Prevalence of baseline polymorphisms for potential resistance to NS5A inhibitors in drug-naive individuals infected with hepatitis C genotypes 1–4

Background: The non-structural 5A (NS5A) protein of HCV is a multifunctional phosphoprotein involved in regulation of viral replication and virion assembly. NS5A inhibitors targeting domain I of NS5A protein have demonstrated high potency and pan-genotypic antiviral activity, however they possess a low genetic barrier to resistance. At present, only genotype 1, the most prevalent HCV genotype has been studied in detail for resistant variants. Methods: Utilising a panel of genotypic-specific resistance assays, population sequencing was performed on plasma derived viral RNA isolated from 138 patients infected with HCV genotypes 1-4 and not treated with directly acting anti-viral agents (DAAs). Amino acid changes in HCV NS5A domain I at codon positions 28, 30, 31, 32 and 93, reported to confer reduced susceptibility to certain NS5A inhibitors were examined. Additionally, genotypic outcome based on NS5A sequences were compared with LiPA and Abbott® real time. Results: Amino acid substitutions associated with moderate to high level resistance to NS5A inhibitors were detected in 2/42 (4.76%) HCV-1a, 3/23 (13.04%) HCV-1b, 4/26 ( 15.38% ) HCV-2, 1/24 (4.17%) HCV-3 and 1/23 (4.35%) HCV-4 infected patients who had not been treated with NS5A inhibitors. Genotype prediction based on NS5A sequences were concordant with LiPA and/or Abbott® real-time for 97.10% of cases. Conclusion: Primary resistance mutations associated with resistance to first generation NS5A inhibitors such as Daclatasvir (DCV) were observed in all genotypes, albeit at low frequencies. An excellent correlation based on NS5A genotyping and LiPA or Abbott® real-time was achieved

PAMELA, DAMA, INTEGRAL and Signatures of Metastable Excited WIMPs

Models of dark matter with ~ GeV scale force mediators provide attractive explanations of many high energy anomalies, including PAMELA, ATIC, and the WMAP haze. At the same time, by exploiting the ~ MeV scale excited states that are automatically present in such theories, these models naturally explain the DAMA/LIBRA and INTEGRAL signals through the inelastic dark matter (iDM) and exciting dark matter (XDM) scenarios, respectively. Interestingly, with only weak kinetic mixing to hypercharge to mediate decays, the lifetime of excited states with delta < 2 m_e is longer than the age of the universe. The fractional relic abundance of these excited states depends on the temperature of kinetic decoupling, but can be appreciable. There could easily be other mechanisms for rapid decay, but the consequences of such long-lived states are intriguing. We find that CDMS constrains the fractional relic population of ~100 keV states to be <~ 10^-2, for a 1 TeV WIMP with sigma_n = 10^-40 cm^2. Upcoming searches at CDMS, as well as xenon, silicon, and argon targets, can push this limit significantly lower. We also consider the possibility that the DAMA excitation occurs from a metastable state into the XDM state, which decays via e+e- emission, which allows lighter states to explain the INTEGRAL signal due to the small kinetic energies required. Such models yield dramatic signals from down-scattering, with spectra peaking at high energies, sometimes as high as ~1 MeV, well outside the usual search windows. Such signals would be visible at future Ar and Si experiments, and may be visible at Ge and Xe experiments. We also consider other XDM models involving ~ 500 keV metastable states, and find they can allow lighter WIMPs to explain INTEGRAL as well.Comment: 22 pages, 7 figure

Charged and Pseudoscalar Higgs production at a Muon Collider

We consider single charged Higgs ($H^{\pm}$) and pseudoscalar Higgs ($A^0$) production in association with a gauge boson at $\mu^+\mu^-$ colliders. We find that the tree-level t-channel and s-channel contributions to $\mu^+\mu^-\to H^{\pm}W^{\mp}, A^0Z$ are enhanced for large values of $\tan\beta$, allowing sizeable cross-sections whose analogies at $e^+e^-$ colliders would be very small. These processes provide attractive new ways of producing such particles at $\mu^+\mu^-$ colliders and are superior to the conventional methods in regions of parameter space.Comment: 11 pages Latex, 5 figures, formulae added in sections 2.2 and 2.3, extra discussion in section 2.3, references adde

Constraint methods for determining pathways and free energy of activated processes

Activated processes from chemical reactions up to conformational transitions of large biomolecules are hampered by barriers which are overcome only by the input of some free energy of activation. Hence, the characteristic and rate-determining barrier regions are not sufficiently sampled by usual simulation techniques. Constraints on a reaction coordinate r have turned out to be a suitable means to explore difficult pathways without changing potential function, energy or temperature. For a dense sequence of values of r, the corresponding sequence of simulations provides a pathway for the process. As only one coordinate among thousands is fixed during each simulation, the pathway essentially reflects the system's internal dynamics. From mean forces the free energy profile can be calculated to obtain reaction rates and insight in the reaction mechanism. In the last decade, theoretical tools and computing capacity have been developed to a degree where simulations give impressive qualitative insight in the processes at quantitative agreement with experiments. Here, we give an introduction to reaction pathways and coordinates, and develop the theory of free energy as the potential of mean force. We clarify the connection between mean force and constraint force which is the central quantity evaluated, and discuss the mass metric tensor correction. Well-behaved coordinates without tensor correction are considered. We discuss the theoretical background and practical implementation on the example of the reaction coordinate of targeted molecular dynamics simulation. Finally, we compare applications of constraint methods and other techniques developed for the same purpose, and discuss the limits of the approach

The PAMELA Positron Excess from Annihilations into a Light Boson

Recently published results from the PAMELA experiment have shown conclusive evidence for an excess of positrons at high (~ 10 - 100 GeV) energies, confirming earlier indications from HEAT and AMS-01. Such a signal is generally expected from dark matter annihilations. However, the hard positron spectrum and large amplitude are difficult to achieve in most conventional WIMP models. The absence of any associated excess in anti-protons is highly constraining on any model with hadronic annihilation modes. We revisit an earlier proposal, whereby the dark matter annihilates into a new light (<~GeV) boson phi, which is kinematically constrained to go to hard leptonic states, without anti-protons or pi0's. We find this provides a very good fit to the data. The light boson naturally provides a mechanism by which large cross sections can be achieved through the Sommerfeld enhancement, as was recently proposed. Depending on the mass of the WIMP, the rise may continue above 300 GeV, the extent of PAMELA's ability to discriminate electrons and positrons.Comment: 4 pages, 2 figures; v3 separated pions plot, references adde

Flavor changing Z-decays from scalar interactions at a Giga-Z Linear Collider

The flavor changing decay Z -> d_I \bar{d}_J is investigated with special emphasis on the b \bar{s} final state. Various models for flavor violation are considered: two Higgs doublet models (2HDM's), supersymmetry (SUSY) with flavor violation in the up and down-type squark mass matrices and SUSY with flavor violation mediated by R-parity-violating interaction. We find that, within the SUSY scenarios for flavor violation, the branching ratio for the decay Z -> b \bar{s} can reach 10^{-6} for large \tan\beta values, while the typical size for this branching ratio in the 2HDM's considered is about two orders of magnitudes smaller at best. Thus, flavor changing SUSY signatures in radiative Z decays such as Z -> b \bar{s} may be accessible to future ``Z factories'' such as a Giga-Z version of the TESLA design.Comment: 27 pages, 15 figures, REVTeX4. A new section added and a few minor corrections were made in the tex

Grain Surface Models and Data for Astrochemistry

AbstractThe cross-disciplinary field of astrochemistry exists to understand the formation, destruction, and survival of molecules in astrophysical environments. Molecules in space are synthesized via a large variety of gas-phase reactions, and reactions on dust-grain surfaces, where the surface acts as a catalyst. A broad consensus has been reached in the astrochemistry community on how to suitably treat gas-phase processes in models, and also on how to present the necessary reaction data in databases; however, no such consensus has yet been reached for grain-surface processes. A team of ∼25 experts covering observational, laboratory and theoretical (astro)chemistry met in summer of 2014 at the Lorentz Center in Leiden with the aim to provide solutions for this problem and to review the current state-of-the-art of grain surface models, both in terms of technical implementation into models as well as the most up-to-date information available from experiments and chemical computations. This review builds on the results of this workshop and gives an outlook for future directions

Spin asymmetry A_1^d and the spin-dependent structure function g_1^d of the deuteron at low values of x and Q^2

We present a precise measurement of the deuteron longitudinal spin asymmetry A_1^d and of the deuteron spin-dependent structure function g_1^d at Q^2 < 1 GeV^2 and 4*10^-5 < x < 2.5*10^-2 based on the data collected by the COMPASS experiment at CERN during the years 2002 and 2003. The statistical precision is tenfold better than that of the previous measurement in this region. The measured A_1^d and g_1^d are found to be consistent with zero in the whole range of x.Comment: 17 pages, 10 figure

Gluon polarization in the nucleon from quasi-real photoproduction of high-pT hadron pairs

We present a determination of the gluon polarization Delta G/G in the nucleon, based on the helicity asymmetry of quasi-real photoproduction events, Q^2<1(GeV/c)^2, with a pair of large transverse-momentum hadrons in the final state. The data were obtained by the COMPASS experiment at CERN using a 160 GeV polarized muon beam scattered on a polarized 6-LiD target. The helicity asymmetry for the selected events is = 0.002 +- 0.019(stat.) +- 0.003(syst.). From this value, we obtain in a leading-order QCD analysis Delta G/G=0.024 +- 0.089(stat.) +- 0.057(syst.) at x_g = 0.095 and mu^2 =~ 3 (GeV}/c)^2.Comment: 10 pages, 3 figure

The Deuteron Spin-dependent Structure Function g1d and its First Moment

We present a measurement of the deuteron spin-dependent structure function g1d based on the data collected by the COMPASS experiment at CERN during the years 2002-2004. The data provide an accurate evaluation for Gamma_1^d, the first moment of g1d(x), and for the matrix element of the singlet axial current, a0. The results of QCD fits in the next to leading order (NLO) on all g1 deep inelastic scattering data are also presented. They provide two solutions with the gluon spin distribution function Delta G positive or negative, which describe the data equally well. In both cases, at Q^2 = 3 (GeV/c)^2 the first moment of Delta G is found to be of the order of 0.2 - 0.3 in absolute value.Comment: fits redone using MRST2004 instead of MRSV1998 for G(x), correlation matrix adde