Influenza A virus NS1 gene mutations F103L and M106I increase replication and virulence

<p>Abstract</p> <p>Background</p> <p>To understand the evolutionary steps required for a virus to become virulent in a new host, a human influenza A virus (IAV), A/Hong Kong/1/68(H3N2) (HK-wt), was adapted to increased virulence in the mouse. Among eleven mutations selected in the NS1 gene, two mutations F103L and M106I had been previously detected in the highly virulent human H5N1 isolate, A/HK/156/97, suggesting a role for these mutations in virulence in mice and humans.</p> <p>Results</p> <p>To determine the selective advantage of these mutations, reverse genetics was used to rescue viruses containing each of the NS1 mouse adapted mutations into viruses possessing the HK-wt NS1 gene on the A/PR/8/34 genetic backbone. Both F103L and M106I NS1 mutations significantly enhanced growth <it>in vitro </it>(mouse and canine cells) and <it>in vivo </it>(BALB/c mouse lungs) as well as enhanced virulence in the mouse. Only the M106I NS1 mutation enhanced growth in human cells. Furthermore, these NS1 mutations enhanced early viral protein synthesis in MDCK cells and showed an increased ability to replicate in mouse interferon β (IFN-β) pre-treated mouse cells relative to rPR8-HK-NS-wt NS1. The double mutant, rPR8-HK-NS-F103L + M106I, demonstrated growth attenuation late in infection due to increased IFN-β induction in mouse cells. We then generated a rPR8 virus possessing the A/HK/156/97 NS gene that possesses 103L + 106I, and then rescued the L103F + I106M mutant. The 103L + 106I mutations increased virulence by >10 fold in BALB/c mice. We also inserted the avian A/Ck/Beijing/1/95 NS1 gene (the source lineage of the A/HK/156/97 NS1 gene) that possesses 103L + 106I, onto the A/WSN/33 backbone and then generated the L103F + I106M mutant. None of the H5N1 and H9N2 NS containing viruses resulted in increased IFN-β induction. The rWSN-A/Ck/Beijing/1/95-NS1 gene possessing 103L and 106I demonstrated 100 fold enhanced growth and >10 fold enhanced virulence that was associated with increased tropism for lung alveolar and bronchiolar tissues relative to the corresponding L103F and I106M mutant.</p> <p>Conclusions</p> <p>The F103L and M106I NS1 mutations were adaptive genetic determinants of growth and virulence in both human and avian NS1 genes in the mouse model.</p

Electron-lattice relaxation, and soliton structures and their interactions in polyenes

Density matrix renormalisation group calculations of a suitably parametrised model of long polyenes (polyacetylene oligomers), which incorporates both long range Coulomb interactions and adiabatic lattice relaxation, are presented. The triplet and 2Ag states are found to have a 2-soliton and 4-soliton form, respectively, both with large relaxation energies. The 1Bu state forms an exciton-polaron and has a very small relaxation energy. The relaxed energy of the 2Ag state lies below that of the 1Bu state. The soliton/anti-soliton pairs are bound.Comment: RevTeX, 5 pages, 4 eps figures included using epsf. To appear in Physical Review Letters. Fig. 1 fixed u

Current localisation and redistribution as the basis of discontinuous current controlled negative differential resistance in NbOx

In-situ thermo-reflectance imaging is used to show that the discontinuous, snap-back mode of current-controlled negative differential resistance (CC-NDR) in NbOx-based devices is a direct consequence of current localization and redistribution. Current localisation is shown to result from the creation of a conductive filament either during electroforming or from current bifurcation due to the super-linear temperature dependence of the film conductivity. The snap-back response then arises from current redistribution between regions of low and high current-density due to the rapid increase in conductivity created within the high current density region. This redistribution is further shown to depend on the relative resistance of the low current-density region with the characteristics of NbOx cross-point devices transitioning between continuous and discontinuous snap-back modes at critical values of film conductivity, area, thickness and temperature, as predicted. These results clearly demonstrate that snap-back is a generic response that arises from current localization and redistribution within the oxide film rather than a material-specific phase transition, thus resolving a long-standing controversy.Comment: 21 Page

Excitons in quasi-one dimensional organics: Strong correlation approximation

An exciton theory for quasi-one dimensional organic materials is developed in the framework of the Su-Schrieffer-Heeger Hamiltonian augmented by short range extended Hubbard interactions. Within a strong electron-electron correlation approximation, the exciton properties are extensively studied. Using scattering theory, we analytically obtain the exciton energy and wavefunction and derive a criterion for the existence of a $B_u$ exciton. We also systematically investigate the effect of impurities on the coherent motion of an exciton. The coherence is measured by a suitably defined electron-hole correlation function. It is shown that, for impurities with an on-site potential, a crossover behavior will occur if the impurity strength is comparable to the bandwidth of the exciton, corresponding to exciton localization. For a charged impurity with a spatially extended potential, in addition to localization the exciton will dissociate into an uncorrelated electron-hole pair when the impurity is sufficiently strong to overcome the Coulomb interaction which binds the electron-hole pair. Interchain coupling effects are also discussed by considering two polymer chains coupled through nearest-neighbor interchain hopping $t_{\perp}$ and interchain Coulomb interaction $V_{\perp}$. Within the $t$ matrix scattering formalism, for every center-of-mass momentum, we find two poles determined only by $V_{\perp}$, which correspond to the interchain excitons. Finally, the exciton state is used to study the charge transfer from a polymer chain to an adjacent dopant molecule.Comment: 24 pages, 23 eps figures, pdf file of the paper availabl

Zero frequency divergence and gauge phase factor in the optical response theory

The static current-current correlation leads to the definitional zero frequency divergence (ZFD) in the optical susceptibilities. Previous computations have shown nonequivalent results between two gauges (${\bf p\cdot A}$ and ${\bf E \cdot r}$) under the exact same unperturbed wave functions. We reveal that those problems are caused by the improper treatment of the time-dependent gauge phase factor in the optical response theory. The gauge phase factor, which is conventionally ignored by the theory, is important in solving ZFD and obtaining the equivalent results between these two gauges. The Hamiltonians with these two gauges are not necessary equivalent unless the gauge phase factor is properly considered in the wavefunctions. Both Su-Shrieffer-Heeger (SSH) and Takayama-Lin-Liu-Maki (TLM) models of trans-polyacetylene serve as our illustrative examples to study the linear susceptibility $\chi^{(1)}$ through both current-current and dipole-dipole correlations. Previous improper results of the $\chi^{(1)}$ calculations and distribution functions with both gauges are discussed. The importance of gauge phase factor to solve the ZFD problem is emphasized based on SSH and TLM models. As a conclusion, the reason why dipole-dipole correlation favors over current-current correlation in the practical computations is explained.Comment: 17 pages, 7 figures, submitted to Phys. Rev.

Mott-Peierls Transition in the extended Peierls-Hubbard model

The one-dimensional extended Peierls-Hubbard model is studied at several band fillings using the density matrix renormalization group method. Results show that the ground state evolves from a Mott-Peierls insulator with a correlation gap at half-filling to a soliton lattice with a small band gap away from half-filling. It is also confirmed that the ground state of the Peierls-Hubbard model undergoes a transition to a metallic state at finite doping. These results show that electronic correlations effects should be taken into account in theoretical studies of doped polyacetylene. They also show that a Mott-Peierls theory could explain the insulator-metal transition observed in this material.Comment: 4 pages with 3 embedded eps figure

Capacitance fluctuations causing channel noise reduction in stochastic Hodgkin-Huxley systems

Voltage-dependent ion channels determine the electric properties of axonal cell membranes. They not only allow the passage of ions through the cell membrane but also contribute to an additional charging of the cell membrane resulting in the so-called capacitance loading. The switching of the channel gates between an open and a closed configuration is intrinsically related to the movement of gating charge within the cell membrane. At the beginning of an action potential the transient gating current is opposite to the direction of the current of sodium ions through the membrane. Therefore, the excitability is expected to become reduced due to the influence of a gating current. Our stochastic Hodgkin-Huxley like modeling takes into account both the channel noise -- i.e. the fluctuations of the number of open ion channels -- and the capacitance fluctuations that result from the dynamics of the gating charge. We investigate the spiking dynamics of membrane patches of variable size and analyze the statistics of the spontaneous spiking. As a main result, we find that the gating currents yield a drastic reduction of the spontaneous spiking rate for sufficiently large ion channel clusters. Consequently, this demonstrates a prominent mechanism for channel noise reduction.Comment: 18 page

Mutational Analysis of the Chlamydia muridarum Plasticity Zone

Pathogenically diverse Chlamydia spp. can have surprisingly similar genomes. C. trachomatis isolates that cause trachoma, sexually transmitted genital tract infections (chlamydia) and invasive lymphogranuloma venereum (LGV), and the murine strain C. muridarum share 99% of their gene content. A region of high genomic diversity between Chlamydia spp. termed the Plasticity Zone (PZ) may encode niche-specific virulence determinants that dictate pathogenic diversity. We hypothesized that PZ genes might mediate the greater virulence and IFN-γ resistance of C. muridarum compared to C. trachomatis in the murine genital tract. To test this hypothesis, we isolated and characterized a series of C. muridarum PZ nonsense mutants. Strains with nonsense mutations in chlamydial cytotoxins, guaBA-add and a phospholipase D homolog developed normally in cell culture. Two of the cytotoxin mutants were less cytotoxic than wild-type suggesting that the cytotoxins may be functional. However, none of the PZ nonsense mutants exhibited increased IFN-γ sensitivity in cell culture or were profoundly attenuated in a murine genital tract infection model. Our results suggest that C. muridarum PZ genes are transcribed and some may produce functional proteins, but are dispensable for infection of the murine genital tract