The tarantula toxin GxTx detains K+ channel gating charges in their resting conformation.

Allosteric ligands modulate protein activity by altering the energy landscape of conformational space in ligand-protein complexes. Here we investigate how ligand binding to a K+ channel's voltage sensor allosterically modulates opening of its K+-conductive pore. The tarantula venom peptide guangxitoxin-1E (GxTx) binds to the voltage sensors of the rat voltage-gated K+ (Kv) channel Kv2.1 and acts as a partial inverse agonist. When bound to GxTx, Kv2.1 activates more slowly, deactivates more rapidly, and requires more positive voltage to reach the same K+-conductance as the unbound channel. Further, activation kinetics are more sigmoidal, indicating that multiple conformational changes coupled to opening are modulated. Single-channel current amplitudes reveal that each channel opens to full conductance when GxTx is bound. Inhibition of Kv2.1 channels by GxTx results from decreased open probability due to increased occurrence of long-lived closed states; the time constant of the final pore opening step itself is not impacted by GxTx. When intracellular potential is less than 0 mV, GxTx traps the gating charges on Kv2.1's voltage sensors in their most intracellular position. Gating charges translocate at positive voltages, however, indicating that GxTx stabilizes the most intracellular conformation of the voltage sensors (their resting conformation). Kinetic modeling suggests a modulatory mechanism: GxTx reduces the probability of voltage sensors activating, giving the pore opening step less frequent opportunities to occur. This mechanism results in K+-conductance activation kinetics that are voltage-dependent, even if pore opening (the rate-limiting step) has no inherent voltage dependence. We conclude that GxTx stabilizes voltage sensors in a resting conformation, and inhibits K+ currents by limiting opportunities for the channel pore to open, but has little, if any, direct effect on the microscopic kinetics of pore opening. The impact of GxTx on channel gating suggests that Kv2.1's pore opening step does not involve movement of its voltage sensors

Sequential conformational rearrangements in flavivirus membrane fusion

The West Nile Virus (WNV) envelope protein, E, promotes membrane fusion during viral cell entry by undergoing a low-pH triggered conformational reorganization. We have examined the mechanism of WNV fusion and sought evidence for potential intermediates during the conformational transition by following hemifusion of WNV virus-like particles (VLPs) in a single particle format. We have introduced specific mutations into E, to relate their influence on fusion kinetics to structural features of the protein. At the level of individual E subunits, trimer formation and membrane engagement of the threefold clustered fusion loops are rate-limiting. Hemifusion requires at least two adjacent trimers. Simulation of the kinetics indicates that availability of competent monomers within the contact zone between virus and target membrane makes trimerization a bottleneck in hemifusion. We discuss the implications of the model we have derived for mechanisms of membrane fusion in other contexts. DOI: http://dx.doi.org/10.7554/eLife.04389.00

1/m_Q Corrections to the Heavy-to-Light-Vector Transitions in the HQET

Within the HQET, the heavy to light vector meson transitions are systematically analyzed to the order of 1/m_Q. Besides the four universal functions at the leading order, there are twenty-two independent universal form factors at the order of 1/m_Q. Both the semileptonic decay B->\rho which is relevant to the |V_{ub}| extraction, and the penguin induced decay B -> K^* which is important to new physics discovering, depend on these form factors. Phenomenological implications are discussed.Comment: RevTeX, 9 pages, no figure

Top quark electric and chromo electric dipole moments in the general two Higgs Doublet model

We study the electric and chromo electric dipole moment of top quark in the general two Higgs Doublet model (model III). We analyse the dependency of this quantity to the new phases coming from the complex Yukawa couplings and masses of charged and neutral Higgs bosons. We observe that the electric and chromo elecric dipole moments of top quark are at the order of 10^{-21} e cm and 10^{-20} g_s cm, which are extremely large values compared to ones calculated in the SM and also two Higgs Doublet model with real Yukawa couplings.Comment: 9 pages,10 figure

Direct CP violation in radiative b decays in and beyond the Standard Model

We consider the partial rate asymmetry in the inclusive decay modes b to s gamma and b to d gamma, concentrating on non-standard models with new charged Higgs interactions. We find that the charged Higgs contribution to the asymmetry for b to s gamma is small in such models due to a universal cancellation mechanism. The asymmetry is therefore difficult to distinguish experimentally from the Standard Model (SM) value, which is also small. The cancellation mechanism is found to be rendered inoperative in supersymmetry due to the presence of chargino loops. Unlike b to s gamma, the rate asymmetry for b to d gamma in Higgs models can be quite different from its SM value, generally ranging from -20% to +20%. Specific model calculations are performed for the Three-Higgs Doublet Model and the ``Top'' Two-Higgs Doublet Model to serve as illustrations. We also offer some suggestions that may be helpful to experimentalists in the detection of the inclusive mode b to d gamma.Comment: RevTex, 24 pages, 6 figures, minor changes, version to appear in PR

Novel CP-violating Effects in B decays from Charged-Higgs in a Two-Higgs Doublet Model for the Top Quark

We explore charged-Higgs cp-violating effects in a specific type III two-Higgs doublet model which is theoretically attractive as it accommodates the large mass of the top quark in a natural fashion. Two new CP-violating phases arise from the right-handed up quark sector. We consider CP violation in both neutral and charged B decays. Some of the important findings are as follows. 1) Large direct-CP asymmetry is found to be possible for B+- to psi/J K+-. 2) Sizable D-anti-D mixing effect at the percent level is found to be admissible despite the stringent constraints from the data on K-anti-K mixing, b to s gamma and B to tau nu decays. 3) A simple but distinctive CP asymmetry pattern emerges in decays of B_d and B_s mesons, including B_d to psi/J K_S, D+ D-, and B_s to D_s+ D_s-, psi eta/eta^prime, psi/J K_S. 4) The effect of D-anti-D mixing on the CP asymmetry in B+- to D/anti-D K+- and on the extraction of the angle gamma of the unitarity triangle from such decays can be significant.Comment: 32 pages, 5 figures, section V.A revised, version to appear in PR

The lifetime of B_c-meson and some relevant problems

The lifetime of the B_c-meson is estimated with consistent considerations on all of the heavy mesons ($B^0, B^\pm, B_s, D^0, D^\pm D_s$) and the double heavy meson B_c. In the estimate, the framework, where the non-spectator effects for nonleptonic decays are taken into account properly, is adopted, and the parameters needed to be fixed are treated carefully and determined by fitting the available data. The bound-state effects in it are also considered. We find that in decays of the meson B_c, the QCD correction terms of the penguin diagrams and the main component terms c_1O_1, c_2O_2 of the effective interaction Lagrangian have direct interference that causes an enhancement about 3 ~ 4% in the total width of the B_c meson.Comment: 27 pages, 0 figur

Determination of |Vcb| using the semileptonic decay \bar{B}^0 --> D^{*+}e^-\bar{\nu}

We present a measurement of the Cabibbo-Kobayashi-Maskawa (CKM) matrix element |Vcb| using a 10.2 fb^{-1} data sample recorded at the \Upsilon(4S) resonance with the Belle detector at the KEKB asymmetric e^+e^- storage ring. By extrapolating the differential decay width of the \bar{B}^0 --> D^{*+}e^-\bar{\nu} decay to the kinematic limit at which the D^{*+} is at rest with respect to the \bar{B}^0, we extract the product of |Vcb| with the normalization of the decay form factor F(1), |Vcb |F(1)= (3.54+/-0.19+/-0.18)x10^{-2}, where the first error is statistical and the second is systematic. A value of |Vcb| = (3.88+/-0.21+/-0.20+/-0.19)x10^{-2} is obtained using a theoretical calculation of F(1), where the third error is due to the theoretical uncertainty in the value of F(1). The branching fraction B(\bar{B}^0 --> D^{*+}e^-\bar{\nu}) is measured to be (4.59+/-0.23+/-0.40)x10^{-2}.Comment: 20 pages, 6 figures, elsart.cls, submitted to PL

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Multiexon deletion alleles of ATF6 linked to achromatopsia

Achromatopsia (ACHM) is an autosomal recessive disease that results in severe visual loss. Symptoms of ACHM include impaired visual acuity, nystagmus, and photoaversion starting from infancy; furthermore, ACHM is associated with bilateral foveal hypoplasia and absent or severely reduced cone photoreceptor function on electroretinography. Here, we performed genetic sequencing in 3 patients from 2 families with ACHM, identifying and functionally characterizing 2 mutations in the activating transcription factor 6 (ATF6) gene. We identified a homozygous deletion covering exons 8-14 of the ATF6 gene from 2 siblings from the same family. In another patient from a different family, we identified a heterozygous deletion covering exons 2 and 3 of the ATF6 gene found in trans with a previously identified ATF6 c.970C>T (p.Arg324Cys) ACHM disease allele. Recombinant ATF6 proteins bearing these exon deletions showed markedly impaired transcriptional activity by qPCR and RNA-Seq analysis compared with WT-ATF6. Finally, RNAscope revealed that ATF6 and the related ATF6B transcripts were expressed in cones as well as in all retinal layers in normal human retina. Overall, our data identify loss-of-function ATF6 disease alleles that cause human foveal disease