Complex Relationships between HIV-1 Integrase and Its Cellular Partners

RNA viruses, in pursuit of genome miniaturization, tend to employ cellular proteins to facilitate their replication. HIV-1, one of the most well-studied retroviruses, is not an exception. There is numerous evidence that the exploitation of cellular machinery relies on nucleic acid-protein and protein-protein interactions. Apart from Vpr, Vif, and Nef proteins that are known to regulate cellular functioning via interaction with cell components, another viral protein, integrase, appears to be crucial for proper virus-cell dialog at different stages of the viral life cycle. The goal of this review is to summarize and systematize existing data on known cellular partners of HIV-1 integrase and their role in the HIV-1 life cycle.     

Cooling-Rate Computer Simulations for the Description of Crystallization of Organic Phase-Change Materials

A molecular-level insight into phase transformations is in great demand for many molecular systems. It can be gained through computer simulations in which cooling is applied to a system at a constant rate. However, the impact of the cooling rate on the crystallization process is largely unknown. To this end, here we performed atomic-scale molecular dynamics simulations of organic phase-change materials (paraffins), in which the cooling rate was varied over four orders of magnitude. Our computational results clearly show that a certain threshold (1.2 × 10¹¹ K/min) in the values of cooling rates exists. When cooling is slower than the threshold, the simulations qualitatively reproduce an experimentally observed abrupt change in the temperature dependence of the density, enthalpy, and thermal conductivity of paraffins upon crystallization. Beyond this threshold, when cooling is too fast, the paraffin’s properties in simulations start to deviate considerably from experimental data: the faster the cooling, the larger part of the system is trapped in the supercooled liquid state. Thus, a proper choice of a cooling rate is of tremendous importance in computer simulations of organic phase-change materials, which are of great promise for use in domestic heat storage devices.     

Nucleoside Analogs and Perylene Derivatives Modulate Phase Separation of SARS-CoV-2 N Protein and Genomic RNA In Vitro

The life cycle of severe acute respiratory syndrome coronavirus 2 includes several steps that are supposedly mediated by liquid–liquid phase separation (LLPS) of the viral nucleocapsid protein (N) and genomic RNA. To facilitate the rational design of LLPS-targeting therapeutics, we modeled N-RNA biomolecular condensates in vitro and analyzed their sensitivity to several small-molecule antivirals. The model condensates were obtained and visualized under physiological conditions using an optimized RNA sequence enriched with N-binding motifs. The antivirals were selected based on their presumed ability to compete with RNA for specific N sites or interfere with non-specific pi–pi/cation–pi interactions. The set of antivirals included fleximers, 5′-norcarbocyclic nucleoside analogs, and perylene-harboring nucleoside analogs as well as non-nucleoside amphiphilic and hydrophobic perylene derivatives. Most of these antivirals enhanced the formation of N-RNA condensates. Hydrophobic perylene derivatives and 5′-norcarbocyclic derivatives caused up to 50-fold and 15-fold enhancement, respectively. Molecular modeling data argue that hydrophobic compounds do not hamper specific N-RNA interactions and may promote non-specific ones. These findings shed light on the determinants of potent small-molecule modulators of viral LLPS.     

Selective Silencing of Disease-Associated B Lymphocytes from Hashimoto’s Thyroiditis Patients by Chimeric Protein Molecules

Hashimoto’s thyroiditis is one of the most common endocrine disorders, affecting up to 20% of the adult population. No treatment or prevention exists except hormonal substitution for hypothyroidism. We hypothesize that it may be possible to selectively suppress anti-thyroglobulin (Tg) IgG antibody-producing B lymphocytes from HT patients by a chimeric protein molecule containing a monoclonal antibody specific for the human inhibitory receptor CR1, coupled to peptide epitopes derived from Tg protein. We expect that this treatment will down-regulate B-cell autoreactivity by delivering a strong inhibitory signal. Three peptides—two epitope-predicted ones derived from Tg and another irrelevant peptide—were synthesized and then coupled with monoclonal anti-human CR1 antibody to construct three chimeric molecules. The binding to CD35 on human B cells and the effects of the chimeric constructs on PBMC and TMC from patients with HT were tested using flow cytometry, ELISpot assay, and immunoenzyme methods. We found that after the chemical conjugation, all chimeras retained their receptor-binding capacity, and the Tg epitopes could be recognized by anti-Tg autoantibodies in the patients’ sera. This treatment downregulated B-cell autoreactivity and cell proliferation, inhibited Tg-specific B-cell differentiation to plasmablasts and promoted apoptosis to the targeted cells. The treatment of PBMCs from HT patients with Tg-epitope-carrying chimeric molecules affects the activity of Tg-specific autoreactive B lymphocytes, delivering to them a strong suppressive signal.     

In Silico Genome-Scale Analysis of Molecular Mechanisms Contributing to the Development of a Persistent Infection with Methicillin-Resistant Staphylococcus aureus (MRSA) ST239

The increasing frequency of isolation of methicillin-resistant Staphylococcus aureus (MRSA) limits the chances for the effective antibacterial therapy of staphylococcal diseases and results in the development of persistent infection such as bacteremia and osteomyelitis. The aim of this study was to identify features of the MRSA_ST239 0943-1505-2016 (SA943) genome that contribute to the formation of both acute and chronic musculoskeletal infections. The analysis was performed using comparative genomics data of the dominant epidemic S. aureus lineages, namely ST1, ST8, ST30, ST36, and ST239. The SA943 genome encodes proteins that provide resistance to the host’s immune system, suppress immunological memory, and form biofilms. The molecular mechanisms of adaptation responsible for the development of persistent infection were as follows: amino acid substitution in PBP2 and PBP2a, providing resistance to ceftaroline; loss of a large part of prophage DNA and restoration of the nucleotide sequence of beta-hemolysin, that greatly facilitates the escape of phagocytosed bacteria from the phagosome and formation of biofilms; dysfunction of the AgrA system due to the presence of psm-mec and several amino acid substitutions in the AgrC; partial deletion of the nucleotide sequence in genomic island vSAβ resulting in the loss of two proteases of Spl—operon; and deletion of SD repeats in the SdrE amino acid sequence.     

Chiral 1-Phosphabarrelene-Pyridines as Suitable Ligands for the Rh/Ir-Catalyzed Asymmetric Hydrogenation of Olefins

Herein, we report the synthesis of chiral phosphabarrelene-pyridine ligands. Their synthesis benefit from modified reaction conditions to overcome the low yields normally associated with the [4+2] cycloaddition reaction of phosphinines with hexafluoro-2-butyne, which is a key to install the P-stereocenter in the phosphabarrelene. Their potential as chelating ligands in asymmetric catalysis was assessed in the Rh- and Ir-catalyzed hydrogenation of cyclic β-enamides and β-dehydroamino acid derivatives. The catalytic system containing a tert-butyl substituent at the ortho position of the phosphabarrelene moiety successfully hydrogenates a range of cyclic β-enamides (ee's between 92% to 94%) and β-dehydroamino acid derivatives (ee's between 93% to 95%). Moreover, the reactions can be carried out in the environmentally friendly 1,2-propylene carbonate as solvent with no loss of enantioselectivity. Mechanistic studies with the Rh/P,N catalytic systems agree with the Landis-Halpern mechanism and explain the influence of the substituent at the phosphabarrelene on enantioselectivity. Finally, the hydrogenation reactions can be carried out at large scale maintaining high enantioselectivities.     

Combustion characteristics of novel hybrid nanoenergetic formulations

This paper presents the combustion characteristics of various copper oxide (CuO) nanorods/aluminum (Al) nanothermite compositions and hybrid nanoenergetic mixtures formed by combining nanothermites with either ammonium nitrate (NH₄NO₃) or secondary explosives such as RDX and CL-20 in different weight proportions. The different types of nanorods prepared in this study are referred to as CuO-VD (dried under vacuum at 25 °C for 24 h), CuO-100 (at 100 °C for 16 h) and CuO-400 (short time (1 min) calcination at 400 °C). The physical and chemical characteristics of these different kinds of CuO nanorods were determined using a variety of analytical tools such as X-ray diffractometer, transmission electron microscope (TEM), Fourier transform infrared spectrometer (FTIR), surface area analyzer and simultaneous differential scanning calorimeter (DSC)/thermogravimetric analyzer (TGA). These measured characteristics were correlated with the combustion behavior of the nanoenergetic compositions synthesized in this work. The use of different drying and calcination parameters produced the synthesis of CuO nanorods with varying amount of hydroxyl (OH) and CH_n (n = 2, 3) functional groups. The experimental observations confirm that the presence of these functional groups on the surface of CuO nanorods enabled the formation of assembled nanoenergetic composite, upon mixed with Al nanoparticles. A facile one-step synthesis of assembled composite through surface functionalization is reported and it can be extended to large-scale preparation of assembled nanoenergetic mixtures. The combustion behavior was studied by measuring both combustion wave speed and pressure–time characteristics. Pressurization rate was determined by monitoring the pressure–time characteristics during the combustion reaction initiated by a hot wire in a fully-confined geometry. Different amounts of nanothermite powder were packed in the same volume of combustion chamber by applying different packing pressures and the pressure–time characteristics were measured as a function of varying percent theoretical maximum density (% TMD). The experimental setup used in this work enabled us to study the functional behavior of initiating explosives such as NH₄NO₃ nanoparticles, RDX and CL-20 using nanothermites under fully-confined test geometry. The dent tests performed on lead witness plates support the experimental observations obtained from pressure–time and combustion wave speed measurements of hybrid mixtures.     

Nanostructured rapidly solidified LaMg11Ni alloy. II. In situ synchrotron X-ray diffraction studies of hydrogen absorption–desorption behaviours

Recently, the present authors [17] have reported dramatic improvements in the hydrogenation behaviours of nanostructured LaMg₁₁Ni prepared by Rapid Solidification, caused by modifications of the microstructure and crystal structure. The aim of the present work was to study the mechanism and kinetics of the hydrogen interaction with rapidly solidified LaMg₁₁Ni by employing in situ synchrotron X-Ray diffraction studies of hydrogen absorption–desorption processes in hydrogen gas or in vacuum.