Peptidyl-prolyl cis-trans isomerases (immunophilins) and their roles in parasite biochemistry, host-parasite interaction and antiparasitic drug action.

Immunophilin is the collective name given to the cyclophilin and FK506-binding protein (FKBP) families. As the name suggests, these include the major binding proteins of certain immunosuppressive drugs: cyclophilins for the cyclic peptide cyclosporin A and FKBPs for the macrolactones FK506 and rapamycin. Both families, although dissimilar in sequence, possess peptidyl-prolyl <i>cis-trans</i> isomerase activity in vitro and can play roles in protein folding and transport, RNA splicing and the regulation of multiprotein complexes in cells. In addition to enzymic activity, many immunophilins act as molecular chaperones. This property may be conferred by the isomerase domain and/or by additional domains. Recent years have seen a great increase in the number of known immunophilin genes in parasitic protozoa and helminths and in many cases their products have been characterized biochemically and their temporal and spatial expression patterns have been examined. Some of these genes represent novel types: one example is a <i>Toxoplasma gondii</i> gene encoding a protein with both cyclophilin and FKBP domains. Likely roles in protein folding and oligomerisation, RNA splicing and sexual differentiation have been suggested for parasite immunophilins. In addition, unexpected roles in parasite virulence (Mip FKBP of <i>Trypanosoma cruzi</i>) and host immuno-modulation (e.g. 18-kDa cyclophilin of <i>Toxoplasma gondii</i>) have been established. Furthermore, in view of the potent antiparasitic activities of cyclosporins, macrolactones and nonimmunosuppressive derivatives of these compounds, immunophilins may mediate drug action and/or may themselves represent potential drug targets. Investigation of the mechanisms of action of these agents may lead to the design of potent and selective antimalarial and other antiparasitic drugs. This review discusses the properties of immunophilins in parasites and the 'animal model' <i>Caenorhabditis elegans</i> and relates these to our understanding of the roles of these proteins in cellular biochemistry, host-parasite interaction and the antiparasitic mechanisms of the drugs that bind to them

Overtone spectra and intensities of tetrahedral molecules in boson-realization models

The stretching and bending vibrational spectrum and the intensities of infrared transitions in a tetrahedral molecule are studied in two boson-realization models, where the interactions between stretching and bending vibrations are described by a quadratic cross term and by Fermi resonance terms, called harmonically coupled and Fermi resonance boson-realization model, respectively. The later is a development of our recent model. As an example, the two models are applied to the overtone spectrum and the intensities of silicon tetrafluorde. Those models provide fits to the published experimental vibrational eigenvalues with standard deviations 1.956 cm$^{-1}$ and 0.908 cm$^{-1}$, respectively. The intensities of infrared transitions of its complete vibrations are calculated in the two models, and results show a good agreement with the observed data.Comment: 14 pages Revtex, no figure, to appear in Annals of Physic

Quark matter in compact stars?

Ozel, in a recent reanalysis of EXO 0748-676 observational data (astro-ph/0605106), concluded that quark matter probably does not exist in the center of compact stars. We show that the data is actually consistent with the presence of quark matter in compact stars.Comment: 4 pages, LaTeX; New title and overall rewrite to reflect version published in Nature. Conclusions unchange

Higgs bosons near 125 GeV in the NMSSM with constraints at the GUT scale

We study the NMSSM with universal Susy breaking terms (besides the Higgs sector) at the GUT scale. Within this constrained parameter space, it is not difficult to find a Higgs boson with a mass of about 125 GeV and an enhanced cross section in the diphoton channel. An additional lighter Higgs boson with reduced couplings and a mass <123 GeV is potentially observable at the LHC. The NMSSM-specific Yukawa couplings lambda and kappa are relatively large and tan(beta) is small, such that lambda, kappa and the top Yukawa coupling are of order 1 at the GUT scale. The lightest stop can be as light as 105 GeV, and the fine-tuning is modest. WMAP constraints can be satisfied by a dominantly higgsino-like LSP with substantial bino, wino and singlino admixtures and a mass of ~60-90 GeV, which would potentially be detectable by XENON100.Comment: 20 pages, 14 figure

Inhibition of synaptic transmission and G protein modulation by synthetic CaV2.2 Ca2+ channel peptides

Abstract: Modulation of presynaptic voltage-dependent Ca+ channels is a major means of controlling neurotransmitter release. The CaV 2.2 Ca2+ channel subunit contains several inhibitory interaction sites for Gβγ subunits, including the amino terminal (NT) and I–II loop. The NT and I–II loop have also been proposed to undergo a G protein-gated inhibitory interaction, whilst the NT itself has also been proposed to suppress CaV 2 channel activity. Here, we investigate the effects of an amino terminal (CaV 2.2[45–55]) ‘NT peptide’ and a I–II loop alpha interaction domain (CaV 2.2[377–393]) ‘AID peptide’ on synaptic transmission, Ca2+ channel activity and G protein modulation in superior cervical ganglion neurones (SCGNs). Presynaptic injection of NT or AID peptide into SCGN synapses inhibited synaptic transmission and also attenuated noradrenaline-induced G protein modulation. In isolated SCGNs, NT and AID peptides reduced whole-cell Ca2+ current amplitude, modified voltage dependence of Ca2+ channel activation and attenuated noradrenaline-induced G protein modulation. Co-application of NT and AID peptide negated inhibitory actions. Together, these data favour direct peptide interaction with presynaptic Ca2+ channels, with effects on current amplitude and gating representing likely mechanisms responsible for inhibition of synaptic transmission. Mutations to residues reported as determinants of Ca2+ channel function within the NT peptide negated inhibitory effects on synaptic transmission, Ca2+ current amplitude and gating and G protein modulation. A mutation within the proposed QXXER motif for G protein modulation did not abolish inhibitory effects of the AID peptide. This study suggests that the CaV 2.2 amino terminal and I–II loop contribute molecular determinants for Ca2+ channel function; the data favour a direct interaction of peptides with Ca2+ channels to inhibit synaptic transmission and attenuate G protein modulation. Non-technical summary: Nerve cells (neurones) in the body communicate with each other by releasing chemicals (neurotransmitters) which act on proteins called receptors. An important group of receptors (called G protein coupled receptors, GPCRs) regulate the release of neurotransmitters by an action on the ion channels that let calcium into the cell. Here, we show for the first time that small peptides based on specific regions of calcium ion channels involved in GPCR signalling can themselves inhibit nerve cell communication. We show that these peptides act directly on calcium channels to make them more difficult to open and thus reduce calcium influx into native neurones. These peptides also reduce GPCR-mediated signalling. This work is important in increasing our knowledge about modulation of the calcium ion channel protein; such knowledge may help in the development of drugs to prevent signalling in pathways such as those involved in pain perception

The foundations of statistical mechanics from entanglement: Individual states vs. averages

We consider an alternative approach to the foundations of statistical mechanics, in which subjective randomness, ensemble-averaging or time-averaging are not required. Instead, the universe (i.e. the system together with a sufficiently large environment) is in a quantum pure state subject to a global constraint, and thermalisation results from entanglement between system and environment. We formulate and prove a "General Canonical Principle", which states that the system will be thermalised for almost all pure states of the universe, and provide rigorous quantitative bounds using Levy's Lemma.Comment: 12 pages, v3 title changed, v2 minor change

Hawking Radiation due to Photon and Gravitino Tunneling

Applying the Hamilton--Jacobi method we investigate the tunneling of photon across the event horizon of a static spherically symmetric black hole. The necessity of the gauge condition on the photon field, to derive the semiclassical Hawking temperature, is explicitly shown. Also, the tunneling of photon and gravitino beyond this semiclassical approximation are presented separately. Quantum corrections of the action for both cases are found to be proportional to the semiclassical contribution. Modifications to the Hawking temperature and Bekenstein-Hawking area law are thereby obtained. Using this corrected temperature and Hawking's periodicity argument, the modified metric for the Schwarzschild black hole is given. This corrected version of the metric, upto $\hbar$ order is equivalent to the metric obtained by including one loop back reaction effect. Finally, the coefficient of the leading order correction of entropy is shown to be related to the trace anomaly.Comment: LaTex, 19 pages, no figures, extended version, new references added, to appear in Annals of Phy

Unified model of baryonic matter and dark components

We investigate an interacting two-fluid cosmological model and introduce a scalar field representation by means of a linear combination of the individual energy densities. Applying the integrability condition to the scalar field equation we show that this "exotic quintessence" is driven by an exponential potential and the two-fluid mixture can be considered as a model of three components. These components are associated with baryonic matter, dark matter and dark energy respectively. We use the Simon, Verde & Jimenez (2005) determination of the redshift dependence of the Hubble parameter to constrain the current density parameters of this model. With the best fit density parameters we obtain the transition redshift between non accelerated and accelerated regimes z_{acc}=0.66 and the time elapsed since the initial singularity t_0= 19.8 Gyr. We study the perturbation evolution of this model and find that the energy density perturbation decreases with the cosmological time.Comment: 8 pages, 6 figures A new section adde

A Disc-Corona Model for a Rotating Black Hole

We propose a disc-corona model in which a geometrically thin, optically thick disc surrounds a Kerr black hole, and magnetic fields exert a time-steady torque on the inner edge of the accretion disc. The analytical expression of the total gravitational power is derived from the thin-disc dynamics equations by using this new boundary condition. It is shown that the magnetic torque can considerably enhance the amount of energy released in the disc-corona system. Furthermore, the global solutions of this disc-corona system are obtained numerically. We find that the fraction of the power dissipated into the corona in the total for such disc-corona system increases with the increasing dimensionless black hole spin parameter $a_\ast$, but is insensitive on the $\Delta \varepsilon$ which is the additional radiative efficiency parameter relevant to magnetic torque, for $\Delta\varepsilon > 1$. In addition, the emerged spectra from this disc-corona system are simulated by using Monte-Carlo method, and the effect of the different parameters on the output spectra is discussed