Three-Dimensional Structure of the Magnetic Field in the Disk of the Milky Way

We present Rotation Measures (RM) of the diffuse Galactic synchrotron emission from the Canadian Galactic Plane Survey (CGPS) and compare them to RMs of extragalactic sources in order to study the large-scale reversal in the Galactic magnetic field (GMF). Using Stokes Q, U and I measurements of the Galactic disk collected with the Synthesis Telescope at the Dominion Radio Astrophysical Observatory, we calculate RMs over an extended region of the sky, focusing on the low longitude range of the CGPS (l=52deg to l=72deg). We note the similarity in the structures traced by the compact sources and the extended emission and highlight the presence of a gradient in the RM map across an approximately diagonal line, which we identify with the well-known field reversal of the Sagittarius-Carina arm. We suggest that the orientation of this reversal is a geometric effect resulting from our location within a GMF structure arising from current sheets that are not perpendicular to the Galactic plane, as is required for a strictly radial field reversal, but that have at least some component parallel to the disk. Examples of models that fit this description are the three-dimensional dynamo-based model of Gressel et al. (2013) and a Galactic scale Parker spiral (Akasofu & Hakamada 1982), although the latter may be problematic in terms of Galactic dynamics. We emphasize the importance of constructing three-dimensional models of the GMF to account for structures like the diagonal RM gradient observed in this dataset.Comment: Published in Astronomy and Astrophysics, Accepted 23 April, 201

Multimode electromagnetically-induced transparency on a single atomic line

We experimentally investigate electromagnetically-induced transparency (EIT) created on an inhomogeneously broadened 5S_1/2-5P_1/2 transition in rubidium vapor using a control field of a complex temporal shape. A comb-shaped transparency spectrum enhances the delay-bandwidth product and the light storage capacity for a matched probe pulse by a factor of about 50 compared to a single EIT line [D. D. Yavuz, Phys. Rev. A 75, 031801 (2007)]. If the temporal mode of the control field is slowly changed while the probe is propagating through the EIT medium, the probe will adiabatically follow, providing a means to perform frequency conversion and optical routing

Faraday Rotation of Extended Emission as a Probe of the Large-Scale Galactic Magnetic Field

The Galactic magnetic field is an integral constituent of the interstellar medium (ISM), and knowledge of its structure is crucial to understanding Galactic dynamics. The Rotation Measures (RM) of extragalactic (EG) sources have been the basis of comprehensive Galactic magnetic field models. Polarised extended emission (XE) is also seen along lines of sight through the Galactic disk, and also displays the effects of Faraday rotation. Our aim is to investigate and understand the relationship between EG and XE RMs near the Galactic plane, and to determine how the XE RMs, a hitherto unused resource, can be used as a probe of the large-scale Galactic magnetic field. We used polarisation data from the Canadian Galactic Plane Survey (CGPS), observed near 1420 MHz with the Dominion Radio Astrophysical Observatory (DRAO) Synthesis Telescope. We calculated RMs from a linear fit to the polarisation angles as a function of wavelength squared in four frequency channels, for both the EG sources and the XE. Across the CGPS area, $55^{\circ} < {\ell} <193^{\circ}, -3^{\circ} < b < 5^{\circ}$, the RMs of the XE closely track the RMs of the EG sources, with XE RMs about half the value of EG-source RMs. The exceptions are places where large local HII complexes heavily depolarise more distant emission. We conclude that there is valuable information in the XE RM dataset. The factor of 2 between the two types of RM values is close to that expected from a Burn slab model of the ISM. This result indicates that, at least in the outer Galaxy, the EG and XE sources are likely probing similar depths, and that the Faraday rotating medium and the synchrotron emitting medium have similar variation with galactocentric distance.Comment: Accepted to Galaxies, March 22, 201

Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression.

Gastrointestinal stromal tumors (GIST) arise within the interstitial cell of Cajal (ICC) lineage due to activating KIT/PDGFRA mutations. Both ICC and GIST possess primary cilia (PC), which coordinate PDGFRA and Hedgehog signaling, regulators of gastrointestinal mesenchymal development. Therefore, we hypothesized that Hedgehog signaling may be altered in human GIST and controls KIT expression. Quantitative RT-PCR, microarrays, and next generation sequencing were used to describe Hedgehog/PC-related genes in purified human ICC and GIST. Genetic and pharmacologic approaches were employed to investigate the effects of GLI manipulation on KIT expression and GIST cell viability. We report that Hedgehog pathway and PC components are expressed in ICC and GIST and subject to dysregulation during GIST oncogenesis, irrespective of KIT/PDGFRA mutation status. Using genomic profiling, 10.2% of 186 GIST studied had potentially deleterious genomic alterations in 5 Hedgehog-related genes analyzed, including in the PTCH1 tumor suppressor (1.6%). Expression of the predominantly repressive GLI isoform, GLI3, was inversely correlated with KIT mRNA levels in GIST cells and non-KIT/non-PDGFRA mutant GIST. Overexpression of the 83-kDa repressive form of GLI3 or small interfering RNA-mediated knockdown of the activating isoforms GLI1/2 reduced KIT mRNA. Treatment with GLI1/2 inhibitors, including arsenic trioxide, significantly increased GLI3 binding to the KIT promoter, decreased KIT expression, and reduced viability in imatinib-sensitive and imatinib-resistant GIST cells. These data offer new evidence that genes necessary for Hedgehog signaling and PC function in ICC are dysregulated in GIST. Hedgehog signaling activates KIT expression irrespective of mutation status, offering a novel approach to treat imatinib-resistant GIST

Structure in the Magnetic Field of the Milky Way Disk and Halo traced by Faraday Rotation

Magnetic fields in the ionized medium of the disk and halo of the Milky Way impose Faraday rotation on linearly polarized radio emission. We compare two surveys mapping the Galactic Faraday rotation, one showing the rotation measures of extragalactic sources seen through the Galaxy (from Hutschenreuter et al 2022), and one showing the Faraday depth of the diffuse Galactic synchrotron emission from the Global Magneto-Ionic Medium Survey. Comparing the two data sets in 5deg x 10deg bins shows good agreement at intermediate latitudes, 10 < |b| < 50 deg, and little correlation between them at lower and higher latitudes. Where they agree, both tracers show clear patterns as a function of Galactic longitude: in the Northern Hemisphere a strong sin(2 x longitude) pattern, and in the Southern hemisphere a sin(longitude + pi) pattern. Pulsars with height above or below the plane |z| > 300 pc show similar longitude dependence in their rotation measures. Nearby non-thermal structures show rotation measure shadows as does the Orion-Eridanus superbubble. We describe families of dynamo models that could explain the observed patterns in the two hemispheres. We suggest that a field reversal, known to cross the plane a few hundred pc inside the solar circle, could shift to positive z with increasing Galactic radius to explain the sin(2xlongitude) pattern in the Northern Hemisphere. Correlation shows that rotation measures from extragalactic sources are one to two times the corresponding rotation measure of the diffuse emission, implying Faraday complexity along some lines of sight, especially in the Southern hemisphere.Comment: 37 pages, 26 figures, Ap. J. accepte

Membrane-To-Nucleus Signaling Links Insulin-Like Growth Factor-1- and Stem Cell Factor-Activated Pathways

Stem cell factor (mouse: Kitl, human: KITLG) and insulin-like growth factor-1 (IGF1), acting via KIT and IGF1 receptor (IGF1R), respectively, are critical for the development and integrity of several tissues. Autocrine/paracrine KITLG-KIT and IGF1-IGF1R signaling are also activated in several cancers including gastrointestinal stromal tumors (GIST), the most common sarcoma. In murine gastric muscles, IGF1 promotes Kitl-dependent development of interstitial cells of Cajal (ICC), the non-neoplastic counterpart of GIST, suggesting cooperation between these pathways. Here, we report a novel mechanism linking IGF1-IGF1R and KITLG-KIT signaling in both normal and neoplastic cells. In murine gastric muscles, the microenvironment for ICC and GIST, human hepatic stellate cells (LX-2), a model for cancer niches, and GIST cells, IGF1 stimulated Kitl/KITLG protein and mRNA expression and promoter activity by activating several signaling pathways including AKT-mediated glycogen synthase kinase-3β inhibition (GSK3i). GSK3i alone also stimulated Kitl/KITLG expression without activating mitogenic pathways. Both IGF1 and GSK3i induced chromatin-level changes favoring transcriptional activation at the Kitl promoter including increased histone H3/H4 acetylation and H3 lysine (K) 4 methylation, reduced H3K9 and H3K27 methylation and reduced occupancy by the H3K27 methyltransferase EZH2. By pharmacological or RNA interference-mediated inhibition of chromatin modifiers we demonstrated that these changes have the predicted impact on KITLG expression. KITLG knock-down and immunoneutralization inhibited the proliferation of GIST cells expressing wild-type KIT, signifying oncogenic autocrine/paracrine KITLG-KIT signaling. We conclude that membrane-to-nucleus signaling involving GSK3i establishes a previously unrecognized link between the IGF1-IGF1R and KITLG-KIT pathways, which is active in both physiologic and oncogenic contexts and can be exploited for therapeutic purposes

The Global Magneto-Ionic Medium Survey: A Faraday Depth Survey of the Northern Sky Covering 1280-1750 MHz

The Galactic interstellar medium hosts a significant magnetic field, which can be probed through the synchrotron emission produced from its interaction with relativistic electrons. Linearly polarized synchrotron emission is generated throughout the Galaxy, and at longer wavelengths, modified along nearly every path by Faraday rotation in the intervening magneto-ionic medium. Full characterization of the polarized emission requires wideband observations with many frequency channels. We have surveyed polarized radio emission from the Northern sky over the the range 1280-1750 MHz, with channel width 236.8 kHz, using the John A. Galt Telescope (diameter 25.6 m) at the Dominion Radio Astrophysical Observatory, as part of the Global Magneto-Ionic Medium Survey. The survey covered 72% of the sky, declinations -30 to +87 degrees at all right ascensions. The intensity scale was absolutely calibrated, based on the flux density and spectral index of Cygnus A. Polarization angle was calibrated using the extended polarized emission of the Fan Region. Data are presented as brightness temperatures with angular resolution 40'. Sensitivity in Stokes Q and U is 45 mK rms in a 1.18 MHz band. We have applied rotation measure synthesis to the data to obtain a Faraday depth cube of resolution 150 radians per square metre and sensitivity 3 mK rms of polarized intensity. Features in Faraday depth up to a width of 110 radians per square metre are represented. The maximum detectable Faraday depth is +/- 20,000 radians per square metre. The survey data are available at the Canadian Astronomy Data Centre.Comment: Accepted for publication in the Astronomical Journa

The effects of repetitive use and pathological remodeling on channelrhodopsin function in cardiomyocytes

Aim: Channelrhodopsins (ChRs) are a large family of light-gated ion channels with distinct properties, which is of great importance in the selection of a ChR variant for a given application. However, data to guide such selection for cardiac optogenetic applications are lacking. Therefore, we investigated the functioning of different ChR variants in normal and pathological hypertrophic cardiomyocytes subjected to various illumination protocols.Methods and Results: Isolated neonatal rat ventricular cardiomyocytes (NRVMs) were transduced with lentiviral vectors to express one of the following ChR variants: H134R, CatCh, ReaChR, or GtACR1. NRVMs were treated with phenylephrine (PE) to induce pathological hypertrophy (PE group) or left untreated [control (CTL) group]. In these groups, ChR currents displayed unique and significantly different properties for each ChR variant on activation by a single 1-s light pulse (1 mW/mm(2): 470, 565, or 617 nm). The concomitant membrane potential (V-m) responses also showed a ChR variant-specific profile, with GtACR1 causing a slight increase in average V-m during illumination (V-plateau: -38 mV) as compared with a V-plateau > -20 mV for the other ChR variants. On repetitive activation at increasing frequencies (10-ms pulses at 1-10 Hz for 30 s), peak currents, which are important for cardiac pacing, decreased with increasing activation frequencies by 17-78% (p 0.05).Conclusion: Our data show that ChR variants function equally well in cell culture models of healthy and pathologically hypertrophic myocardium but show strong, variant-specific use-dependence. This use-dependent nature of ChR function should be taken into account during the design of cardiac optogenetic studies and the interpretation of the experimental findings thereof.Cardiolog

Oncogenic gene expression and epigenetic remodeling of cis-regulatory elements in ASXL1-mutant chronic myelomonocytic leukemia

Myeloid neoplasms are clonal hematopoietic stem cell disorders driven by the sequential acquisition of recurrent genetic lesions. Truncating mutations in the chromatin remodeler ASXL1 (ASXL1MT) are associated with a high-risk disease phenotype with increased proliferation, epigenetic therapeutic resistance, and poor survival outcomes. We performed a multi-omics interrogation to define gene expression and chromatin remodeling associated with ASXL1MT in chronic myelomonocytic leukemia (CMML). ASXL1MT are associated with a loss of repressive histone methylation and increase in permissive histone methylation and acetylation in promoter regions. ASXL1MT are further associated with de novo accessibility of distal enhancers binding ETS transcription factors, targeting important leukemogenic driver genes. Chromatin remodeling of promoters and enhancers is strongly associated with gene expression and heterogenous among overexpressed genes. These results provide a comprehensive map of the transcriptome and chromatin landscape of ASXL1MT CMML, forming an important framework for the development of novel therapeutic strategies targeting oncogenic cis interactions

Dystrophin Is a Tumor Suppressor in Human Cancers with Myogenic Programs

Many common human mesenchymal tumors, including gastrointestinal stromal tumor (GIST), rhabdomyosarcoma (RMS), and leiomyosarcoma (LMS), feature myogenic differentiation1–3. Here we report that intragenic deletion of the dystrophin-encoding and muscular dystrophy-associated DMD gene is a frequent mechanism by which myogenic tumors progress to high-grade, lethal sarcomas. Dystrophin is expressed in nonneoplastic and benign counterparts for GIST, RMS and LMS, and the DMD deletions inactivate larger dystrophin isoforms, including 427kDa dystrophin, while preserving expression of an essential 71kDa isoform. Dystrophin inhibits myogenic sarcoma cell migration, invasion, anchorage independence, and invadopodia formation, and dystrophin inactivation was found in 96%, 100%, and 62% of metastatic GIST, embryonal RMS, and LMS, respectively. These findings validate dystrophin as a tumor suppressor and likely anti-metastatic factor, suggesting that therapies in development for muscular dystrophies may also have relevance in treatment of cancer