Modelling the Fluid Mechanics of Cilia and Flagella in Reproduction and Development

Cilia and flagella are actively bending slender organelles, performing functions such as motility, feeding and embryonic symmetry breaking. We review the mechanics of viscous-dominated microscale flow, including time-reversal symmetry, drag anisotropy of slender bodies, and wall effects. We focus on the fundamental force singularity, higher order multipoles, and the method of images, providing physical insight and forming a basis for computational approaches. Two biological problems are then considered in more detail: (1) left-right symmetry breaking flow in the node, a microscopic structure in developing vertebrate embryos, and (2) motility of microswimmers through non-Newtonian fluids. Our model of the embryonic node reveals how particle transport associated with morphogenesis is modulated by the gradual emergence of cilium posterior tilt. Our model of swimming makes use of force distributions within a body-conforming finite element framework, allowing the solution of nonlinear inertialess Carreau flow. We find that a three-sphere model swimmer and a model sperm are similarly affected by shear-thinning; in both cases swimming due to a prescribed beat is enhanced by shear-thinning, with optimal Deborah number around 0.8. The sperm exhibits an almost perfect linear relationship between velocity and the logarithm of the ratio of zero to infinite shear viscosity, with shear-thickening hindering cell progress.Comment: 20 pages, 24 figure

Lethal Mutagenesis of Poliovirus Mediated by a Mutagenic Pyrimidine Analogue

Lethal mutagenesis is the mechanism of action of ribavirin against poliovirus (PV) and numerous other RNA viruses. However, there is still considerable debate regarding the mechanism of action of ribavirin against a variety of RNA viruses. Here we show by using T7 RNA polymerase mediated production of PV genomic RNA, PV polymerase-catalyzed primer extension and cell-free PV synthesis that a pyrimidine ribonucleoside triphosphate analogue (rPTP) with ambiguous basepairing capacity is an efficient mutagen of the PV genome. The in vitro incorporation properties of rPTP are superior to ribavirin triphosphate. We observed a log-linear relationship between virus titer reduction and the number of rPMP molecules incorporated. A PV genome encoding a high-fidelity polymerase was more sensitive to rPMP incorporation, consistent with diminished mutational robustness of high-fidelity PV. The nucleoside (rP) did not exhibit antiviral activity in cell culture owing to the inability of rP to be converted to rPMP by cellular nucleotide kinases. rP was also a poor substrate for herpes simplex virus thymidine kinase. The block to nucleoside phosphorylation could be bypassed by treatment with the P nucleobase, which exhibited both antiviral activity and mutagenesis, presumably a reflection of rP nucleotide formation by a nucleotide salvage pathway. These studies provide additional support for lethal mutagenesis as an antiviral strategy, suggest that rPMP prodrugs may be highly efficacious antiviral agents, and provide a new tool to determine the sensitivity of RNA virus genomes to mutagenesis as well as interrogation of the impact of mutational load on the population dynamics of these viruses

Lethal Mutagenesis of Picornaviruses with N-6-Modified Purine Nucleoside Analogues

RNA viruses exhibit extraordinarily high mutation rates during genome replication. Nonnatural ribonucleosides that can increase the mutation rate of RNA viruses by acting as ambiguous substrates during replication have been explored as antiviral agents acting through lethal mutagenesis. We have synthesized novel N-6-substituted purine analogues with ambiguous incorporation characteristics due to tautomerization of the nucleobase. The most potent of these analogues reduced the titer of poliovirus (PV) and coxsackievirus (CVB3) over 1,000-fold during a single passage in HeLa cell culture, with an increase in transition mutation frequency up to 65-fold. Kinetic analysis of incorporation by the PV polymerase indicated that these analogues were templated ambiguously with increased efficiency compared to the known mutagenic nucleoside ribavirin. Notably, these nucleosides were not efficient substrates for cellular ribonucleotide reductase in vitro, suggesting that conversion to the deoxyriboucleoside may be hindered, potentially limiting genetic damage to the host cell. Furthermore, a high-fidelity PV variant (G64S) displayed resistance to the antiviral effect and mutagenic potential of these analogues. These purine nucleoside analogues represent promising lead compounds in the development of clinically useful antiviral therapies based on the strategy of lethal mutagenesis

Density reconstruction from biased tracers and its application to primordial non-Gaussianity

Large-scale Fourier modes of the cosmic density field are of great value for learning about cosmology because of their well-understood relationship to fluctuations in the early universe. However, cosmic variance generally limits the statistical precision that can be achieved when constraining model parameters using these modes as measured in galaxy surveys, and moreover, these modes are sometimes inaccessible due to observational systematics or foregrounds. For some applications, both limitations can be circumvented by reconstructing large-scale modes using the correlations they induce between smaller-scale modes of an observed tracer (such as galaxy positions). In this paper, we further develop a formalism for this reconstruction, using a quadratic estimator similar to the one used for lensing of the cosmic microwave background. We incorporate nonlinearities from gravity, nonlinear biasing, and local-type primordial non-Gaussianity, and verify that the estimator gives the expected results when applied to N-body simulations. We then carry out forecasts for several upcoming surveys, demonstrating that, when reconstructed modes are included alongside directly-observed tracer density modes, constraints on local primordial non-Gaussianity are generically tightened by tens of percents compared to standard single-tracer analyses. In certain cases, these improvements arise from cosmic variance cancellation, with reconstructed modes taking the place of modes of a separate tracer, thus enabling an effective "multitracer" approach with single-tracer observations.Comment: 30 pages plus 14 pages appendices, 19 figure

Measurement of CP asymmetry in D 0 → K - K + and D 0 → π - π decays

Time-integrated CP asymmetries in D 0 decays to the final states K - K + and π - π + are measured using proton-proton collisions corresponding to 3fb-1 of integrated luminosity collected at centre-of-mass energies of 7 TeV and 8 TeV. The D 0 mesons are produced in semileptonic b-hadron decays, where the charge of the accompanying muon is used to determine the initial flavour of the charm meson. The difference in CP asymmetries between the two final states is measured to be Δ ACP = ACP (K- K +) ACP (π- π+) = (+ 0.14 ± 0.16 (stat) ± 0.08 (syst)) %. A measurement of A CP (K - K +) is obtained assuming negligible CP violation in charm mixing and in Cabibbo-favoured D decays. It is found to be ACP (K- K+) = (- 0.06 ± 0.15 (stat) ± 0.10 (syst)) %, where the correlation coefficient between ΔA CP and A CP (K - K +) is ρ = 0.28. By combining these results, the CP asymmetry in the D 0 → π - π + channel is A CP (π - π +) = (-0.20 ± 0.19 (stat) ± 0.10 (syst))%

Measurement of the Xi(-)(b) and Omega(-)(b) baryon lifetimes

Using a data sample of pp collisions corresponding to an integrated luminosity of 3 fb−1, the Ξ−b and Ω−b baryons are reconstructed in the Ξ−b → J/ψΞ− and Ω−b → J/ψΩ− decay modes and their lifetimes measured to be τ(Ξ−b) = 1.55+0.10−0.09 (stat) ± 0.03 (syst) ps, τ(Ω−b) = 1.54+0.26−0.21 (stat) ± 0.05 (syst) ps. These are the most precise determinations to date. Both measurements are in good agreement with previous experimental results and with theoretical predictions

Measurement of the resonant and CP components in B¯ 0 → J=ψπþπ− decays

The resonant structure of the reaction B¯0→J/ψπ+π− is studied using data from 3  fb−1 of integrated luminosity collected by the LHCb experiment, one third at 7 TeV center-of-mass energy and the remainder at 8 TeV. The invariant mass of the π+π− pair and three decay angular distributions are used to determine the fractions of the resonant and nonresonant components. Six interfering π+π− states, ρ(770), f0(500), f2(1270), ρ(1450), ω(782) and ρ(1700), are required to give a good description of invariant mass spectra and decay angular distributions. The positive and negative charge parity fractions of each of the resonant final states are determined. The f0(980) meson is not seen and the upper limit on its presence, compared with the observed f0(500) rate, is inconsistent with a model where these scalar mesons are formed from two quarks and two antiquarks (tetraquarks) at the eight standard deviation level. In the qq¯ model, the absolute value of the mixing angle between the f0(980) and the f0(500) scalar mesons is limited to be less than 17° at 90% confidence level

Study of beauty hadron decays into pairs of charm hadrons

First observations of the decays Λb 0 → Λc +D(s) - are reported using data corresponding to an integrated luminosity of 3fb-1 collected at 7 and 8 TeV center-of-mass energies in proton-proton collisions with the LHCb detector. In addition, the most precise measurement of the branching fraction B(Bs 0→D+Ds -) is made and a search is performed for the decays B(s) 0→Λc +Λc -. The results obtained are B(Λb 0→Λc +D-)/ B(Λb 0→Λc +D s -)=0.042±0.003(stat)±0.003(syst), [B(Λb 0→Λc +D s -)/B(B̄0→D+D s -)]/[B(Λb 0→Λ c +π-)/B(B̄0→D +π-)]=0.96±0.02(stat)±0.06(syst),B(B s 0→D+Ds -)/ B(B̄0→D+Ds -)=0. 038±0.004(stat)±0.003(syst),B(B̄0→Λ c +Λc -)/B(B̄ 0→D+Ds -)<0.0022[95%C.L.], B(Bs 0→Λc +Λ c -)/B(Bs 0→D+D s -)<0.30[95%C.L.]. Measurement of the mass of the Λb 0 baryon relative to the B̄0 meson gives M(Λb 0)-M(B̄0)=339. 72±0.24(stat)±0.18(syst)MeV/c2. This result provides the most precise measurement of the mass of the Λb 0 baryon to date