1,577 research outputs found

    Combinations of β-lactam or aminoglycoside antibiotics with plectasin are synergistic against methicillin-sensitive and methicillin-resistant Staphylococcus aureus.

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    Bacterial infections remain the leading killer worldwide which is worsened by the continuous emergence of antibiotic resistance. In particular, methicillin-sensitive (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) are prevalent and the latter can be difficult to treat. The traditional strategy of novel therapeutic drug development inevitably leads to emergence of resistant strains, rendering the new drugs ineffective. Therefore, rejuvenating the therapeutic potentials of existing antibiotics offers an attractive novel strategy. Plectasin, a defensin antimicrobial peptide, potentiates the activities of other antibiotics such as β-lactams, aminoglycosides and glycopeptides against MSSA and MRSA. We performed in vitro and in vivo investigations to test against genetically diverse clinical isolates of MSSA (n = 101) and MRSA (n = 115). Minimum inhibitory concentrations (MIC) were determined by the broth microdilution method. The effects of combining plectasin with β-lactams, aminoglycosides and glycopeptides were examined using the chequerboard method and time kill curves. A murine neutropenic thigh model and a murine peritoneal infection model were used to test the effect of combination in vivo. Determined by factional inhibitory concentration index (FICI), plectasin in combination with aminoglycosides (gentamicin, neomycin or amikacin) displayed synergistic effects in 76-78% of MSSA and MRSA. A similar synergistic response was observed when plectasin was combined with β-lactams (penicillin, amoxicillin or flucloxacillin) in 87-89% of MSSA and MRSA. Interestingly, no such interaction was observed when plectasin was paired with vancomycin. Time kill analysis also demonstrated significant synergistic activities when plectasin was combined with amoxicillin, gentamicin or neomycin. In the murine models, plectasin at doses as low as 8 mg/kg augmented the activities of amoxicillin and gentamicin in successful treatment of MSSA and MRSA infections. We demonstrated that plectasin strongly rejuvenates the therapeutic potencies of existing antibiotics in vitro and in vivo. This is a novel strategy that can have major clinical implications in our fight against bacterial infections

    Natural Inflation: Particle Physics Models, Power Law Spectra for Large Scale Structure, and Constraints from COBE

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    A pseudo-Nambu-Goldstone boson, with a potential of the form V(ϕ)=Λ4[1±cos(ϕ/f)],naturallygivesrisetoinflationifV(\phi) = \Lambda^4[1 \pm \cos(\phi/f)], naturally gives rise to inflation if f \sim M_{Pl}and and \Lambda \sim M_{GUT}.Weshowhowthiscanariseintechnicolorlikeandsuperstringmodels,andworkoutanexplicitstringexampleinthecontextofmultiplegauginocondensationmodels.Westudythecosmologyofthismodelindetail,andfindthatsufficientreheatingtoensurethatbaryogenesiscantakeplacerequires. We show how this can arise in technicolor-like and superstring models, and work out an explicit string example in the context of multiple gaugino condensation models. We study the cosmology of this model in detail, and find that sufficient reheating to ensure that baryogenesis can take place requires f > 0.3 M_{Pl}.Theprimordialdensityfluctuationspectrumgeneratedisanonscaleinvariantpowerlaw,. The primordial density fluctuation spectrum generated is a non-scale-invariant power law, P(k) \propto k^{n_s},with, with n_s \simeq 1 - (M^2_{Pl}/8\pi f^2),leadingtomorepoweronlargelengthscalesthanthe, leading to more power on large length scales than the n_s = 1HarrisonZeldovichspectrum.ThestandardCDMmodelwith Harrison-Zeldovich spectrum. The standard CDM model with 0 \la n_s \la 0.6-0.7couldinprincipleexplainthelargescaleclusteringobservedintheAPMandIRASgalaxysurveysaswellaslargescaleflows,buttheCOBEmicrowaveanisotropyimpliessuchlowamplitudes(orhighbiasfactors, could in principle explain the large-scale clustering observed in the APM and IRAS galaxy surveys as well as large-scale flows, but the COBE microwave anisotropy implies such low amplitudes (or high bias factors, b>2)fortheseCDMmodelsthatgalaxyformationoccurstoolatetobeviable;combiningCOBEwithsufficientlyearlygalaxyformationorthelargescaleflowsleadsto) for these CDM models that galaxy formation occurs too late to be viable; combining COBE with sufficiently early galaxy formation or the large-scale flows leads to n_s >0.6,or, or f > 0.3 M_{Pl}aswell.Forextendedandpowerlawinflationmodels,thisconstraintiseventighter, as well. For extended and power law inflation models, this constraint is even tighter, n_s > 0.7$; combined with other bounds on large bubbles in extended inflation, this leaves little room for most extended models.Comment: 42 pages, (12 figures not included but available from the authors

    Maximum Likelihood Analysis of Clusters of Ultra-High Energy Cosmic Rays

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    We present a numerical code designed to conduct a likelihood analysis for clusters of nucleons above 10**19 eV originating from discrete astrophysical sources such as powerful radio galaxies, gamma-ray bursts or topological defects. The code simulates the propagation of nucleons in a large-scale magnetic field and constructs the likelihood of a given observed event cluster as a function of the average time delay due to deflection in the magnetic field, the source activity time scale, the total fluence of the source, and the power law index of the particle injection spectrum. Other parameters such as the coherence length and the power spectrum of the magnetic field are also considered. We apply it to the three pairs of events above 4X10**19 eV recently reported by the Akeno Giant Air Shower Array (AGASA) experiment, assuming that these pairs were caused by nucleon primaries which originated from a common source. Although current data are too sparse to fully constrain each of the parameters considered, and/or to discriminate models of the origin of ultra-high energy cosmic rays, several tendencies are indicated. If the clustering suggested by AGASA is real, next generation experiments with their increased exposure should detect more than 10 particles per source over a few years and our method will put strong constraints on both the large-scale magnetic field parameters and the nature of these sources.Comment: 11 latex pages, 8 postscript figures included, uses revtex.sty in two-column format and epsf.sty. Submitted to Physical Review

    Dose-associated changes in safety and efficacy parameters observed in a 24-week maintenance trial of olanzapine long-acting injection in patients with schizophrenia

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    <p>Abstract</p> <p>Background</p> <p>In a recently published 24-week maintenance study of olanzapine long-acting injection (LAI) in schizophrenia (Kane et al., 2010), apparent dose-associated changes were noted in both efficacy and safety parameters. To help clinicians balance safety and efficacy when choosing a dose of olanzapine LAI, we further studied these changes.</p> <p>Methods</p> <p>Outpatients with schizophrenia who had maintained stability on open-label oral olanzapine for 4 to 8 weeks were randomly assigned to "low" (150 mg/2 weeks; N = 140), "medium" (405 mg/4 weeks; N = 318), or "high" (300 mg/2 weeks; N = 141) dosages of olanzapine LAI for 24 weeks. Potential relationships between dose and several safety or efficacy measures were examined via regression analysis, the Jonckheere-Terpstra test (continuous data), or the Cochran-Armitage test (categorical data).</p> <p>Results</p> <p>Safety parameters statistically significantly related to dose were mean weight change (low: +0.67 [SD = 4.38], medium: +0.89 [SD = 3.87], high: +1.70 [SD = 4.14] kg, p = .024; effect size [ES] = 0.264 high vs. low dose), mean change in prolactin (low: -5.61 [SD = 12.49], medium: -2.76 [SD = 19.02]), high: +3.58 [SD = 33.78] μg/L, p = .001; ES = 0.410 high vs. low dose), fasting triglycerides change from normal at baseline to high (low: 3.2%, medium: 6.0%, high: 18.9%, p = .001; NNT = 7 high vs. low dose) and fasting high-density lipoprotein cholesterol change from normal at baseline to low (low: 13.8%, medium: 19.6%, high: 30.7%, p = .019; NNT = 6 high vs. low dose). Efficacy measures significantly related to dose included Positive and Negative Syndrome Scale total score mean change (low: +2.66 [SD = 14.95], medium: -0.09 [SD = 13.47], high: -2.19 [SD = 13.11], p <.01; ES = 0.356 high vs. low dose), relapse rate (low: 16%, medium: 10%, high: 5%, p = .003; NNT = 9 high vs. low dose), all-cause discontinuation rate (low: 36%, medium: 30%, high: 24%, p = .037; NNT = 9 high vs. low dose), and rate of discontinuation due to efficacy-related reasons (low: 20%, medium: 14%, high: 6%, p <.001). Time to all-cause discontinuation (p = .035) and time to relapse (p = .005) were also significantly related to dose.</p> <p>Conclusions</p> <p>Analyses of several safety and efficacy parameters revealed significant associations with dose of olanzapine LAI, with the highest dose generally showing greater efficacy as well as greater adverse changes in metabolic safety measures. When considering olanzapine LAI, as with all antipsychotics, it is important to carefully consider the potential benefits and risks for an individual patient.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00088491">NCT00088491</a></p

    C-Band All-Sky Survey (C-BASS): Simulated parametric fitting in single pixels in total intensity and polarization

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    The cosmic microwave background (CMB) B-mode signal is potentially weaker than the diffuse Galactic foregrounds over most of the sky at any frequency. A common method of separating the CMB from these foregrounds is via pixel-based parametric-model fitting. There are not currently enough all-sky maps to fit anything more than the most simple models of the sky. By simulating the emission in seven representative pixels, we demonstrate that the inclusion of a 5 GHz data point allows for more complex models of low-frequency foregrounds to be fitted than at present. It is shown that the inclusion of the C-BASS data will significantly reduce the uncertainties in a number of key parameters in the modelling of both the galactic foregrounds and the CMB. The extra data allow estimates of the synchrotron spectral index to be constrained much more strongly than is presently possible, with corresponding improvements in the accuracy of the recovery of the CMB amplitude. However, we show that to place good limits on models of the synchrotron spectral curvature will require additional low-frequency data

    The C-Band All-Sky Survey (C-BASS): Simulated parametric fitting in single pixels in total intensity and polarization

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    The cosmic microwave background (CMB) B-mode signal is potentially weaker than the diffuse Galactic foregrounds over most of the sky at any frequency. A common method of separating the CMB from these foregrounds is via pixel-based parametric-model fitting. There are not currently enough all-sky maps to fit anything more than the most simple models of the sky. By simulating the emission in seven representative pixels, we demonstrate that the inclusion of a 5 GHz data point allows for more complex models of low-frequency foregrounds to be fitted than at present. It is shown that the inclusion of the C-BASS data will significantly reduce the uncertainties in a number of key parameters in the modelling of both the galactic foregrounds and the CMB. The extra data allow estimates of the synchrotron spectral index to be constrained much more strongly than is presently possible, with corresponding improvements in the accuracy of the recovery of the CMB amplitude. However, we show that to place good limits on models of the synchrotron spectral curvature will require additional low-frequency data

    The wide-field, multiplexed, spectroscopic facility WEAVE: Survey design, overview, and simulated implementation

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    © 2023 The Author(s) . Published by Oxford University Press on behalf of Royal Astronomical Society. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/WEAVE, the new wide-field, massively multiplexed spectroscopic survey facility for the William Herschel Telescope, will see first light in late 2022. WEAVE comprises a new 2-degree field-of-view prime-focus corrector system, a nearly 1000-multiplex fibre positioner, 20 individually deployable 'mini' integral field units (IFUs), and a single large IFU. These fibre systems feed a dual-beam spectrograph covering the wavelength range 366-959\,nm at R5000R\sim5000, or two shorter ranges at R20000R\sim20\,000. After summarising the design and implementation of WEAVE and its data systems, we present the organisation, science drivers and design of a five- to seven-year programme of eight individual surveys to: (i) study our Galaxy's origins by completing Gaia's phase-space information, providing metallicities to its limiting magnitude for \sim3 million stars and detailed abundances for 1.5\sim1.5 million brighter field and open-cluster stars; (ii) survey 0.4\sim0.4 million Galactic-plane OBA stars, young stellar objects and nearby gas to understand the evolution of young stars and their environments; (iii) perform an extensive spectral survey of white dwarfs; (iv) survey 400\sim400 neutral-hydrogen-selected galaxies with the IFUs; (v) study properties and kinematics of stellar populations and ionised gas in z1z1 million spectra of LOFAR-selected radio sources; (viii) trace structures using intergalactic/circumgalactic gas at z>2z>2. Finally, we describe the WEAVE Operational Rehearsals using the WEAVE Simulator.Peer reviewe
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