Exploiting Thiol Modifications

Molecular oxygen may be necessary for life but with its beneficial properties comes formation of potentially toxic reactive oxygen species. One of the ways in which bacteria protect themselves is explaine

Resistance to the antimicrobial agent fosmidomycin and an FR900098 prodrug through mutations in the deoxyxylulose phosphate reductoisomerase gene (dxr)

There is a pressing need for new antimicrobial therapies to combat globally important drug-resistant human pathogens, including Plasmodium falciparum malarial parasites, Mycobacterium tuberculosis, and Gram-negative bacteria, including Escherichia coli. These organisms all possess the essential methylerythritol phosphate (MEP) pathway of isoprenoid biosynthesis, which is not found in humans. The first dedicated enzyme of the MEP pathway, 1-deoxy-d-xylulose 5-phosphate reductoisomerase (Dxr), is inhibited by the phosphonic acid antibiotic fosmidomycin and its analogs, including the N-acetyl analog FR900098 and the phosphoryl analog fosfoxacin. In order to identify mutations in dxr that confer resistance to these drugs, a library of E. coli dxr mutants was screened at lethal fosmidomycin doses. The most resistant allele (with the S222T mutation) alters the fosmidomycin-binding site of Dxr. The expression of this resistant allele increases bacterial resistance to fosmidomycin and other fosmidomycin analogs by 10-fold. These observations confirm that the primary cellular target of fosmidomycin is Dxr. Furthermore, cell lines expressing Dxr-S222T will be a powerful tool to confirm the mechanisms of action of future fosmidomycin analogs

Pneumococcal Gene Complex Involved in Resistance to Extracellular Oxidative Stress

Streptococcus pneumoniae is a Gram-positive bacterium which is a member of the normal human nasopharyngeal flora but can also cause serious disease such as pneumonia, bacteremia, and meningitis. Throughout its life cycle, S. pneumoniae is exposed to significant oxidative stress derived from endogenously produced hydrogen peroxide (H2O2) and from the host through the oxidative burst. How S. pneumoniae, an aerotolerant anaerobic bacterium that lacks catalase, protects itself against hydrogen peroxide stress is still unclear. Bioinformatic analysis of its genome identified a hypothetical open reading frame belonging to the thiol-specific antioxidant (TlpA/TSA) family, located in an operon consisting of three open reading frames. For all four strains tested, deletion of the gene resulted in an approximately 10-fold reduction in survival when strains were exposed to external peroxide stress. However, no role for this gene in survival of internal superoxide stress was observed. Mutagenesis and complementation analysis demonstrated that all three genes are necessary and sufficient for protection against oxidative stress. Interestingly, in a competitive index mouse pneumonia model, deletion of the operon had no impact shortly after infection but was detrimental during the later stages of disease. Thus, we have identified a gene complex involved in the protection of S. pneumoniae against external oxidative stress, which plays an important role during invasive disease.

Tests of Lorentz violation in muon antineutrino to electron antineutrino oscillations

A recently developed Standard-Model Extension (SME) formalism for neutrino oscillations that includes Lorentz and CPT violation is used to analyze the sidereal time variation of the neutrino event excess measured by the Liquid Scintillator Neutrino Detector (LSND) experiment. The LSND experiment, performed at Los Alamos National Laboratory, observed an excess, consistent with neutrino oscillations, of ${\bar\nu}_e$ in a beam of ${\bar\nu}_\mu$. It is determined that the LSND oscillation signal is consistent with no sidereal variation. However, there are several combinations of SME coefficients that describe the LSND data; both with and without sidereal variations. The scale of Lorentz and CPT violation extracted from the LSND data is of order $10^{-19}$ GeV for the SME coefficients $a_L$ and $E \times c_L$. This solution for Lorentz and CPT violating neutrino oscillations may be tested by other short baseline neutrino oscillation experiments, such as the MiniBooNE experiment.Comment: 10 pages, 10 figures, 2 tables, uses revtex4 replaced with version to be published in Physical Review D, 11 pages, 11 figures, 2 tables, uses revtex

Borrelia burgdorferi membranes are the primary targets of reactive oxygen species

Spirochetes living in an oxygen-rich environment or when challenged by host immune cells are exposed to reactive oxygen species (ROS). These species can harm/destroy cysteinyl residues, iron-sulphur clusters, DNA and polyunsaturated lipids, leading to inhibition of growth or cell death. Because Borrelia burgdorferi contains no intracellular iron, DNA is most likely not a major target for ROS via Fenton reaction. In support of this, growth of B. burgdorferi in the presence of 5 mM H2O2 had no effect on the DNA mutation rate (spontaneous coumermycin A1 resistance), and cells treated with 10 mM t-butyl hydroperoxide or 10 mM H2O2 show no increase in DNA damage. Unlike most bacteria, B. burgdorferi incorporates ROS-susceptible polyunsaturated fatty acids from the environment into their membranes. Analysis of lipoxidase-treated B. burgdorferi cells by Electron Microscopy showed significant irregularities indicative of membrane damage. Fatty acid analysis of cells treated with lipoxidase indicated that host-derived linoleic acid had been dramatically reduced (50-fold) in these cells, with a corresponding increase in the levels of malondialdehyde by-product (fourfold). These data suggest that B. burgdorferi membrane lipids are targets for attack by ROS encountered in the various stages of the infective cycle

The OscSNS White Paper

There exists a need to address and resolve the growing evidence for short-baseline neutrino oscillations and the possible existence of sterile neutrinos. Such non-standard particles require a mass of $\sim 1$ eV/c$^2$, far above the mass scale associated with active neutrinos, and were first invoked to explain the LSND $\bar \nu_\mu \rightarrow \bar \nu_e$ appearance signal. More recently, the MiniBooNE experiment has reported a $2.8 \sigma$ excess of events in antineutrino mode consistent with neutrino oscillations and with the LSND antineutrino appearance signal. MiniBooNE also observed a $3.4 \sigma$ excess of events in their neutrino mode data. Lower than expected neutrino-induced event rates using calibrated radioactive sources and nuclear reactors can also be explained by the existence of sterile neutrinos. Fits to the world's neutrino and antineutrino data are consistent with sterile neutrinos at this $\sim 1$ eV/c$^2$ mass scale, although there is some tension between measurements from disappearance and appearance experiments. In addition to resolving this potential major extension of the Standard Model, the existence of sterile neutrinos will impact design and planning for all future neutrino experiments. It should be an extremely high priority to conclusively establish if such unexpected light sterile neutrinos exist. The Spallation Neutron Source (SNS) at Oak Ridge National Laboratory, built to usher in a new era in neutron research, provides a unique opportunity for US science to perform a definitive world-class search for sterile neutrinos.Comment: This white paper is submitted as part of the SNOWMASS planning proces

Search for π0→νμνˉμ\pi^0 \to \nu_{\mu}\bar\nu_{\mu} Decay in LSND

We observe a net beam-excess of $8.7 \pm 6.3$ (stat) $\pm 2.4$ (syst) events, above 160 MeV, resulting from the charged-current reaction of $\nu_{\mu}$ and/or $\bar\nu_{\mu}$ on C and H in the LSND detector. No beam related muon background is expected in this energy regime. Within an analysis framework of $\pi^0 \to \nu_{\mu}\bar\nu_{\mu}$, we set a direct upper limit for this branching ratio of $\Gamma(\pi^0 \to \nu_\mu \bar\nu_\mu) / \Gamma(\pi^0 \to all) < 1.6 \times 10^{-6}$ at 90% confidence level.Comment: 4 pages, 4 figure

Measurement of the antineutrino neutral-current elastic differential cross section

arXiv:1309.7257v1 [hep-ex

Shell-model calculations of neutrino scattering from 12C

Neutrino reaction cross-sections, $(\nu_\mu,\mu^-)$, $(\nu_e,e^-)$, $\mu$-capture and photoabsorption rates on $^{12}$C are computed within a large-basis shell-model framework, which included excitations up to $4\hbar\omega$. When ground-state correlations are included with an open $p$-shell the predictions of the calculations are in reasonable agreement with most of the experimental results for these reactions. Woods-Saxon radial wave functions are used, with their asymptotic forms matched to the experimental separation energies for bound states, and matched to a binding energy of 0.01 MeV for unbound states. For comparison purposes, some results are given for harmonic oscillator radial functions. Closest agreement between theory and experiment is achieved with unrestricted shell-model configurations and Woods-Saxon radial functions. We obtain for the neutrino-absorption inclusive cross sections: $\bar{\sigma} = 13.8 \times 10^{-40}$ cm$^2$ for the $(\nu_{\mu},\mu^{-})$ decay-in-flight flux in agreement with the LSND datum of $(12.4 \pm 1.8) \times 10^{-40}$ cm$^2$; and $\bar{\sigma} = 12.5 \times 10^{-42}$ cm$^2$ for the $(\nu_{e},e^{-})$ decay-at-rest flux, less than the experimental result of $(14.4 \pm 1.2) \times 10^{-42}$ cm$^2$.Comment: 19 pages. ReVTeX. No figure