Strategies and Approaches for Discovery of Small Molecule Disruptors of Biofilm Physiology

Biofilms, the predominant growth mode of microorganisms, pose a significant risk to human health. The protective biofilm matrix, typically composed of exopolysaccharides, proteins, nucleic acids, and lipids, combined with biofilm-grown bacteria’s heterogenous physiology, leads to enhanced fitness and tolerance to traditional methods for treatment. There is a need to identify biofilm inhibitors using diverse approaches and targeting different stages of biofilm formation. This review discusses discovery strategies that successfully identified a wide range of inhibitors and the processes used to characterize their inhibition mechanism and further improvement. Additionally, we examine the structure–activity relationship (SAR) for some of these inhibitors to optimize inhibitor activity.     

A coupled WC-TL SPH method for simulation of hydroelastic problems

A coupled weakly compressible (WC) and total Lagrangian (TL) smoothed particle hydrodynamics (SPH) method is developed for simulating hydroelastic problems. The fluid phase is simulated using WCSPH method, while the structural dynamics are solved using TLSPH method. Fluid and solid components of the method are validated separately. A sloshing water tank problem is solved to test the WCSPH method while oscillation of a thin plate and large deformation of a cantilever beam are simulated to test the TLSPH method. After validating each component, the coupled WC-TL SPH scheme is used to simulate two benchmark hydroelastic problems. The first test case shows the evolution of water column with an elastic boundary gate, and the second one investigates the breaking water column impact on elastic structures. The agreement between WC-TL SPH results and literature data shows the ability of the proposed method in simulating hydroelastic phenomena.     

The dispersion polymerization of unsaturated monomers initiated by the macromonomeric initiator

The dispersion polymerizations of styrene (St) and methyl methacrylate (MMA) initiated by poly(oxyethylene) macroinimer (PEO-MIM) in ethanol/water were investigated at 50, 60 and 80°C. The polymerisation rate vs. conversion dependence was described by with a maxim at the beginning of polymerisation. Polymerization was faster with MMA than with St. The limiting conversion was inversely proportional to temperature and was much more pronounced with St. The rate of polymerization increased with temperature. The overall initial activation energy increased with conversion and reached value ca. 25 kJ.mol⁻¹ for MMA and 50 kJ.mol⁻¹ for styrene at ca. 60% conversion. The particle size was observed to decrease with increasing the macroinimer concentration. The polymer dispersions were unstable and a large amount of coagulum appeared during the polymerisation especially in the styrene-containing reaction system.     

CP violation in gauge theories and the electric dipole moment of the neutron

A nonvanishing contribution to the neutron electric dipole moment in CP-violating gauge theories of the weak interactions, arising from interaction of the photon with two-quark subsystems of the three-bound-quark neutron system, is calculated. In the Kobayashi-Maskawa model the resulting value of the moment is estimated as O(10^?32) e cm; however, strong interaction corrections (gluonic radiative corrections) give quark moment contributions which may be numerically larger (possibly 10^?30±1 e cm). Either case clearly distinguishes gauge-sector CP violation from Higgs-sector CP violation which typically gives a neutron moment of order 10^?24 e cm.     

Computational Insights on the Hydride and Proton Transfer Mechanisms of D-Arginine Dehydrogenase

D-Arginine dehydrogenase from Pseudomonas aeruginosa (PaDADH) is an amine oxidase which catalyzes the conversion of D-arginine into iminoarginine. It contains a non-covalent FAD cofactor that is involved in the oxidation mechanism. Based on substrate, solvent, and multiple kinetic isotope effects studies, a stepwise hydride transfer mechanism is proposed. It was shown that D-arginine binds to the active site of enzyme as α-amino group protonated, and it is deprotonated before a hydride ion is transferred from its α-C to FAD. Based on a mutagenesis study, it was concluded that a water molecule is the most likely catalytic base responsible from the deprotonation of α-amino group. In this study, we formulated computational models based on ONIOM method to elucidate the oxidation mechanism of D-arginine into iminoarginine using the crystal structure of enzyme complexed with iminoarginine. The calculations showed that Arg222, Arg305, Tyr249, Glu87, His 48, and two active site water molecules play key roles in binding and catalysis. Model systems showed that the deprotonation step occurs prior to hydride transfer step, and active site water molecule(s) may have participated in the deprotonation process.