Difluoromethylornithine (DFMO), an Inhibitor of Polyamine Biosynthesis,and Antioxidant N-Acetylcysteine Potentiate Immune Response in Mice to the Recombinant Hepatitis C Virus NS5B Protein

Hepatitis C virus (HCV) is one of the main triggers of chronic liver disease. Despite tremendous progress in the HCV field, there is still no vaccine against this virus. Potential vaccines can be based on its recombinant proteins. To increase the humoral and, especially, cellular immune response to them, more effective adjuvants are needed. Here, we evaluated a panel of compounds as potential adjuvants using the HCV NS5B protein as an immunogen. These compounds included inhibitors of polyamine biosynthesis and urea cycle, the mTOR pathway, antioxidants, and cellular receptors. A pronounced stimulation of cell proliferation and interferon-γ (IFN-γ) secretion in response to concanavalin A was shown for antioxidant N-acetylcysteine (NAC), polyamine biosynthesis inhibitor 2-difluoromethylornithine (DFMO), and TLR9 agonist CpG ODN 1826 (CpG). Their usage during the immunization of mice with the recombinant NS5B protein significantly increased antibody titers, enhanced lymphocyte proliferation and IFN-γ production. NAC and CpG decreased relative Treg numbers; CpG increased the number of myeloid-derived suppressor cells (MDSCs), whereas neither NAC nor DFMO affected MDSC counts. NAC and DFMO suppressed NO and interleukin 10 (IL-10) production by splenocytes, while DFMO increased the levels of IL-12. This is the first evidence of immunomodulatory activity of NAC and DFMO during prophylactic immunization against infectious diseases.     

Complex Transposon Insertion as a Novel Cause of Pompe Disease

Pompe disease (OMIM#232300) is an autosomal recessive lysosomal storage disorder caused by mutations in the GAA gene. According to public mutation databases, more than 679 pathogenic variants have been described in GAA, none of which are associated with mobile genetic elements. In this article, we report a novel molecular genetic cause of Pompe disease, which could be hardly detected using routine molecular genetic analysis. Whole genome sequencing followed by comprehensive functional analysis allowed us to discover and characterize a complex mobile genetic element insertion deep in the intron 15 of the GAA gene in a patient with infantile onset Pompe disease.     

Complex Formation of Divalent Cations with Carboxylic Acid Resins as a Factor Determining Different Stationary States of Their Swelling

Three samples of carboxylic acid gel-type cross-linked polyelectrolytes were examined by registering the extent and kinetics of their volume change depending on the temperature, concentration, and nature of external electrolyte solutions, as well as the initial state (ionic form, water content) of the bead. It is found that in some systems the swelling of the bead (as a result of lowering the temperature) proceeds much more slowly than the preceding shrinking (as a result of the increase of temperature). Moreover, the initial volume of the bead is not restored, and a new stationary state of swelling is established. By means of optical dilatometry, it is found that in the systems in which the differences in the stationary states of swelling are found, the beads display plasto-elastic properties, whereas in the absence of such differences the beads show elastic properties. It is found that different stationary states of swelling are also established when the beads of copolymer of methacrylic acid cross-linked with divinylbenzene in Na⁺ form in the dry state and in the NaCl solution-swollen state are placed into a solution of a divalent cation salt. The difference in the stationary states of swelling reaches 12% in 4 N NiCl₂ solution. The substantial differences in the swelling behavior and viscoelastic properties of the resins in their Na⁺, Mg²⁺, Ca²⁺, and Ni²⁺ forms are interpreted in terms of formation of different kinds of complexes of functional groups of the polymer with Ca²⁺ and Ni²⁺ ions.     

Interdiffusion between silica thin films and soda-lime glass substrate during annealing at high temperature

We study the diffusive interaction between soda-lime glass substrates and sputtered aluminum-doped silica thin films at 650°C, the temperature of commercial soda-lime glass shaping or tempering. A first rapid migration of alkali ions from substrate to thin film has been described in a companion paper (J Am Ceram Soc. 2018;101:1516). Using the same samples as (J Am Ceram Soc. 2018;101:1516), we focus here on later interactions, when the layer is consumed by the substrate resulting from diffusive interactions. Using Secondary Ion Mass Spectroscopy profilometry, we show that the interdiffusion rate increases with the aluminum doping content of the layer. We show that the alkali uptake of silica layers accelerates diffusive exchanges with the substrate, consistently with a decrease of viscosity of the layer. Diffusion profiles of silicon are well reproduced when solving the diffusion equation for a diffusivity having an exponential dependence with silicon concentration. The diffusivity of aluminum is shown to be 10 times slower than the diffusion of silicon. Specific exchanges of the two network formers with network modifiers are deduced from the composition-space trajectories, providing evidence for multicomponent diffusive couplings between species.     

Influence of the Type and Method of Injection of Oxides Admixtures of Rare Earth Elements on Colour and other Properties of Dental Porcelain

A glassceramic material, which can be used in stomatology for production of dentinal layer of the dental crown multilayer coating, was received. In order to colour the material the admixtures of Tb and Ce compounds were used, as well as composite admixture representing a mixture of Ce, Nd and La oxides. It was demonstrated that the admixture of Tb oxide tones the material only when it is used together with Ce oxide. It was found that the more admixtures of rare earth elements oxides are contained in the sample composition, the higher the colour strength of the sintered material is. The wave length for the test samples is in the range of 600～650 nm, which corresponds to the yellow-orange and orange-red spectral range.     

Monte Carlo Simulation of the Neurofilament Brush

Grand canonical Monte Carlo (MC) simulations are performed to analyse conformations of projection domains in a neurofilament (NF) brush composed of three types of tails (L, M, and H) at different concentrations of added salt. The NF is modelled as a rigid, uniformly charged cylinder (backbone), surrounded by tethered, flexible polyampholytic chains with charge distributions and stoichiometry similar to those in natural NFs. We calculate the equilibrium trajectory for each projection; that is, the average distance of the amino acid residue from the surface of the backbone as a function of its ranking number. These trajectories demonstrate the tendency for projections to fold back and adopt loop-like conformations at moderate solution salinities. We also perform extended analysis of MC data to identify metastable states of the system, and demonstrate representative snapshots of tail conformations in major metastable states.     

Four-Variable Model of an Enzymatic Oscillator Based on Trypsin

This paper describes a four-variable model for an enzymatic oscillator based on trypsin. Variables in this model are concentrations of the essential proteins (trypsin and trypsinogen) and small molecules (masked and active inhibitors of trypsin) within the network. Importantly, to simplify the model, non-essential side reactions are neglected and essential reactions are assumed to follow first or second order kinetics. Numerical solutions of this reduced model semi-quantitatively reproduce experimentally determined periods, amplitudes, and phase shifts of oscillations in the concentrations of several species in the network. Moreover, linear stability analysis shows that oscillations in the trypsin oscillator emerge and disappear through Hopf bifurcation. The model will be helpful in situations where simplicity is necessary such as detailed analysis of dynamics and modeling of reaction-diffusion systems.