Molecular bases determining daptomycin resistance-mediated re-sensitization to β-lactams ("see-saw effect") in MRSA

Antimicrobial resistance is recognized as one of the principal threats to public health worldwide, yet the problem is increasing. Methicillin-resistant Staphylococcus aureus (MRSA) are among the most difficult to treat in clinical settings due to the resistance to nearly all available antibiotics. The cyclic anionic lipopeptide antibiotic Daptomycin (DAP) is the clinical mainstay of anti-MRSA therapy. Decreased susceptibility to DAP (DAPR) reported in MRSA is frequently accompanied with a paradoxical decrease in β-lactam resistance, a process known as the "see-saw" effect. Despite the observed discordance in resistance phenotypes, the combination of DAP/β-lactams has been proven clinically effective for the prevention and treatment of infections due to DAPR-MRSA strains. However, the mechanisms underlying the interactions between DAP and β-lactams are largely unknown. Herein, we studied the role of DAP-induced mutated mprF in β-lactam sensitization and its involvement in the effective killing by the DAP/OXA combination. DAP/OXA-mediated effects resulted in cell-wall perturbations including changes in peptidoglycan (PG) insertion, penicillin-binding protein 2 (PBP2) delocalization and reduced membrane amounts of penicillin-binding protein 2a (PBP2a) contents despite increased transcription of mecA through mec regulatory elements. We have found that the VraSR sensor-regulator is a key component of DAP resistance, triggering mutated mprF-mediated cell membrane (CM) modifications and resulting in impairment of PrsA location and chaperone functions, both essentials for PBP2a maturation, the key determinant of β-lactam resistance. These observations provide first time evidence that synergistic effects between DAP and β-lactams involve PrsA post-transcriptional regulation of CM-associated PBP2a

Evolving MRSA : high-level β-lactam resistance in Staphylococcus aureus is associated with RNA Polymerase alterations and fine tuning of gene expression

Most clinical MRSA (methicillin-resistant S. aureus) isolates exhibit low-level β-lactam resistance (oxacillin MIC 2–4 μg/ml) due to the acquisition of a novel penicillin binding protein (PBP2A), encoded by mecA. However, strains can evolve high-level resistance (oxacillin MIC ≥256 μg/ml) by an unknown mechanism. Here we have developed a robust system to explore the basis of the evolution of high-level resistance by inserting mecA into the chromosome of the methicillin-sensitive S. aureus SH1000. Low-level mecA-dependent oxacillin resistance was associated with increased expression of anaerobic respiratory and fermentative genes. High-level resistant derivatives had acquired mutations in either rpoB (RNA polymerase subunit β) or rpoC (RNA polymerase subunit β’) and these mutations were shown to be responsible for the observed resistance phenotype. Analysis of rpoB and rpoC mutants revealed decreased growth rates in the absence of antibiotic, and alterations to, transcription elongation. The rpoB and rpoC mutations resulted in decreased expression to parental levels, of anaerobic respiratory and fermentative genes and specific upregulation of 11 genes including mecA. There was however no direct correlation between resistance and the amount of PBP2A. A mutational analysis of the differentially expressed genes revealed that a member of the S. aureus Type VII secretion system is required for high level resistance. Interestingly, the genomes of two of the high level resistant evolved strains also contained missense mutations in this same locus. Finally, the set of genetically matched strains revealed that high level antibiotic resistance does not incur a significant fitness cost during pathogenesis. Our analysis demonstrates the complex interplay between antibiotic resistance mechanisms and core cell physiology, providing new insight into how such important resistance properties evolve

Adult attachment style across individuals and role-relationships: Avoidance is relationship-specific, but anxiety shows greater generalizability

A generalisability study examined the hypotheses that avoidant attachment, reflecting the representation of others, should be more relationship-specific (vary across relationships more than across individuals), while attachment anxiety, reflecting self-representation, should be more generalisable across a person’s relationships. College students responded to 6-item questionnaire measures of these variables for 5 relationships (mother, father, best same-gender friend, romantic partner or best opposite-gender friend, other close person), on 3 (N = 120) or 2 (N = 77) occasions separated by a few weeks. Results supported the hypotheses, with the person variance component being larger than the relationship-specific component for anxiety, and the opposite happening for avoidance. Anxiety therefore seems not to be as relationship-specific as previous research suggested. Possible reasons for discrepancies between the current and previous studies are discussed

Anthropogenic Space Weather

Anthropogenic effects on the space environment started in the late 19th century and reached their peak in the 1960s when high-altitude nuclear explosions were carried out by the USA and the Soviet Union. These explosions created artificial radiation belts near Earth that resulted in major damages to several satellites. Another, unexpected impact of the high-altitude nuclear tests was the electromagnetic pulse (EMP) that can have devastating effects over a large geographic area (as large as the continental United States). Other anthropogenic impacts on the space environment include chemical release ex- periments, high-frequency wave heating of the ionosphere and the interaction of VLF waves with the radiation belts. This paper reviews the fundamental physical process behind these phenomena and discusses the observations of their impacts.Comment: 71 pages, 35 figure

Cosmological evolution of interacting dark energy in Lorentz violation

The cosmological evolution of an interacting scalar field model in which the scalar field interacts with dark matter, radiation, and baryon via Lorentz violation is investigated. We propose a model of interaction through the effective coupling $\bar{\beta}$. Using dynamical system analysis, we study the linear dynamics of an interacting model and show that the dynamics of critical points are completely controlled by two parameters. Some results can be mentioned as follows. Firstly, the sequence of radiation, the dark matter, and the scalar field dark energy exist and baryons are sub dominant. Secondly, the model also allows the possibility of having a universe in the phantom phase with constant potential. Thirdly, the effective gravitational constant varies with respect to time through $\bar{\beta}$. In particular, we consider a simple case where $\bar{\beta}$ has a quadratic form and has a good agreement with the modified $\Lambda$CDM and quintessence models. Finally, we also calculate the first post--Newtonian parameters for our model.Comment: 14 pages, published versio

Toward an internally consistent astronomical distance scale

Accurate astronomical distance determination is crucial for all fields in astrophysics, from Galactic to cosmological scales. Despite, or perhaps because of, significant efforts to determine accurate distances, using a wide range of methods, tracers, and techniques, an internally consistent astronomical distance framework has not yet been established. We review current efforts to homogenize the Local Group's distance framework, with particular emphasis on the potential of RR Lyrae stars as distance indicators, and attempt to extend this in an internally consistent manner to cosmological distances. Calibration based on Type Ia supernovae and distance determinations based on gravitational lensing represent particularly promising approaches. We provide a positive outlook to improvements to the status quo expected from future surveys, missions, and facilities. Astronomical distance determination has clearly reached maturity and near-consistency.Comment: Review article, 59 pages (4 figures); Space Science Reviews, in press (chapter 8 of a special collection resulting from the May 2016 ISSI-BJ workshop on Astronomical Distance Determination in the Space Age

Search for displaced vertices arising from decays of new heavy particles in 7 TeV pp collisions at ATLAS

We present the results of a search for new, heavy particles that decay at a significant distance from their production point into a final state containing charged hadrons in association with a high-momentum muon. The search is conducted in a pp-collision data sample with a center-of-mass energy of 7 TeV and an integrated luminosity of 33 pb^-1 collected in 2010 by the ATLAS detector operating at the Large Hadron Collider. Production of such particles is expected in various scenarios of physics beyond the standard model. We observe no signal and place limits on the production cross-section of supersymmetric particles in an R-parity-violating scenario as a function of the neutralino lifetime. Limits are presented for different squark and neutralino masses, enabling extension of the limits to a variety of other models.Comment: 8 pages plus author list (20 pages total), 8 figures, 1 table, final version to appear in Physics Letters

Measurement of the polarisation of W bosons produced with large transverse momentum in pp collisions at sqrt(s) = 7 TeV with the ATLAS experiment

This paper describes an analysis of the angular distribution of W->enu and W->munu decays, using data from pp collisions at sqrt(s) = 7 TeV recorded with the ATLAS detector at the LHC in 2010, corresponding to an integrated luminosity of about 35 pb^-1. Using the decay lepton transverse momentum and the missing transverse energy, the W decay angular distribution projected onto the transverse plane is obtained and analysed in terms of helicity fractions f0, fL and fR over two ranges of W transverse momentum (ptw): 35 < ptw < 50 GeV and ptw > 50 GeV. Good agreement is found with theoretical predictions. For ptw > 50 GeV, the values of f0 and fL-fR, averaged over charge and lepton flavour, are measured to be : f0 = 0.127 +/- 0.030 +/- 0.108 and fL-fR = 0.252 +/- 0.017 +/- 0.030, where the first uncertainties are statistical, and the second include all systematic effects.Comment: 19 pages plus author list (34 pages total), 9 figures, 11 tables, revised author list, matches European Journal of Physics C versio

Observation of a new chi_b state in radiative transitions to Upsilon(1S) and Upsilon(2S) at ATLAS

The chi_b(nP) quarkonium states are produced in proton-proton collisions at the Large Hadron Collider (LHC) at sqrt(s) = 7 TeV and recorded by the ATLAS detector. Using a data sample corresponding to an integrated luminosity of 4.4 fb^-1, these states are reconstructed through their radiative decays to Upsilon(1S,2S) with Upsilon->mu+mu-. In addition to the mass peaks corresponding to the decay modes chi_b(1P,2P)->Upsilon(1S)gamma, a new structure centered at a mass of 10.530+/-0.005 (stat.)+/-0.009 (syst.) GeV is also observed, in both the Upsilon(1S)gamma and Upsilon(2S)gamma decay modes. This is interpreted as the chi_b(3P) system.Comment: 5 pages plus author list (18 pages total), 2 figures, 1 table, corrected author list, matches final version in Physical Review Letter

Measurement of the inclusive isolated prompt photon cross-section in pp collisions at sqrt(s)= 7 TeV using 35 pb-1 of ATLAS data

A measurement of the differential cross-section for the inclusive production of isolated prompt photons in pp collisions at a center-of-mass energy sqrt(s) = 7 TeV is presented. The measurement covers the pseudorapidity ranges |eta|<1.37 and 1.52<=|eta|<2.37 in the transverse energy range 45<=E_T<400GeV. The results are based on an integrated luminosity of 35 pb-1, collected with the ATLAS detector at the LHC. The yields of the signal photons are measured using a data-driven technique, based on the observed distribution of the hadronic energy in a narrow cone around the photon candidate and the photon selection criteria. The results are compared with next-to-leading order perturbative QCD calculations and found to be in good agreement over four orders of magnitude in cross-section.Comment: 7 pages plus author list (18 pages total), 2 figures, 4 tables, final version published in Physics Letters