Cholesterol Recognition Motifs (CRAC) in the S Protein of Coronavirus: A Possible Target for Antiviral Therapy?

Some interactions of enveloped viruses with the host cell membrane have a cholesterol-dependent component, which may account for clinical manifestations of the infectious disease and can be used for the development of antiviral drugs. These cholesterol-dependent interactions can be mediated by cholesterol-recognition amino-acid consensus (CRAC) motifs present in viral proteins. The S protein of the SARS-CoV and SARS-CoV2 coronaviruses contains CRAC motifs that can be involved in the process of virus entry into the cell. Besides, during viral envelope formation, CRAC motifs can be responsible for binding of cell membrane cholesterol, leading to depletion of cell membrane cholesterol and subsequent malfunctioning of cellular cholesterol-dependent proteins, destabilization and permeabilization of cell membranes and, ultimately, to the death of infected cells. Understanding the mechanisms of cholesterol-dependent virus–cell interactions and the role of CRAC-containing viral proteins in the pathogenesis of the disease can serve as the basis for the development of new drugs that prevent both coronavirus entry into the cell and the damage of the infected cell during the viral morphogenesis. The target for such drugs can be the S-protein/cholesterol interface. CRAC-containing peptides derived from viral proteins may be among these agents. These peptides can also be used as experimental tools to study cholesterol-dependent virus–cell interactions

Effect of desmin peptides and the characterization of nebulin family proteins in glial cells

A 3-dimensional highly integrated cytoskeletal network dynamically responds to numerous mechanical stresses faced by cells in various tissue types. Intermediate filament proteins are a major part of the cytoskeleton of cells specified in a tissue-dependent, cell-type dependent manner that play a central role in the maintenance of cellular integrity and adaptation to mechanical stress. Limited information is available in regards to the functional interplay between microtubules and intermediate filaments to maintain cellular homeostasis. Recently, it was reported that tubulin-binding intermediate filament (IF) (neurofilament NFL and vimentin) specifically killed glioma cells but not healthy astrocytes (Bouquet et. al, 2009; Berges et al. 2012). Because it is known that desmin IFs contains four binding sites predicted to bind tubulin, based on SPOT peptide arrays, that also share homology to desmin nebulin-binding peptides (Bouquet, 2009; Conover and Gregorio, 2011), we hypothesized that a conserved function of nebulin to bind IFs to stabilize actin found in myocytes could also be maintained in nerve cells. This project aims to first investigate the uptake ability of desmin peptides homologous to NFL peptides and next test their effect on the distribution of the cytoskeleton of glioma T98G cells and astrocytes. Our results show that most of the desmin peptides were internalized into glioma cells with similar efficiencies as the vimentin (58-81) peptide without causing significant apoptosis or necrosis. Surprisingly, we found that some of the desmin peptides promoted cell survival and appeared to enhance mitochondria activity. Addition of the desmin peptides did not significantly prevent tubulin polymerization assays in vitro. Moreover, immunofluorescence studies showed that the majority of the desmin peptides collapsed the microtubule networks but had little effect on the actin and vimentin cytoskeletons. Notably, we found a novel speckled nuclear staining for nebulin in glial cells, and a close association of tubulin to nebulette. Consistent with our results, the nebulin mRNA expression was recently reported in neurons and glia cells (Laitila et al, 2012), while in myocytes, nebulin and nebulette directly binds to desmin (Conover et al 2009, Dunina-Barkoskaya et al, 2014 under review). Future studies should address whether the actin-binding nebulin or nebulette proteins are capable of directly binding tubulin and further investigate their relationship to the IF cytoskeleton of nerve cells

Supernova Ia: a Converging Delayed Detonation Wave

A model of a carbon-oxygen (C--O) presupernova core with an initial mass 1.33 M_\odot, an initial carbon mass fraction 0.27, and with an average mass growth-rate 5 x 10^{-7} M_\odot/yr due to accretion in a binary system was evolved from initial central density 10^9 g/cm^3, and temperature 2.05 x 10^8 K through convective core formation and its subsequent expansion to the carbon runaway at the center. The only thermonuclear reaction contained in the equations of evolution and runaway was the carbon burning reaction 12C + 12C with an energy release corresponding to the full transition of carbon and oxygen (with the same rate as carbon) into 56Ni. As a parameter we take \alpha_c - a ratio of a mixing length to the size of the convective zone. In spite of the crude assumptions, we obtained a pattern of the runaway acceptable for the supernova theory with the strong dependence of its duration on \alpha_c. In the variants with large enough values of \alpha_c=4.0 x 10^{-3} and 3.0 x 10^{-3} the fuel combustion occurred from the very beginning as a prompt detonation. In the range of 2.0 x 10^{-3} >= \alpha_c >= 3.0 x 10^{-4} the burning started as a deflagration with excitation of stellar pulsations with growing amplitude. Eventually, the detonation set in, which was activated near the surface layers of the presupernova (with m about 1.33 M_\odot) and penetrated into the star down to the deflagration front. Excitation of model pulsations and formation of a detonation front are described in detail for the variant with \alpha_c=1.0 x 10^{-3}.Comment: 13 pages, 11 figures, to appear in Astronomy Letter

A New Mechanism of Model Membrane Fusion Determined from Monte Carlo Simulation

We have carried out extensive Monte Carlo simulations of the fusion of tense apposed bilayers formed by amphiphilic molecules within the framework of a coarse grained lattice model. The fusion pathway differs from the usual stalk mechanism. Stalks do form between the apposed bilayers, but rather than expand radially to form an axial-symmetric hemifusion diaphragm of the trans leaves of both bilayers, they promote in their vicinity the nucleation of small holes in the bilayers. Two subsequent paths are observed: (i) The stalk encircles a hole in one bilayer creating a diaphragm comprised of both leaves of the other intact bilayer, and which ruptures to complete the fusion pore. (ii) Before the stalk can encircle a hole in one bilayer, a second hole forms in the other bilayer, and the stalk aligns and encircles them both to complete the fusion pore. Both pathways give rise to mixing between the cis and trans leaves of the bilayer and allow for transient leakage.Comment: revised version, accepted to Biophys. J. (11 figures

The origin of intergalactic thermonuclear supernovae

The population synthesis method is used to study the possibility of explaining the appreciable fraction (20^+12_15%) of the intergalactic (no-host) type Ia supernovae observed in galaxy clusters (Gal-Yam ete al. 2003) by binary whote dwarf merginngs in the cores of globular clusters. In a typical globular cluster, the number of merging double white dwarfs is fount to be smaller than 10^{-13} per year per average cluster star during the entire evolution of the cluster, which is a factor of 3 higher than in a Milky-Way-type galaxy. From 5 to 30% of the merging white dwarfs are dynamically expelled from the cluster with barycenter velocities up to 150 km/s. SN Ia explosions during the mergers of binary white dwarfs in dense star clusters may account for \sim 1% of the total rate of SN Ia in the central parts of galaxy clusters if the baryon mass fraction in such star clusters is \sim 0.3%.Comment: 8 pages, 3 figs. Astronomy Letters (in press

Dynamics and Radiation of Young Type-Ia Supernova Remnants: Important Physical Processes

We examine and analyze the physical processes that should be taken into account when modeling young type-Ia SNRs, with ages of several hundred years. It is shown, that energy losses in the metal-rich ejecta can be essential for remnants already at this stage of evolution. The influence of electron thermal conduction and the rate of the energy exchange between electrons and ions on the temperature distribution and the X-radiation from such remnants is studied. The data for Tycho SNR from the XMM-Newton X-ray telescope have been employed for the comparison of calculations with observations.Comment: 19 pages, 8 figure

Neutron stars in globular clusters: formation and observational manifestations

Population synthesis is used to model the number of neutron stars in globular clusters that are observed as LMXBs and millisecond PSRs. The dynamical interaction between binary and single stars in a GC are assumed to take place with a permanently replenished "background" of single stars whose density distribution keeps track with the cluster evolution as a whole and evolution of single stars. We use the hypothesis (Podsiadlowski et al) that NS forming in binary systems from components with initial masses \sim 8-12 M_\odot during the electron-capture collapse of the degenerate O-Ne-Mg core do not acquire a high space velocities (kicks). The remaining NSs (i.e. from single stars with M>8 M_\odot or binary comonents with M>12 M_\odot) are assumed to be born with high kicks, as found from obsrevations of single pulsars (Hobbs et al. 2005). Under this assumption, a sizeable fraction of NSs remain in GCs (about 1000 NSs in a GC with a mass of 5\times 10^5 M_\odot). The number of ms PSRs formed in the cluster via accretion spin-up in binaries is then about 10, which is consistent with observations. Our modelling reproduces the observed shape of the X-ray luminosity function for accreting NSs in binaries with normal and degenerate components and the distribution of spin periods of ms PSRs in GCs under the assumption of accretion-driven magnetic field decay of NSs up to a bottom value of 10^8 G. The number of LMXBs and ms PSRs dynamically expelling from GCs is also calculated.Comment: LATEX, 21 pages, 8 gif figures, Astronomy Letters, in pres