. Among many other therapeutic areas, the indole scaffold has been used to design aromatic compounds useful to interfere with enzymes engaged in the regulation of substrate acylation status, such as sirtuins. However, the planarity of the indole ring is not necessarily optimal for all target enzymes, especially when functionalization with aromatic side chains is required. Replacement of flat scaffolds by nonplanar molecular cores dominated by sp³ hybridization is a common strategy to avoid the disadvantages associated with poor solubility and high promiscuity, while covering less-well-explored areas of chemical space. Thus, we synthesized fragment-like tetrahydroindoles suitable for fragment-based drug discovery as well as a well-characterized small library intended as multipurpose screening compounds. For proof of principle, these compounds were screened against sirtuins 1–3, enzymes known to be addressable by indoles. We found that 2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamides are potent and selective SIRT2 inhibitors. Compound 16 t displayed an IC₅₀ value of 0.98 μm and could serve as exquisite starting point for hit-to-lead profiling.     

Sofosbuvir Selects for Drug-Resistant Amino Acid Variants in the Zika Virus RNA-Dependent RNA-Polymerase Complex In Vitro

The nucleotide analog sofosbuvir, licensed for the treatment of hepatitis C, recently revealed activity against the Zika virus (ZIKV) in vitro and in animal models. However, the ZIKV genetic barrier to sofosbuvir has not yet been characterized. In this study, in vitro selection experiments were performed in infected human hepatoma cell lines. Increasing drug pressure significantly delayed viral breakthrough (p = 0.029). A double mutant in the NS5 gene (V360L/V607I) emerged in 3 independent experiments at 40–80 µM sofosbuvir resulting in a 3.9 ± 0.9-fold half- maximal inhibitory concentration (IC₅₀) shift with respect to the wild type (WT) virus. A triple mutant (C269Y/V360L/V607I), detected in one experiment at 80 µM, conferred a 6.8-fold IC₅₀ shift with respect to the WT. Molecular dynamics simulations confirmed that the double mutant V360L/V607I impacts the binding mode of sofosbuvir, supporting its role in sofosbuvir resistance. Due to the distance from the catalytic site and to the lack of reliable structural data, the contribution of C269Y was not investigated in silico. By a combination of sequence analysis, phenotypic susceptibility testing, and molecular modeling, we characterized a double ZIKV NS5 mutant with decreased sofosbuvir susceptibility. These data add important information to the profile of sofosbuvir as a possible lead for anti-ZIKV drug development.     

CFD Modeling of Active Volume Creation in a Non‐Newtonian Fluid Agitated by Submerged Recirculating Jets

Computational fluid dynamics (CFD) models were employed to investigate flow conditions inside a model reactor in which yield stress non‐Newtonian liquid is mobilized using submerged recirculating jets. The simulation results agree well with the experimental results of active volume in the reactor obtained using flow visualization by the authors in a previous study. The models developed are capable of predicting a critical jet velocity (v_c) that determines the extent of active volume obtained due to jet mixing. The v_c values are influenced both by the rheological properties of the liquid and the nozzle orientation. The liquid with higher effective viscosity leads to higher v_c for a downward facing injection nozzle. However, an upward facing injection nozzle along with a downward facing suction nozzle generates enhanced complementary flow fields which overcome the rheological constraints of the liquid and lead to lower v_c.     

Genes Identification,Molecular Docking and Dynamics Simulation Analysis of Laccases from Amylostereum areolatum Provides Molecular Basis of Laccase Bound to Lignin

An obligate mutualistic relationship exists between the fungus Amylostereum areolatum and woodwasp Sirex noctilio. The fungus digests lignin in the host pine, providing essential nutrients for the growing woodwasp larvae. However, the functional properties of this symbiosis are poorly described. In this study, we identified, cloned, and characterized 14 laccase genes from A. areolatum. These genes encoded proteins of 508 to 529 amino acids and contained three typical copper-oxidase domains, necessary to confer laccase activity. Besides, we performed molecular docking and dynamics simulation of the laccase proteins in complex with lignin compounds (monomers, dimers, trimers, and tetramers). AaLac2, AaLac3, AaLac6, AaLac8, and AaLac10 were found that had low binding energies with all lignin model compounds tested and three of them could maintain stability when binding to these compounds. Among these complexes, amino acid residues ALA, GLN, LEU, PHE, PRO, and SER were commonly present. Our study reveals the molecular basis of A. areolatum laccases interacting with lignin, which is essential for understanding how the fungus provides nutrients to S. noctilio. These findings might also provide guidance for the control of S. noctilio by informing the design of enzyme mutants that could reduce the efficiency of lignin degradation.     

Sequence-Dependent Nanofiber Structures of Phenylalanine and Isoleucine Tripeptides

The molecular design of short peptides to achieve a tailor-made functional architecture has attracted attention during the past decade but remains challenging as a result of insufficient understanding of the relationship between peptide sequence and assembled supramolecular structures. We report a hybrid-resolution model to computationally explore the sequence–structure relationship of self-assembly for tripeptides containing only phenylalanine and isoleucine. We found that all these tripeptides have a tendency to assemble into nanofibers composed of laterally associated filaments. Molecular arrangements within the assemblies are diverse and vary depending on the sequences. This structural diversity originates from (1) distinct conformations of peptide building blocks that lead to different surface geometries of the filaments and (2) unique sidechain arrangements at the filament interfaces for each sequence. Many conformations are available for tripeptides in solution, but only an extended β-strand and another resembling a right-handed turn are observed in assemblies. It was found that the sequence dependence of these conformations and the packing of resulting filaments are determined by multiple competing noncovalent forces, with hydrophobic interactions involving Phe being particularly important. The sequence pattern for each type of assembly conformation and packing has been identified. These results highlight the importance of the interplay between conformation, molecular packing, and sequences for determining detailed nanostructures of peptides and provide a detailed insight to support a more precise design of peptide-based nanomaterials.     

Grain size dependence of hardness in nanocrystalline silicon carbide

The response of nanocrystalline silicon carbide (nc-SiC) to nanoindentation is investigated using molecular dynamics (MD) simulation. It is found that the hardness of the nc-SiC decreases with decreasing grain size, showing an inverse Hall-Petch relationship. The behavior is primarily attributed to the reduced number of intact covalent bonds with grain refinement. Dislocation nucleation and growth in nc-SiC are strongly suppressed by the grain boundaries (GBs). In addition to the dislocation region in the grains, the indentation-induced amorphization of nanograins proceeds preferentially from the GBs, leading to grain shrinkage until the grains are fully amorphized. The results provide an improved understanding of the mechanical properties in nc-SiC and other nanostructured covalent materials.