Novel, synergistic antifungal combinations that target translation fidelity

There is an unmet need for new antifungal or fungicide treatments, as resistance to existing treatments grows. Combination treatments help to combat resistance. Here we develop a novel, effective target for combination antifungal therapy. Different aminoglycoside antibiotics combined with different sulphate-transport inhibitors produced strong, synergistic growth-inhibition of several fungi. Combinations decreased the respective MICs by ≥8 fold. Synergy was suppressed in yeast mutants resistant to effects of sulphate-mimetics (like chromate or molybdate) on sulphate transport. By different mechanisms, aminoglycosides and inhibition of sulphate transport cause errors in mRNA translation. The mistranslation rate was stimulated up to 10-fold when the agents were used in combination, consistent with this being the mode of synergistic action. A range of undesirable fungi were susceptible to synergistic inhibition by the combinations, including the human pathogens Candida albicans, C. glabrata and Cryptococcus neoformans, the food spoilage organism Zygosaccharomyces bailii and the phytopathogens Rhizoctonia solani and Zymoseptoria tritici. There was some specificity as certain fungi were unaffected. There was no synergy against bacterial or mammalian cells. The results indicate that translation fidelity is a promising new target for combinatorial treatment of undesirable fungi, the combinations requiring substantially decreased doses of active components compared to each agent alone

Differential branching fraction and angular analysis of Λb0→Λμ+μ−\Lambda^{0}_{b} \rightarrow \Lambda \mu^+\mu^- decays

The differential branching fraction of the rare decay $\Lambda^{0}_{b} \rightarrow \Lambda \mu^+\mu^-$ is measured as a function of $q^{2}$, the square of the dimuon invariant mass. The analysis is performed using proton-proton collision data, corresponding to an integrated luminosity of 3.0 \mbox{ fb}^{-1}, collected by the LHCb experiment. Evidence of signal is observed in the $q^2$ region below the square of the $J/\psi$ mass. Integrating over 15 < q^{2} < 20 \mbox{ GeV}^2/c^4 the branching fraction is measured as d\mathcal{B}(\Lambda^{0}_{b} \rightarrow \Lambda \mu^+\mu^-)/dq^2 = (1.18 ^{+ 0.09} _{-0.08} \pm 0.03 \pm 0.27) \times 10^{-7} ( \mbox{GeV}^{2}/c^{4})^{-1}, where the uncertainties are statistical, systematic and due to the normalisation mode, $\Lambda^{0}_{b} \rightarrow J/\psi \Lambda$, respectively. In the $q^2$ intervals where the signal is observed, angular distributions are studied and the forward-backward asymmetries in the dimuon ($A^{l}_{\rm FB}$) and hadron ($A^{h}_{\rm FB}$) systems are measured for the first time. In the range 15 < q^2 < 20 \mbox{ GeV}^2/c^4 they are found to be A^{l}_{\rm FB} = -0.05 \pm 0.09 \mbox{ (stat)} \pm 0.03 \mbox{ (syst)} and A^{h}_{\rm FB} = -0.29 \pm 0.07 \mbox{ (stat)} \pm 0.03 \mbox{ (syst)}.Comment: 27 pages, 10 figures, Erratum adde

Bayesian molecular clock dating of species divergences in the genomics era

It has been five decades since the proposal of the molecular clock hypothesis, which states that the rate of evolution at the molecular level is constant through time and among species. This hypothesis has become a powerful tool in evolutionary biology, making it possible to use molecular sequences to estimate the geological ages of species divergence events. With recent advances in Bayesian clock dating methodology and the explosive accumulation of genetic sequence data, molecular clock dating has found widespread applications, from tracking virus pandemics, to studying the macroevolutionary process of speciation and extinction, to estimating a timescale for Life on Earth

Study of B0(s)→K0Sh+h′− decays with first observation of B0s→K0SK±π∓ and B0s→K0Sπ+π−

A search for charmless three-body decays of B 0 and B0s mesons with a K0S meson in the final state is performed using the pp collision data, corresponding to an integrated luminosity of 1.0 fb−1, collected at a centre-of-mass energy of 7 TeV recorded by the LHCb experiment. Branching fractions of the B0(s)→K0Sh+h′− decay modes (h (′) = π, K), relative to the well measured B0→K0Sπ+π− decay, are obtained. First observation of the decay modes B0s→K0SK±π∓ and B0s→K0Sπ+π− and confirmation of the decay B0→K0SK±π∓ are reported. The following relative branching fraction measurements or limits are obtained B(B0→K0SK±π∓)B(B0→K0Sπ+π−)=0.128±0.017(stat.)±0.009(syst.), B(B0→K0SK+K−)B(B0→K0Sπ+π−)=0.385±0.031(stat.)±0.023(syst.), B(B0s→K0Sπ+π−)B(B0→K0Sπ+π−)=0.29±0.06(stat.)±0.03(syst.)±0.02(fs/fd), B(B0s→K0SK±π∓)B(B0→K0Sπ+π−)=1.48±0.12(stat.)±0.08(syst.)±0.12(fs/fd)B(B0s→K0SK+K−)B(B0→K0Sπ+π−)∈[0.004;0.068]at90%CL

Study of Bc+B_c^+ decays to the K+K−π+K^+K^-\pi^+ final state and evidence for the decay Bc+→χc0π+B_c^+\to\chi_{c0}\pi^+

A study of $B_c^+\to K^+K^-\pi^+$ decays is performed for the first time using data corresponding to an integrated luminosity of 3.0 $\mathrm{fb}^{-1}$ collected by the LHCb experiment in $pp$ collisions at centre-of-mass energies of $7$ and $8$ TeV. Evidence for the decay $B_c^+\to\chi_{c0}(\to K^+K^-)\pi^+$ is reported with a significance of 4.0 standard deviations, resulting in the measurement of $\frac{\sigma(B_c^+)}{\sigma(B^+)}\times\mathcal{B}(B_c^+\to\chi_{c0}\pi^+)$ to be $(9.8^{+3.4}_{-3.0}(\mathrm{stat})\pm 0.8(\mathrm{syst}))\times 10^{-6}$. Here $\mathcal{B}$ denotes a branching fraction while $\sigma(B_c^+)$ and $\sigma(B^+)$ are the production cross-sections for $B_c^+$ and $B^+$ mesons. An indication of $\bar b c$ weak annihilation is found for the region $m(K^-\pi^+)<1.834\mathrm{\,Ge\kern -0.1em V\!/}c^2$, with a significance of 2.4 standard deviations.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2016-022.html, link to supplemental material inserted in the reference

Interaction of Polysialic Acid with CCL21 Regulates the Migratory Capacity of Human Dendritic Cells

Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs). Immature DCs (iDCs) are situated in the periphery where they capture pathogen. Subsequently, they migrate as mature DCs (mDCs) to draining lymph nodes to activate T cells. CCR7 and CCL21 contribute to the migratory capacity of the DC, but it is not completely understood what molecular requirements are involved. Here we demonstrate that monocyte-derived DCs dramatically change ST8Sia IV expression during maturation, leading to the generation of polysialic acid (polySia). PolySia expression is highly upregulated after 2 days Toll-like receptor-4 (TLR4) triggering. Surprisingly, only immunogenic and not tolerogenic mDCs upregulated polySia expression. Furthermore, we show that polySia expression on DCs is required for CCL21-directed migration, whereby polySia directly captures CCL21. Corresponding to polySia, the expression level of CCR7 is maximal two days after TLR4 triggering. In contrast, although TLR agonists other than LPS induce upregulation of CCR7, they achieve only a moderate polySia expression. In situ we could detect polySia-expressing APCs in the T cell zone of the lymph node and in the deep dermis. Together our results indicate that prolonged TLR4 engagement is required for the generation of polySia-expressing DCs that facilitate CCL21 capture and subsequent CCL21-directed migration

Measuring affective well-being at work using short-form scales : implications for affective structures and participant instructions

Measuring affective well-being in organizational studies has become increasingly widespread, given its association with key work-performance and other markers of organizational functioning. As such, researchers and policy-makers need to be confident that well-being measures are valid, reliable and robust. To reduce the burden on participants in applied settings, short-form measures of affective well-being are proving popular. However, these scales are seldom validated as standalone, comprehensive measures in their own right. In this article, we used a short-form measure of affective well-being with 10 items: the Daniels five-factor measure of affective well-being (D-FAW). In Study 1, across six applied sample groups (N = 2624), we found that the factor structure of the short-form D-FAW is robust when issued as a standalone measure, and that it should be scored differently depending on the participant instruction used. When participant instructions focus on now or today, then affect is best represented by five discrete emotion factors. When participant instructions focus on the past week, then affect is best represented by two or three mood-based factors. In Study 2 (N = 39), we found good construct convergent validity of short-form D-FAW with another widely used scale (PANAS). Implications for the measurement and structure of affect are discussed

Observation of Bc+ →j /ψD (∗)K (∗) decays

A search for the decays B+c→J/ψD(*)0K+ and B+c→J/ψD(*)+K*0 is performed with data collected at the LHCb experiment corresponding to an integrated luminosity of 3 fb−1. The decays B+c→J/ψ0K+ and B+c→J/ψD*0K+ are observed for the first time, while first evidence is reported for the B+c→JψD*+K*0 and B+c→J/ψD+K*0 decays. The branching fractions of these decays are determined relative to the B+c→J/ψπ+ decay. The B+c mass is measured, using the J/ψD0K+ final state, to be 6274.28±1.40(stat)±0.32(syst) MeV/c2. This is the most precise single measurement of the B+c mass to date

Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection

BACKGROUND Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively. METHODS We conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population. RESULTS In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, −10.1 percentage points; 95% confidence interval [CI], −15.9 to −4.3; P<0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference, −9.9 percentage points; 95% CI, −15.5 to −4.3; P<0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs. 28% [109 of 395]; adjusted difference, −11.6 percentage points; 95% CI, −17.4 to −5.9; P<0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, −10.7 percentage points; 95% CI, −16.4 to −5.1; P<0.001). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea. CONCLUSIONS Among participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. (Funded by Merck; MODIFY I and MODIFY II ClinicalTrials.gov numbers, NCT01241552 and NCT01513239.

Does public awareness increase support for invasive species management?:Promising evidence across taxa and landscape types

Management of invasive species often raises substantial conflicts of interest. Since such conflicts can hamper proposed management actions, managers, decision makers and researchers increasingly recognize the need to consider the social dimensions of invasive species management. In this exploratory study, we aimed (1) to explore whether species’ taxonomic position (i.e. animals vs. plants) and type of invaded landscape (i.e. urban vs. nonurban) might influence public perception about the management of invasive species, and (2) to assess the potential of public awareness to increase public support for invasive species management. We reviewed the scientific literature on the conflicts of interest around the management of alien species and administered two-phased questionnaires (before and after providing information on the target species and its management) to members of the public in South Africa and the UK (n = 240). Our review suggests that lack of public support for the management of invasive animals in both urban and non-urban areas derives mainly from moralistic value disagreements, while the management of invasive plants in non-urban areas mostly causes conflicts based on utilitarian value disagreements. Despite these general trends, conflicts are context dependent and can originate from a wide variety of different views. Notably, informing the public about the invasive status and negative impacts of the species targeted for management appeared to increase public support for the management actions. Therefore, our results align with the view that increased public awareness might increase the public support for the management of invasive species, independent of taxonomic position and type of landscape