Cheminformatics in MS-based environmental exposomics: Current achievements and future directions

Compound annotation using MS/MS data is the major bottleneck in interpretation of mass spectrometry data during non-targeted screening and suspect screening exposomics studies. Apart from compound identification using available databases or mass spectral libraries, the true challenge comes when completely new compounds have to be identified. Along with recent advances in MS instrumentation that set grounds to a new revolutionary age in environmental exposomics, a multitude of cheminformatics annotation approaches has been developed. Herein, we review the basic principles of the cutting-edge cheminformatics MS-based approaches employed in eco-exposome annotation.We give a solid background discussing the eco-exposome concept in relation to the advances in MS instrumentation, and define the three crucial cheminformatics tasks used in the eco-exposome annotation: molecular formula assignment, compound prioritization and compound annotation. The basic principles of compound annotation are discussed, which are based on three approaches of utilizing structural information inherent to MS data. These involve direct, indirect and joint annotation approaches. We assess their performance through the ability to annotate eco-exposome constituents. We discuss future perspectives and give directions to new annotation strategies and performance evaluation protocols aiming to solve current issues hampering the incorporation of cheminformatics annotation approaches in regular eco-exposome annotation workflows.     

Fabrication of high performance Matrimid/polysulfone dual-layer hollow fiber membranes for O2/N2 separation

Matrimid/polysulfone (PSf) dual-layer hollow fiber membranes were fabricated by using co-extrusion and dry-jet wet-spinning phase-inversion techniques. The effects of the spinning dope composition, spinneret dimension, spinneret temperature and the air gap distance on the hollow fiber membranes separation performance were studied. Aging phenomenon was also studied. After coated by 3 wt% silicon solution, the hollow fiber membranes have an O₂/N₂ selectivity of 7.55 at 25 °C, 506.625 kPa which exceeds the intrinsic value of Matrimid. The membranes have an O₂ permeance of 9.36 GPU with an apparent dense-layer thickness of 1421 Å calculated from the O₂ permeability. SEM images show the high porosity underneath the dense skin. It indicates that non-solvent addition is not necessary in the inner spinning dope to induce the macroviod formation. The binodals of the Matrimid/solvent/H₂O and PSf/solvent/H₂O indicate that the composition of the spinning dope plays an important role in the structure and the gas separation performance of the dual-layer hollow fiber membranes. The delayed demixing of the inner spinning dope may fabricate low resistance support layers in the dual-layer hollow fiber membranes.     

Acoustic attenuation analysis of network systems by using impedance matrix method

An impedance matrix method is proposed to predict the acoustic attenuation characteristics of network systems. The system may contain several silencer modules and each module may be composed of complex components such as multiply connected tubes, portions with any-shaped cross-section and dissipative parts. The technique of substructuring is adopted and the system is divided into several substructure modules. Three strategies: boundary element method (BEM), numerical point collocation approach and numerical mode matching technique are introduced and the impedance matrix of each module may be computed by a certain appropriate methodology according to the dimensions and geometry of the substructure. Impedance matrix synthesis is employed to obtain the resultant impedance matrix and then transmission loss may be calculated. All the calculation results are verified by experimental measurements and 3-D BEM predictions.     

Identification of potential Tpx inhibitors against pathogen-host interactions

Yersinia organisms cause many infectious diseases by invading human cells and delivering their virulence factors via the type three secretion system (T3SS). One alternative strategy in the fight against these pathogenic organisms is to interfere with their T3SS. Previous studies demonstrated that thiol peroxidase, Tpx is functional in the assembly of T3SS and its inhibition by salicylidene acylhydrazides prevents the secretion of pathogenic effectors. In this study, the aim was to identify potential inhibitors of Tpx using an integrated approach starting with high throughput virtual screening and ending with molecular dynamics simulations of selected ligands. Virtual screening of ZINC database of 500,000 compounds via ligand-based and structure-based pharmacophore models retrieved 10,000 hits. The structure-based pharmacophore model was validated using high-throughput virtual screening (HTVS). After multistep docking (SP and XP), common scaffolds were used to find common substructures and the ligand binding poses were optimized using induced fit docking. The stability of the protein–ligand complex was examined with molecular dynamics simulations and the binding free energy of the complex was calculated. As a final outcome eight compounds with different chemotypes were proposed as potential inhibitors for Tpx. The eight ligands identified by a detailed virtual screening protocol can serve as leads in future drug design efforts against the destructive actions of pathogenic bacteria.     

On the rhodanines and their presence in biologically active ligands

An innovative use of cluster analysis is presented to compare the output from different levels of theory. A dendrogram shows the relative energies of the tautomers of methylidene rhodanine (5-methylene-2-thioxo-thiazolidin-4-one), computed by the semiempirical molecular orbital method AM1, are remarkably similar to the ab initio values from the LANL2DZ++(d,p) basis set, which involves effective core potentials augmented by polarization and diffuse functions. However, the optimized bond lengths and bond angles at the AM1 and AM1/SM1 levels do not agree well with those obtained at the 6–31G^* and LANL2DZ++(d,p) levels of theory or with experiment. Database searching is used to obtain an indication of how common the rhodanine ring is. The prevalence of rhodanine-containing compounds of pharmaceutical interest is very small despite the fact that the compounds exhibit a wide variety of bioactivity.     

Complex dynamics of multicomponent biological coacervates

Phase transitions and coacervates play key roles in natural and synthetic soft matter. In particular, the past few years have seen a rapid expansion in studies of these phenomena in the context of dynamic cellular compartmentalization. In this brief review, we mainly focus on a few concepts and selected in vitro and cellular examples of recent developments in the areas of dynamics and multicomponent systems. Topics covered include the flexibility and conformational dynamics of polymeric species involved in phase separation, valence and non-monotonic effects, noise modulation and feedback loops, and multicomponent systems and substructure. The fundamental concepts discussed in this review are widely applicable, including in the context of cellular function and the development of materials with novel properties.     

Nonlinear normal modes in multi-mode models of an inertially coupled elastic structure

Nonlinear normal modes for elastic structures have been studied extensively in the literature. Most studies have been limited to small nonlinear motions and to structures with geometric nonlinearities. This work investigates the nonlinear normal modes in elastic structures that contain essential inertial nonlinearities. For such structures, based on the works of Crespo da Silva and Meirovitch, a general methodology is developed for obtaining multi-degree-of-freedom discretized models for structures in planar motion. The motion of each substructure is represented by a finite number of substructure admissible functions in a way that the geometric compatibility conditions are automatically assured. The multi degree-of-freedom reduced-order models capture the essential dynamics of the system and also retain explicit dependence on important physical parameters such that parametric studies can be conducted. The specific structure considered is a 3-beam elastic structure with a tip mass. Internal resonance conditions between different linear modes of the structure are identified. For the case of 1:2 internal resonance between two global modes of the structure, a two-mode nonlinear model is then developed and nonlinear normal modes for the structure are studied by the method of multiple time scales as well as by a numerical shooting technique. Bifurcations in the nonlinear normal modes are shown to arise as a function of the internal mistuning that represents variations in the tip mass in the structure. The results of the two techniques are also compared.