Systematic and Stochastic Variations in Pulsar Dispersion Measures

We analyze deterministic and random temporal variations in dispersion measure (DM) from the full three-dimensional velocities of pulsars with respect to the solar system, combined with electron-density variations on a wide range of length scales. Previous treatments have largely ignored the pulsar's changing distance while favoring interpretations involving the change in sky position from transverse motion. Linear trends in pulsar DMs seen over 5-10~year timescales may signify sizable DM gradients in the interstellar medium (ISM) sampled by the changing direction of the line of sight to the pulsar. We show that motions parallel to the line of sight can also account for linear trends, for the apparent excess of DM variance over that extrapolated from scintillation measurements, and for the apparent non-Kolmogorov scalings of DM structure functions inferred in some cases. Pulsar motions through atomic gas may produce bow-shock ionized gas that also contributes to DM variations. We discuss possible causes of periodic or quasi-periodic changes in DM, including seasonal changes in the ionosphere, annual variation of the solar elongation angle, structure in the heliosphere-ISM boundary, and substructure in the ISM. We assess the solar cycle's role on the amplitude of ionospheric and solar-wind variations. Interstellar refraction can produce cyclic timing variations from the error in transforming arrival times to the solar system barycenter. We apply our methods to DM time series and DM gradient measurements in the literature and assess consistency with a Kolmogorov medium. Finally, we discuss the implications of DM modeling in precision pulsar timing experiments.Comment: 24 pages, 17 figures, published in Ap

Alternative Strategies for the Treatment of Classical Congenital Adrenal Hyperplasia: Pitfalls and Promises

Despite decades of different treatment algorithms, the management of congenital adrenal hyperplasia (CAH) remains clinically challenging. This is due to the inherent difficulty of suppressing adrenal androgen production using near physiological dosing of glucocorticoids (GC). As a result, alternating cycles of androgen versus GC excess can occur and may lead to short stature, obesity, virilization, and alterations in puberty. Novel therapeutic alternatives, including new and more physiological means of GC delivery, inhibitors at the level of CRH or ACTH secretion and/or action, as well as “rescue strategies”, such as GnRH analogs, anti-androgens, aromatase inhibitors, and estrogen receptor blockers, are available; many of these agents, however, still require active investigation in CAH. Bilateral adrenalectomy is effective but it is also still an experimental approach. Gene therapy and stem cells, to provide functional adrenal cortical tissue, are at preclinical stage but provide exciting avenues for a potential cure for CAH

Cell Cycle-Dependent Localization of Voltage-Dependent Calcium Channels and the Mitotic Apparatus in a Neuroendocrine Cell Line(AtT-20)

Changes in intracellular calcium are necessary for the successful progression of mitosis in many cells. Both elevation and reduction in intracellular calcium can disrupt mitosis by mechanisms that remain ill defined. In this study we explore the role of transmembrane voltage-gated calcium channels (CaV channels) as regulators of mitosis in the mouse corticotroph cell line (AtT-20). We report that the nifedipine-sensitive isoform CaV1.2 is localized to the “poleward side” of kinetechores during metaphase and at the midbody during cytokinesis. A second nifedipine-sensitive isoform, CaV1.3, is present at the mid-spindle zone in telophase, but is also seen at the midbody. Nifedipine reduces the rate of cell proliferation, and, utilizing time-lapse microscopy, we show that this is due to a block at the prometaphase stage of the cell cycle. Using Fluo-4 we detect calcium fluxes at sites corresponding to the mid-spindle zone and the midbody region. Another calcium dye, Fura PE3/AM, causes an inhibition of mitosis prior to anaphase that we attribute to a chelation of intracellular calcium. Our results demonstrate a novel, isoform-specific localization of CaV1 channels during cell division and suggest a possible role for these channels in the calcium-dependent events underlying mitotic progression in pituitary corticotrophs

Conformational changes in alpha 7 acetylcholine receptors underlying allosteric modulation by divalent cations

Abstract Allosteric modulation of membrane receptors is a widespread mechanism by which endogenous and exogenous agents regulate receptor function. For example, several members of the nicotinic receptor family are modulated by physiological concentrations of extracellular calcium ions. In this paper, we examined conformational changes underlying this modulation and compare these with changes evoked by ACh. Two sets of residues in the α7 acetylcholine receptor extracellular domain were mutated to cysteine and analyzed by measuring the rates of modification by the thiol-specific reagent 2-aminoethylmethane thiosulfonate. Using Ba2+ as a surrogate for Ca2+, we found a divalent-dependent decrease the modification rates of cysteine substitutions at M37 and M40, residues at which rates were also slowed by ACh. In contrast, Ba2+ had no significant effect at N52C, a residue where ACh increased the rate of modification. Thus divalent modulators cause some but not all of the conformational effects elicited by agonist. Cysteine substitution of either of two glutamates (E44 or E172), thought to participate in the divalent cation binding site, caused a loss of allosteric modulation, yet Ba2+ still had a significant effect on modification rates of these residues. In addition, the effect of Ba2+ at these residues did not appear to be due to direct occlusion. Our data demonstrate that modulation by divalent cations involves substantial conformational changes in the receptor extracellular domain. Our evidence also suggests the modulation occurs via a binding site distinct from one which includes either (or both) of the conserved glutamates at E44 or E172

The Host Galaxy and Redshift of the Repeating Fast Radio Burst FRB 121102

The precise localization of the repeating fast radio burst (FRB 121102) has provided the first unambiguous association (chance coincidence probability $p\lesssim3\times10^{-4}$) of an FRB with an optical and persistent radio counterpart. We report on optical imaging and spectroscopy of the counterpart and find that it is an extended ($0.6^{\prime\prime}-0.8^{\prime\prime}$) object displaying prominent Balmer and [OIII] emission lines. Based on the spectrum and emission line ratios, we classify the counterpart as a low-metallicity, star-forming, $m_{r^\prime} = 25.1$ AB mag dwarf galaxy at a redshift of $z=0.19273(8)$, corresponding to a luminosity distance of 972 Mpc. From the angular size, the redshift, and luminosity, we estimate the host galaxy to have a diameter $\lesssim4$ kpc and a stellar mass of $M_*\sim4-7\times 10^{7}\,M_\odot$, assuming a mass-to-light ratio between 2 to 3$\,M_\odot\,L_\odot^{-1}$. Based on the H$\alpha$ flux, we estimate the star formation rate of the host to be $0.4\,M_\odot\,\mathrm{yr^{-1}}$ and a substantial host dispersion measure depth $\lesssim 324\,\mathrm{pc\,cm^{-3}}$. The net dispersion measure contribution of the host galaxy to FRB 121102 is likely to be lower than this value depending on geometrical factors. We show that the persistent radio source at FRB 121102's location reported by Marcote et al (2017) is offset from the galaxy's center of light by $\sim$200 mas and the host galaxy does not show optical signatures for AGN activity. If FRB 121102 is typical of the wider FRB population and if future interferometric localizations preferentially find them in dwarf galaxies with low metallicities and prominent emission lines, they would share such a preference with long gamma ray bursts and superluminous supernovae.Comment: 12 pages, 3 figures, Published in ApJ Letters. V2: Corrected mistake in author lis