Measurement of hydrodynamic force generation by swimming dolphins using bubble DPIV

Attempts to measure the propulsive forces produced by swimming dolphins have been limited. Previous uses of computational hydrodynamic models and gliding experiments have provided estimates of thrust production by dolphins, but these were indirect tests that relied on various assumptions. The thrust produced by two actively swimming bottlenose dolphins (Tursiops truncatus) was directly measured using digital particle image velocimetry (DPIV). For dolphins swimming in a large outdoor pool, the DPIV method used illuminated microbubbles that were generated in a narrow sheet from a finely porous hose and a compressed air source. The movement of the bubbles was tracked with a high-speed video camera. Dolphins swam at speeds of 0.7 to 3.4 m s−1 within the bubble sheet oriented along the midsagittal plane of the animal. The wake of the dolphin was visualized as the microbubbles were displaced because of the action of the propulsive flukes and jet flow. The oscillations of the dolphin flukes were shown to generate strong vortices in the wake. Thrust production was measured from the vortex strength through the Kutta–Joukowski theorem of aerodynamics. The dolphins generated up to 700 N during small amplitude swimming and up to 1468 N during large amplitude starts. The results of this study demonstrated that bubble DPIV can be used effectively to measure the thrust produced by large-bodied dolphins

Plasmodium falciparum Resistance to a Lead Benzoxaborole Due to Blocked Compound Activation and Altered Ubiquitination or Sumoylation.

New antimalarial drugs are needed. The benzoxaborole AN13762 showed excellent activity against cultured Plasmodium falciparum, against fresh Ugandan P. falciparum isolates, and in murine malaria models. To gain mechanistic insights, we selected in vitro for P. falciparum isolates resistant to AN13762. In all of 11 independent selections with 100 to 200 nM AN13762, the 50% inhibitory concentration (IC50) increased from 18-118 nM to 180-890 nM, and whole-genome sequencing of resistant parasites demonstrated mutations in prodrug activation and resistance esterase (PfPARE). The introduction of PfPARE mutations led to a similar level of resistance, and recombinant PfPARE hydrolyzed AN13762 to the benzoxaborole AN10248, which has activity similar to that of AN13762 but for which selection of resistance was not readily achieved. Parasites further selected with micromolar concentrations of AN13762 developed higher-level resistance (IC50, 1.9 to 5.0 μM), and sequencing revealed additional mutations in any of 5 genes, 4 of which were associated with ubiquitination/sumoylation enzyme cascades; the introduction of one of these mutations, in SUMO-activating enzyme subunit 2, led to a similar level of resistance. The other gene mutated in highly resistant parasites encodes the P. falciparum cleavage and specificity factor homolog PfCPSF3, previously identified as the antimalarial target of another benzoxaborole. Parasites selected for resistance to AN13762 were cross-resistant with a close analog, AN13956, but not with standard antimalarials, AN10248, or other benzoxaboroles known to have different P. falciparum targets. Thus, AN13762 appears to have a novel mechanism of antimalarial action and multiple mechanisms of resistance, including loss of function of PfPARE preventing activation to AN10248, followed by alterations in ubiquitination/sumoylation pathways or PfCPSF3.IMPORTANCE Benzoxaboroles are under study as potential new drugs to treat malaria. One benzoxaborole, AN13762, has potent activity and promising features, but its mechanisms of action and resistance are unknown. To gain insights into these mechanisms, we cultured malaria parasites with nonlethal concentrations of AN13762 and generated parasites with varied levels of resistance. Parasites with low-level resistance had mutations in PfPARE, which processes AN13762 into an active metabolite; PfPARE mutations prevented this processing. Parasites with high-level resistance had mutations in any of a number of enzymes, mostly those involved in stress responses. Parasites selected for AN13762 resistance were not resistant to other antimalarials, suggesting novel mechanisms of action and resistance for AN13762, a valuable feature for a new class of antimalarial drugs

Falcipain Inhibitors Based on the Natural Product Gallinamide A Are Potent in Vitro and in Vivo Antimalarials

A library of analogues of the cyanobacterium-derived depsipeptide natural product gallinamide A were designed and prepared using a highly efficient and convergent synthetic route. Analogues were shown to exhibit potent inhibitory activity against the Plasmodium falciparum cysteine proteases falcipain 2 and falcipain 3 and against cultured chloroquine-sensitive (3D7) and chloroquine-resistant (W2) strains of P. falciparum. Three lead compounds were selected for evaluation of in vivo efficacy against Plasmodium berghei infection in mice on the basis of their improved blood, plasma, and microsomal stability profiles compared with the parent natural product. One of the lead analogues cured P. berghei-infected mice in the Peters 4 day-suppressive test when administered 25 mg kg–1 intraperitoneally daily for 4 days. The compound was also capable of clearing parasites in established infections at 50 mg kg–1 intraperitoneally daily for 4 days and exhibited moderate activity when administered as four oral doses of 100 mg kg–1.NHMR

Measurement of the lifetime of the B+c meson using the B+c→J/ψπ+ decay mode

See paper for full list of authors - 19 pages, 3 figuresInternational audienceThe difference in total widths between the B+c and B+ mesons is measured using 3.0fb−1 of data collected by the LHCb experiment in 7 and 8 TeV centre-of-mass energy proton-proton collisions at the LHC. Through the study of the time evolution of B+c→J/ψπ+ and B+→J/ψK+ decays, the width difference is measured to beΔΓ≡ΓB+c−ΓB+=4.46±0.14±0.07mm−1c,where the first uncertainty is statistical and the second systematic. The known lifetime of the B+ meson is used to convert this to a precise measurement of the B+c lifetime,τB+c=513.4±11.0±5.7fs,where the first uncertainty is statistical and the second systematic

Determination of gamma and -2beta_s from charmless two-body decays of beauty mesons

See paper for full list of authorsInternational audienceUsing the latest LHCb measurements of time-dependent CP violation in the B^0_s -> K^+K^- decay, a U-spin relation between the decay amplitudes of B^0_s -> K^+K^- and B^0 -> \pi^+\pi^- decay processes allows constraints to be placed on the angle gamma of the unitarity triangle and on the B^0_s mixing phase -2\beta_s. Results from an extended approach, which uses additional inputs on B^0 -> \pi^0\pi^0 and B^+ -> \pi^+\pi^0 decays from other experiments and exploits isospin symmetry, are also presented. The dependence of the results on the maximum allowed amount of U-spin breaking is studied. At 68% probability, the value \gamma = ( 63.5 +7.2 -6.7 ) degrees modulo 180 degrees is determined. In an alternative analysis, the value -2\beta_s = -0.12 +0.14 -0.16 rad is found. In both measurements, the uncertainties due to U-spin breaking effects up to 50% are included

Measurement of the CP-violating phase β in B0→J/ψπ+π− decays and limits on penguin effects

18 pages, 6 figures - See paper for full list of authorsInternational audienceTime-dependent CP violation is measured in the B0→J/ψπ+π− channel for each π+π− resonant final state using data collected with an integrated luminosity of 3.0 fb−1 in pp collisions using the LHCb detector. The final state with the largest rate, J/ψρ0(770), is used to measure the CP-violating angle 2βeff to be (41.7±9.6+2.8−6.3)∘. This result can be used to limit the size of penguin amplitude contributions to CP violation measurements in, for example, B0s→J/ψϕ decays. Assuming approximate SU(3) flavour symmetry and neglecting higher order diagrams, the shift in the CP-violating phase ϕs is limited to be within the interval [−1.05∘, +1.18∘] at 95% confidence level. Changes to the limit due to SU(3) symmetry breaking effects are also discussed

Study of the rare B0s and B0 decays into the π+π−μ+μ− final state

See paper for full list of authors - Submitted to Phys. Lett. BInternational audienceA search for the rare decays B0s→π+π−μ+μ− and B0→π+π−μ+μ− is performed in a data set corresponding to an integrated luminosity of 3.0 fb−1 collected by the LHCb detector in proton-proton collisions at centre-of-mass energies of 7 and 8 TeV. Decay candidates with pion pairs that have invariant mass in the range 0.5-1.3 GeV/c2 and with muon pairs that do not originate from a resonance are considered. The first observation of the decay B0s→π+π−μ+μ− and the first evidence of the decay B0→π+π−μ+μ− are obtained and the branching fractions are measured to be B(B0s→π+π−μ+μ−)=(8.6±1.5(stat)±0.7(syst)±0.7(norm))×10−8 and B(B0→π+π−μ+μ−)=(2.11±0.51(stat)±0.15(syst)±0.16(norm))×10−8, where the third uncertainty is due to the branching fraction of the decay B0→J/ψ(→μ+μ−)K∗(890)0(→K+π−), used as a normalisation