Trace amounts of 8-oxo-dGTP in mitochondrial dNTP pools reduce DNA polymerase γ replication fidelity

Replication of the mitochondrial genome by DNA polymerase γ requires dNTP precursors that are subject to oxidation by reactive oxygen species generated by the mitochondrial respiratory chain. One such oxidation product is 8-oxo-dGTP, which can compete with dTTP for incorporation opposite template adenine to yield A-T to C-G transversions. Recent reports indicate that the ratio of undamaged dGTP to dTTP in mitochondrial dNTP pools from rodent tissues varies from ∼1:1 to >100:1. Within this wide range, we report here the proportion of 8-oxo-dGTP in the dNTP pool that would be needed to reduce the replication fidelity of human DNA polymerase γ. When various in vivo mitochondrial dNTP pools reported previously were used here in reactions performed in vitro, 8-oxo-dGTP was readily incorporated opposite template A and the resulting 8-oxo-G-A mismatch was not proofread efficiently by the intrinsic 3′ exonuclease activity of pol γ. At the dNTP ratios reported in rodent tissues, whether highly imbalanced or relatively balanced, the amount of 8-oxo-dGTP needed to reduce fidelity was <1% of dGTP. Moreover, direct measurements reveal that 8-oxo-dGTP is present at such concentrations in the mitochondrial dNTP pools of several rat tissues. The results suggest that oxidized dNTP precursors may contribute to mitochondrial mutagenesis in vivo, which could contribute to mitochondrial dysfunction and disease

Recent X-ray Observations and the Evolution of Hot Gas in Elliptical Galaxies: Evidence for Circumgalactic Gas

X-ray emitting gaseous halos, such as that in elliptical galaxies like NGC 4472, cannot have been produced solely from gas expelled from galactic stars. In traditional models for the evolution of hot interstellar gas (cooling flows) in ellipticals, the galaxies are assumed to have been cleared of gas by SNII-driven winds at some early time then gas is subsequently replenished by mass loss from an evolving population of old stars. To test this, we accurately determine the stellar and dark halo mass of NGC 4472 using hydrostatic equilibrium, then solve the standard time-dependent cooling flow equations to recover the observed hot gas temperature and density distributions when evolved to the present time. This procedure fails: the computed gas density gradient is too steep, the total gas mass is too low, and the gas temperatures are much too low. All variants on this basic procedure also fail: increasing the SNIa rate, using the mass dropout assumption, arbitrarily adjusting uncertain coefficients, etc. However, agreement is achieved if the galaxy is supplied with additional, spatially-extended hot gas early in its evolution. This old ``circumgalactic'' gas can be retained to the present time and may be related to cosmological ``secondary infall''.Comment: 15 pages in two-column AASTEX LaTeX including 1 table and 8 figures; abstract corrected in replacement; accepted by Astrophysical Journa

Oral Migalastat HCl Leads to Greater Systemic Exposure and Tissue Levels of Active α-Galactosidase A in Fabry Patients when Co-Administered with Infused Agalsidase.

UnlabelledMigalastat HCl (AT1001, 1-Deoxygalactonojirimycin) is an investigational pharmacological chaperone for the treatment of α-galactosidase A (α-Gal A) deficiency, which leads to Fabry disease, an X-linked, lysosomal storage disorder. The currently approved, biologics-based therapy for Fabry disease is enzyme replacement therapy (ERT) with either agalsidase alfa (Replagal) or agalsidase beta (Fabrazyme). Based on preclinical data, migalastat HCl in combination with agalsidase is expected to result in the pharmacokinetic (PK) enhancement of agalsidase in plasma by increasing the systemic exposure of active agalsidase, thereby leading to increased cellular levels in disease-relevant tissues. This Phase 2a study design consisted of an open-label, fixed-treatment sequence that evaluated the effects of single oral doses of 150 mg or 450 mg migalastat HCl on the PK and tissue levels of intravenously infused agalsidase (0.2, 0.5, or 1.0 mg/kg) in male Fabry patients. As expected, intravenous administration of agalsidase alone resulted in increased α-Gal A activity in plasma, skin, and peripheral blood mononuclear cells (PBMCs) compared to baseline. Following co-administration of migalastat HCl and agalsidase, α-Gal A activity in plasma was further significantly increased 1.2- to 5.1-fold compared to agalsidase administration alone, in 22 of 23 patients (95.6%). Importantly, similar increases in skin and PBMC α-Gal A activity were seen following co-administration of migalastat HCl and agalsidase. The effects were not related to the administered migalastat HCl dose, as the 150 mg dose of migalastat HCl increased α-Gal A activity to the same extent as the 450 mg dose. Conversely, agalsidase had no effect on the plasma PK of migalastat. No migalastat HCl-related adverse events or drug-related tolerability issues were identified.Trial registrationClinicalTrials.gov NCT01196871

Contact Interactions and Resonance-Like Physics at Present and Future Colliders from Unparticles

High scale conformal physics can lead to unusual unparticle stuff at our low energies. In this paper we discuss how the exchange of unparticles between Standard Model fields can lead to new contact interaction physics as well as a pseudoresonance-like structure, an unresonance, that might be observable at the Tevatron or LHC in, e.g., the Drell-Yan channel. The specific signatures of this scenario are quite unique and can be used to easily identify this new physics given sufficient integrated luminosity.Comment: 20 pages, 10 figs; minor text changes, ref added; typos correcte

MPS Editor

Previously, it was time-consuming to hand-edit data and then set up simulation runs to find the effect and impact of the input data on a spacecraft. MPS Editor provides the user the capability to create/edit/update models and sequences, and immediately try them out using what appears to the user as one piece of software. MPS Editor provides an integrated sequencing environment for users. It provides them with software that can be utilized during development as well as actual operations. In addition, it provides them with a single, consistent, user friendly interface. MPS Editor uses the Eclipse Rich Client Platform to provide an environment that can be tailored to specific missions. It provides the capability to create and edit, and includes an Activity Dictionary to build the simulation spacecraft models, build and edit sequences of commands, and model the effects of those commands on the spacecraft. MPS Editor is written in Java using the Eclipse Rich Client Platform. It is currently built with four perspectives: the Activity Dictionary Perspective, the Project Adaptation Perspective, the Sequence Building Perspective, and the Sequence Modeling Perspective. Each perspective performs a given task. If a mission doesn't require that task, the unneeded perspective is not added to that project's delivery. In the Activity Dictionary Perspective, the user builds the project-specific activities, observations, calibrations, etc. Typically, this is used during the development phases of the mission, although it can be used later to make changes and updates to the Project Activity Dictionary. In the Adaptation Perspective, the user creates the spacecraft models such as power, data store, etc. Again, this is typically used during development, but will be used to update or add models of the spacecraft. The Sequence Building Perspective allows the user to create a sequence of activities or commands that go to the spacecraft. It provides a simulation of the activities and commands that have been created

Testing the Nature of Kaluza-Klein Excitations at Future Lepton Colliders

With one extra dimension, current high precision electroweak data constrain the masses of the first Kaluza-Klein excitations of the Standard Model gauge fields to lie above $\simeq 4$ TeV. States with masses not much larger than this should be observable at the LHC. However, even for first excitation masses close to this lower bound, the second set of excitations will be too heavy to be produced thus eliminating the possibility of realizing the cleanest signature for KK scenarios. Previous studies of heavy $Z'$ and $W'$ production in this mass range at the LHC have demonstrated that very little information can be obtained about their couplings to the conventional fermions given the limited available statistics and imply that the LHC cannot distinguish an ordinary $Z'$ from the degenerate pair of the first KK excitations of the $\gamma$ and $Z$. In this paper we discuss the capability of lepton colliders with center of mass energies significantly below the excitation mass to resolve this ambiguity. In addition, we examine how direct measurements obtained on and near the top of the first excitation peak at lepton colliders can confirm these results. For more than one extra dimension we demonstrate that it is likely that the first KK excitation is too massive to be produced at the LHC.Comment: 38 pages, 10 Figs, LaTex, comments adde

1S-2S Spectrum of a Hydrogen Bose-Einstein Condensate

We calculate the two-photon 1S-2S spectrum of an atomic hydrogen Bose-Einstein condensate in the regime where the cold collision frequency shift dominates the lineshape. WKB and static phase approximations are made to find the intensities for transitions from the condensate to motional eigenstates for 2S atoms. The excited state wave functions are found using a mean field potential which includes the effects of collisions with condensate atoms. Results agree well with experimental data. This formalism can be used to find condensate spectra for a wide range of excitation schemes.Comment: 13 pages, 4 figure

Polarized light-flavor antiquarks from Drell-Yan processes of h+\vec{N}\to\vec{l^{+-}} + l^{-+} + X

We propose a formula to determine the first moment of difference between the polarized $\bar u$- and $\bar d$-quarks in the nucleon, {\it i.e.} $\Delta\bar u-\Delta \bar d$ from the Drell-Yan processes in collisions of unpolarized hadrons with longitudinally polarized nucleons by measuring outgoing lepton helicities. As coefficients in the differential cross section depend on the $u$- and $d$-quark numbers in the unpolarized hadron beam, the difference $\Delta\bar u-\Delta\bar d$ can be independently tested by changing the hadron beam. Moreover, a formula for estimating the $K$-factor in Drell-Yan processes is also suggested.Comment: 10 pages, 1 figur

Comparison of an approximately isothermal gravitational potentials of elliptical galaxies based on X-ray and optical data

We analyze six X-ray bright elliptical galaxies, observed with Chandra and XMM-Newton, and approximate their gravitational potentials by isothermal spheres phi(r)=v_c^2 ln(r) over a range of radii from ~0.5 to ~25 kpc. We then compare the circular speed v_c derived from X-ray data with the estimators available from optical data. In particular we discuss two simple and robust procedures for evaluating the circular speed of the galaxy using the observed optical surface brightness and the line-of-sight velocity dispersion profiles. The best fitting relation between the circular speeds derived from optical observations of stars and X-ray observations of hot gas is v_{c,opt}~ \eta * v_{c,X}, where \eta=1.10-1.15 (depending on the method), suggesting, albeit with large statistical and systematic uncertainties, that non-thermal pressure on average contributes ~20-30% of the gas thermal pressure.Comment: 24 pages, 15 figures; Accepted for publication in MNRA