120 research outputs found
Purine nucleosides interfere with c-di-AMP levels and act as adjuvants to re-sensitize MRSA to β-lactam antibiotics
The purine-derived signaling molecules c-di-AMP and (p)ppGpp control mecA/PBP2a-mediated β-lactam resistance in methicillin-resistant Staphylococcus aureus (MRSA) raise the possibility that purine availability can control antibiotic susceptibility. Consistent with this, exogenous guanosine and xanthosine, which are fluxed through the GTP branch of purine biosynthesis, were shown to significantly reduce MRSA β-lactam resistance. In contrast, adenosine (fluxed to ATP) significantly increased oxacillin resistance, whereas inosine (which can be fluxed to ATP and GTP via hypoxanthine) only marginally increased oxacillin susceptibility. Furthermore, mutations that interfere with de novo purine synthesis (pur operon), transport (NupG, PbuG, PbuX) and the salvage pathway (DeoD2, Hpt) increased β-lactam resistance in MRSA strain JE2. Increased resistance of a nupG mutant was not significantly reversed by guanosine, indicating that NupG is required for guanosine transport, which is required to reduce β-lactam resistance. Suppressor mutants resistant to oxacillin/guanosine combinations contained several purine salvage pathway mutations, including nupG and hpt. Guanosine significantly increased cell size and reduced levels of c-di-AMP, while inactivation of GdpP, the c-di-AMP phosphodiesterase negated the impact of guanosine on β-lactam susceptibility. PBP2a expression was unaffected in nupG or deoD2 mutants, suggesting that guanosine-induced β-lactam susceptibility may result from dysfunctional c-di-AMP-dependent osmoregulation. These data reveal the therapeutic potential of purine nucleosides, as β-lactam adjuvants that interfere with the normal activation of c-di-AMP are required for high-level β-lactam resistance in MRSA.
IMPORTANCE The clinical burden of infections caused by antimicrobial resistant (AMR) pathogens is a leading threat to public health. Maintaining the effectiveness of existing antimicrobial drugs or finding ways to reintroduce drugs to which resistance is widespread is an important part of efforts to address the AMR crisis. Predominantly, the safest and most effective class of antibiotics are the β-lactams, which are no longer effective against methicillin-resistant Staphylococcus aureus (MRSA). Here, we report that the purine nucleosides guanosine and xanthosine have potent activity as adjuvants that can resensitize MRSA to oxacillin and other β-lactam antibiotics. Mechanistically, exposure of MRSA to these nucleosides significantly reduced the levels of the cyclic dinucleotide c-di-AMP, which is required for β-lactam resistance. Drugs derived from nucleotides are widely used in the treatment of cancer and viral infections highlighting the clinical potential of using purine nucleosides to restore or enhance the therapeutic effectiveness of β-lactams against MRSA and potentially other AMR pathogens
Diffuse inverse Compton and synchrotron emission from dark matter annihilations in galactic satellites
Annihilating dark matter particles produce roughly as much power in electrons
and positrons as in gamma ray photons. The charged particles lose essentially
all of their energy to inverse Compton and synchrotron processes in the
galactic environment. We discuss the diffuse signature of dark matter
annihilations in satellites of the Milky Way (which may be optically dark with
few or no stars), providing a tail of emission trailing the satellite in its
orbit. Inverse Compton processes provide X-rays and gamma rays, and synchrotron
emission at radio wavelengths might be seen. We discuss the possibility of
detecting these signals with current and future observations, in particular
EGRET and GLAST for the gamma rays.Comment: 13 pages, 5 figure
Quasars and their host galaxies
This review attempts to describe developments in the fields of quasar and
quasar host galaxies in the past five. In this time period, the Sloan and 2dF
quasar surveys have added several tens of thousands of quasars, with Sloan
quasars being found to z>6. Obscured, or partially obscured quasars have begun
to be found in significant numbers. Black hole mass estimates for quasars, and
our confidence in them, have improved significantly, allowing a start on
relating quasar properties such as radio jet power to fundamental parameters of
the quasar such as black hole mass and accretion rate. Quasar host galaxy
studies have allowed us to find and characterize the host galaxies of quasars
to z>2. Despite these developments, many questions remain unresolved, in
particular the origin of the close relationship between black hole mass and
galaxy bulge mass/velocity dispersion seen in local galaxies.Comment: Review article, to appear in Astrophysics Update
Constraints on Dark Matter Annihilation in Clusters of Galaxies with the Fermi Large Area Telescope
Nearby clusters and groups of galaxies are potentially bright sources of
high-energy gamma-ray emission resulting from the pair-annihilation of dark
matter particles. However, no significant gamma-ray emission has been detected
so far from clusters in the first 11 months of observations with the Fermi
Large Area Telescope. We interpret this non-detection in terms of constraints
on dark matter particle properties. In particular for leptonic annihilation
final states and particle masses greater than ~200 GeV, gamma-ray emission from
inverse Compton scattering of CMB photons is expected to dominate the dark
matter annihilation signal from clusters, and our gamma-ray limits exclude
large regions of the parameter space that would give a good fit to the recent
anomalous Pamela and Fermi-LAT electron-positron measurements. We also present
constraints on the annihilation of more standard dark matter candidates, such
as the lightest neutralino of supersymmetric models. The constraints are
particularly strong when including the fact that clusters are known to contain
substructure at least on galaxy scales, increasing the expected gamma-ray flux
by a factor of ~5 over a smooth-halo assumption. We also explore the effect of
uncertainties in cluster dark matter density profiles, finding a systematic
uncertainty in the constraints of roughly a factor of two, but similar overall
conclusions. In this work, we focus on deriving limits on dark matter models; a
more general consideration of the Fermi-LAT data on clusters and clusters as
gamma-ray sources is forthcoming.Comment: accepted to JCAP, Corresponding authors: T.E. Jeltema and S. Profumo,
minor revisions to be consistent with accepted versio
Exploring the mechanisms of renoprotection against progressive glomerulosclerosis
In this review, I introduce the strategy developed by our laboratory to explore the mechanisms of renoprotection against progressive glomerulosclerosis leading to renal death. First, I describe the experimental rat model in which disturbances of vascular regeneration and glomerular hemodynamics lead to irreversible glomerulosclerosis. Second, I discuss the possible mechanisms determining the progression of glomerulosclerosis and introduce a new imaging system based on intravital confocal laser scanning microscopy. Third, I provide an in-depth review of the regulatory glomerular hemodynamics at the cellular and molecular levels while focusing on the pivotal role of Ca2+-dependent gap junctional intercellular communication in coordinating the behavior of mesangial cells. Last, I show that local delivery of renoprotective agents, in combination with diagnostic imaging of the renal microvasculature, allows the evaluation of the therapeutic effects of angiotensin II receptor and cyclooxygenase activity local blockade on the progression of glomerulosclerosis, which would otherwise lead to renal death
Physical activity attenuates the influence of FTO variants on obesity risk: A meta-analysis of 218,166 adults and 19,268 children
Background: The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268). Methods and Findings: All studies identified to have data on the FTO rs9939609 variant (or any proxy [r2>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20-1.26), but PA attenuated this effect (pinteraction= 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio = 1.22/allele, 95% CI 1.19-1.25) than in the inactive group (odds ratio = 1.30/allele, 95% CI 1.24-1.36). No such interaction was found in children and adolescents. Concl
The On-orbit Calibrations for the Fermi Large Area Telescope
The Large Area Telescope (LAT) on--board the Fermi Gamma ray Space Telescope
began its on--orbit operations on June 23, 2008. Calibrations, defined in a
generic sense, correspond to synchronization of trigger signals, optimization
of delays for latching data, determination of detector thresholds, gains and
responses, evaluation of the perimeter of the South Atlantic Anomaly (SAA),
measurements of live time, of absolute time, and internal and spacecraft
boresight alignments. Here we describe on orbit calibration results obtained
using known astrophysical sources, galactic cosmic rays, and charge injection
into the front-end electronics of each detector. Instrument response functions
will be described in a separate publication. This paper demonstrates the
stability of calibrations and describes minor changes observed since launch.
These results have been used to calibrate the LAT datasets to be publicly
released in August 2009.Comment: 60 pages, 34 figures, submitted to Astroparticle Physic
Comparison of the antioxidant potential of antiparkinsonian drugs in different in vitro models
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