The Stokes Phenomenon and Schwinger Vacuum Pair Production in Time-Dependent Laser Pulses

Particle production due to external fields (electric, chromo-electric or gravitational) requires evolving an initial state through an interaction with a time-dependent background, with the rate being computed from a Bogoliubov transformation between the in and out vacua. When the background fields have temporal profiles with sub-structure, a semiclassical analysis of this problem confronts the full subtlety of the Stokes phenomenon: WKB solutions are only local, while the production rate requires global information. Incorporating the Stokes phenomenon, we give a simple quantitative explanation of the recently computed [Phys. Rev. Lett. 102, 150404 (2009)] oscillatory momentum spectrum of e+e- pairs produced from vacuum subjected to a time-dependent electric field with sub-cycle laser pulse structure. This approach also explains naturally why for spinor and scalar QED these oscillations are out of phase.Comment: 5 pages, 4 figs.; v2 sign typo corrected, version to appear in PR

Dynamical Evolution of Elliptical Galaxies with Central Singularities

We study the effect of a massive central singularity on the structure of a triaxial galaxy using N-body simulations. Starting from a single initial model, we grow black holes with various final masses Mh and at various rates, ranging from impulsive to adiabatic. In all cases, the galaxy achieves a final shape that is nearly spherical at the center and close to axisymmetric throughout. However, the rate of change of the galaxy's shape depends strongly on the ratio Mh/Mg of black hole mass to galaxy mass. When Mh/Mg < 0.3%, the galaxy evolves in shape on a timescale that exceeds 100 orbital periods, or roughly a galaxy lifetime. When Mh/Mg > 2%, the galaxy becomes axisymmetric in little more than a crossing time. We propose that the rapid evolution toward axisymmetric shapes that occurs when Mh/Mg > 2% provides a negative feedback mechanism which limits the mass of central black holes by cutting off their supply of fuel.Comment: 27 Latex pages, 9 Postscript figures, uses aastex.sty. Accepted for Publication in The Astrophysical Journal, Nov. 26, 199

Borel Summation of the Derivative Expansion and Effective Actions

We give an explicit demonstration that the derivative expansion of the QED effective action is a divergent but Borel summable asymptotic series, for a particular inhomogeneous background magnetic field. A duality transformation B\to iE gives a non-Borel-summable perturbative series for a time dependent background electric field, and Borel dispersion relations yield the non-perturbative imaginary part of the effective action, which determines the pair production probability. Resummations of leading Borel approximations exponentiate to give perturbative corrections to the exponents in the non-perturbative pair production rates. Comparison with a WKB analysis suggests that these divergence properties are general features of derivative expansions and effective actions.Comment: 18 pp, Revtex, 2 fig

Inhomogeneous Condensates in Planar QED

We study the formation of vacuum condensates in $2+1$ dimensional QED in the presence of inhomogeneous background magnetic fields. For a large class of magnetic fields, the condensate is shown to be proportional to the inhomogeneous magnetic field, in the large flux limit. This may be viewed as a {\it local} form of the {\it integrated} degeneracy-flux relation of Aharonov and Casher.Comment: 13 pp, LaTeX, no figures; to appear in Phys. Rev.

New evidence for a massive black hole at the centre of the quiescent galaxy M32

Massive black holes are thought to reside at the centres of many galaxies, where they power quasars and active galactic nuclei. But most galaxies are quiescent, indicating that any central massive black hole present will be starved of fuel and therefore detectable only through its gravitational influence on the motions of the surrounding stars. M32 is a nearby, quiescent elliptical galaxy in which the presence of a black hole has been suspected; however, the limited resolution of the observational data and the restricted classes of models used to interpret this data have made it difficult to rule out alternative explanations, such as models with an anisotropic stellar velocity distribution and no dark mass or models with a central concentration of dark objects (for example, stellar remnants or brown dwarfs). Here we present high-resolution optical HST spectra of M32, which show that the stellar velocities near the centre of this galaxy exceed those inferred from previous ground-based observations. We use a range of general dynamical models to determine a central dark mass concentration of (3.4 +/- 1.6) x 10^6 solar masses, contained within a region only 0.3 pc across. This leaves a massive black hole as the most plausible explanation of the data, thereby strengthening the view that such black holes exist even in quiescent galaxies.Comment: 8 pages, LaTeX, 3 figures; mpeg animation of the stellar motions in M32 available at http://oposite.stsci.edu/pubinfo/Anim.htm

Two-loop self-dual Euler-Heisenberg Lagrangians (II): Imaginary part and Borel analysis

We analyze the structure of the imaginary part of the two-loop Euler-Heisenberg QED effective Lagrangian for a constant self-dual background. The novel feature of the two-loop result, compared to one-loop, is that the prefactor of each exponential (instanton) term in the imaginary part has itself an asymptotic expansion. We also perform a high-precision test of Borel summation techniques applied to the weak-field expansion, and find that the Borel dispersion relations reproduce the full prefactor of the leading imaginary contribution.Comment: 28 pp, 6 eps figure

American Thoracic Society and National Heart, Lung, and Blood Institute Implementation Research Workshop Report

To advance implementation research (IR) in respiratory, sleep, and critical care medicine, the American Thoracic Society and the Division of Lung Diseases from the NHLBI cosponsored an Implementation Research Workshop on May 17, 2014. The goals of IR are to understand the barriers and facilitators of integrating new evidence into healthcare practices and to develop and test strategies that systematically target these factors to accelerate the adoption of evidence-based care. Throughout the workshop, presenters provided examples of IR that focused on the rate of adoption of evidence-based practices, the feasibility and acceptability of interventions to patients and other stakeholders who make healthcare decisions, the fidelity with which practitioners use specific interventions, the effects of specific barriers on the sustainability of an intervention, and the implications of their research to inform policies to improve patients’ access to high-quality care. During the discussions that ensued, investigators’ experience led to recommendations underscoring the importance of identifying and involving key stakeholders throughout the research process, ensuring that those who serve as reviewers understand the tenets of IR, managing staff motivation and turnover, and tackling the challenges of scaling up interventions across multiple settings

Genome Sequencing of SHH Medulloblastoma Predicts Genotype-Related Response to Smoothened Inhibition

SummarySmoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant

Overcoming EGFR T790M and C797S resistance with mutant-selective allosteric inhibitors

EGFR tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib and afatinib are approved treatments for non-small cell lung cancers harboring activating mutations in the EGFR kinase1,2, but resistance arises rapidly, most frequently due to the secondary T790M mutation within the ATP-site of the receptor.3,4 Recently developed mutant-selective irreversible inhibitors are highly active against the T790M mutant5,6, but their efficacy can be compromised by acquired mutation of C797, the cysteine residue with which they form a key covalent bond7. All current EGFR TKIs target the ATP-site of the kinase, highlighting the need for therapeutic agents with alternate mechanisms of action. Here we describe rational discovery of EAI045, an allosteric inhibitor that targets selected drug-resistant EGFR mutants but spares the wild type receptor. A crystal structure shows that the compound binds an allosteric site created by the displacement of the regulatory C-helix in an inactive conformation of the kinase. The compound inhibits L858R/T790M-mutant EGFR with low-nanomolar potency in biochemical assays, but as a single agent is not effective in blocking EGFR-driven proliferation in cells due to differential potency on the two subunits of the dimeric receptor, which interact in an asymmetric manner in the active state8. We observe dramatic synergy of EAI045 with cetuximab, an antibody therapeutic that blocks EGFR dimerization9,10, rendering the kinase uniformly susceptible to the allosteric agent. EAI045 in combination with cetuximab is effective in mouse models of lung cancer driven by L858R/T790M EGFR and by L858R/T790M/C797S EGFR, a mutant that is resistant to all currently available EGFR TKIs. More generally, our findings illustrate the utility of purposefully targeting allosteric sites to obtain mutant-selective inhibitors

FACT, the Bur Kinase Pathway, and the Histone Co-Repressor HirC Have Overlapping Nucleosome-Related Roles in Yeast Transcription Elongation

Gene transcription is constrained by the nucleosomal nature of chromosomal DNA. This nucleosomal barrier is modulated by FACT, a conserved histone-binding heterodimer. FACT mediates transcription-linked nucleosome disassembly and also nucleosome reassembly in the wake of the RNA polymerase II transcription complex, and in this way maintains the repression of ‘cryptic’ promoters found within some genes. Here we focus on a novel mutant version of the yeast FACT subunit Spt16 that supplies essential Spt16 activities but impairs transcription-linked nucleosome reassembly in dominant fashion. This Spt16 mutant protein also has genetic effects that are recessive, which we used to show that certain Spt16 activities collaborate with histone acetylation and the activities of a Bur-kinase/Spt4–Spt5/Paf1C pathway that facilitate transcription elongation. These collaborating activities were opposed by the actions of Rpd3S, a histone deacetylase that restores a repressive chromatin environment in a transcription-linked manner. Spt16 activity paralleling that of HirC, a co-repressor of histone gene expression, was also found to be opposed by Rpd3S. Our findings suggest that Spt16, the Bur/Spt4–Spt5/Paf1C pathway, and normal histone abundance and/or stoichiometry, in mutually cooperative fashion, facilitate nucleosome disassembly during transcription elongation. The recessive nature of these effects of the mutant Spt16 protein on transcription-linked nucleosome disassembly, contrasted to its dominant negative effect on transcription-linked nucleosome reassembly, indicate that mutant FACT harbouring the mutant Spt16 protein competes poorly with normal FACT at the stage of transcription-linked nucleosome disassembly, but effectively with normal FACT for transcription-linked nucleosome reassembly. This functional difference is consistent with the idea that FACT association with the transcription elongation complex depends on nucleosome disassembly, and that the same FACT molecule that associates with an elongation complex through nucleosome disassembly is retained for reassembly of the same nucleosome