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

NASCENT: an automatic protein interaction network generation tool for non-model organisms.

Large quantity of reliable protein interaction data are available for model organisms in public depositories (e.g., MINT, DIP, HPRD, INTERACT). Most data correspond to experiments with the proteins of Saccharomyces cerevisiae, Drosophila melanogaster, Homo sapiens, Caenorhabditis elegans, Escherichia coli and Mus musculus. For other important organisms the data availability is poor or non-existent. Here we present NASCENT, a completely automatic web-based tool and also a downloadable Java program, capable of modeling and generating protein interaction networks even for non-model organisms. The tool performs protein interaction network modeling through gene-name mapping, and outputs the resulting network in graphical form and also in computer-readable graph-forms, directly applicable by popular network modeling software. AVAILABILITY: http://nascent.pitgroup.org

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

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

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

Amenorrhea and pituitary human chorionic gonadotrophin production in a 38-year-old presenting as pregnancy of unknown location: case report and review of literature

Background: Amenorrhea and extraplacental production of serum human chorionic gonadotropin (hCG), particularly in young women, can mimic a pregnancy of unknown location. Elevated serum hCG in the absence of pregnancy can pose a diagnostic dilemma and has led to potentially harmful and unwarranted interventions including chemotherapeutic agents like methotrexate or have led to delay in necessary medical interventions in women. We report a case to demonstrate that amenorrhea and extraplacental human chorionic gonadotropin (hCG) production in young women can mimic a pregnancy of unknown location. Furthermore, we performed a critical review of literature on pituitary hCG production. Case: A 38-year-old woman with a diagnosis of Silver-Russell syndrome, a unicornuate uterus, history of right oophorectomy for a benign serous cystadenoma and a desire for pregnancy presenting with a provisional diagnosis of pregnancy of unknown location.After performing a thorough review of history, physical examination, ultrasound exams, and a review of hormone analysis [including hCG, Tumor markers, Follicle-stimulating hormone (FSH), Luteinizing hormone (LH), Anti-Mullerian Hormone (AMH), Estradiol (E2) levels], we confirmed the diagnosis of premature ovarian insufficiency and pituitary hCG production. Conclusions: In women, serum levels of hCG may increase with age, and are not always an indicator of pregnancy. Therefore, it is imperative to interpret false-positive test results and rule out the extraplacental production of hCG. This will help prevent unnecessary surgical procedures and treatment, including chemotherapy

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.</p

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

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

Characterization of the John A. Galt telescope for radio holography with CHIME

The Canadian Hydrogen Intensity Mapping Experiment (CHIME) will measure the 21 cm emission of astrophysical neutral hydrogen to probe large scale structure at redshifts z=0.8-2.5. However, detecting the 21 cm signal beneath substantially brighter foregrounds remains a key challenge. Due to the high dynamic range between 21 cm and foreground emission, an exquisite calibration of instrument systematics, notably the telescope beam, is required to successfully filter out the foregrounds. One technique being used to achieve a high fidelity measurement of the CHIME beam is radio holography, wherein signals from each of CHIME's analog inputs are correlated with the signal from a co-located reference antenna, the 26 m John A. Galt telescope, as the 26 m Galt telescope tracks a bright point source transiting over CHIME. In this work we present an analysis of several of the Galt telescope's properties. We employ driftscan measurements of several bright sources, along with background estimates derived from the 408 MHz Haslam map, to estimate the Galt system temperature. To determine the Galt telescope's beam shape, we perform and analyze a raster scan of the bright radio source Cassiopeia A. Finally, we use early holographic measurements to measure the Galt telescope's geometry with respect to CHIME for the holographic analysis of the CHIME and Galt interferometric data set