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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
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
p21 produces a bioactive secretome that places stressed cells under immunosurveillance
Immune cells identify and destroy damaged cells to prevent them from causing cancer or other pathologies by mechanisms that remain poorly understood. Here, we report that the cell-cycle inhibitor p21 places cells under immunosurveillance to establish a biological timer mechanism that controls cell fate. p21 activates retinoblastoma protein (Rb)-dependent transcription at select gene promoters to generate a complex bioactive secretome, termed p21-activated secretory phenotype (PASP). The PASP includes the chemokine CXCL14, which promptly attracts macrophages. These macrophages disengage if cells normalize p21 within 4 days, but if p21 induction persists, they polarize toward an M1 phenotype and lymphocytes mount a cytotoxic T cell response to eliminate target cells, including preneoplastic cells. Thus, p21 concurrently induces proliferative arrest and immunosurveillance of cells under duress
The Global Magneto-Ionic Medium Survey (GMIMS): The brightest polarized region in the Southern sky at 75cm and its implications for Radio Loop II
Using the Global Magneto-Ionic Medium Survey (GMIMS) Low-Band South (LBS)
southern sky polarization survey, covering 300 to 480 MHz at 81 arcmin
resolution, we reveal the brightest region in the Southern polarized sky at
these frequencies. The region, G150-50, covers nearly 20deg, near
(l,b)~(150 deg,-50 deg). Using GMIMS-LBS and complementary data at higher
frequencies (~0.6--30 GHz), we apply Faraday tomography and Stokes QU-fitting
techniques. We find that the magnetic field associated with G150-50 is both
coherent and primarily in the plane of the sky, and indications that the region
is associated with Radio Loop II. The Faraday depth spectra across G150-50 are
broad and contain a large-scale spatial gradient. We model the magnetic field
in the region as an expanding shell, and we can reproduce both the observed
Faraday rotation and the synchrotron emission in the GMIMS-LBS band. Using
QU-fitting, we find that the Faraday spectra are produced by several Faraday
dispersive sources along the line-of-sight. Alternatively, polarization horizon
effects that we cannot model are adding complexity to the high-frequency
polarized spectra. The magnetic field structure of Loop II dominates a large
fraction of the sky, and studies of the large-scale polarized sky will need to
account for this object. Studies of G150-50 with high angular resolution could
mitigate polarization horizon effects, and clarify the nature of G150-50.Comment: 25 pages, 14 figures. Accepted for publication in MNRA
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
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
Changes in the gastric enteric nervous system and muscle: A case report on two patients with diabetic gastroparesis
<p>Abstract</p> <p>Background</p> <p>The pathophysiological basis of diabetic gastroparesis is poorly understood, in large part due to the almost complete lack of data on neuropathological and molecular changes in the stomachs of patients. Experimental models indicate various lesions affecting the vagus, muscle, enteric neurons, interstitial cells of Cajal (ICC) or other cellular components. The aim of this study was to use modern analytical methods to determine morphological and molecular changes in the gastric wall in patients with diabetic gastroparesis.</p> <p>Methods</p> <p>Full thickness gastric biopsies were obtained laparoscopically from two gastroparetic patients undergoing surgical intervention and from disease-free areas of control subjects undergoing other forms of gastric surgery. Samples were processed for histological and immunohistochemical examination.</p> <p>Results</p> <p>Although both patients had severe refractory symptoms with malnutrition, requiring the placement of a gastric stimulator, one of them had no significant abnormalities as compared with controls. This patient had an abrupt onset of symptoms with a relatively short duration of diabetes that was well controlled. By contrast, the other patient had long standing brittle and poorly controlled diabetes with numerous episodes of diabetic ketoacidosis and frequent hypoglycemic episodes. Histological examination in this patient revealed increased fibrosis in the muscle layers as well as significantly fewer nerve fibers and myenteric neurons as assessed by PGP9.5 staining. Further, significant reduction was seen in staining for neuronal nitric oxide synthase, heme oxygenase-2, tyrosine hydroxylase as well as for c-KIT.</p> <p>Conclusion</p> <p>We conclude that poor metabolic control is associated with significant pathological changes in the gastric wall that affect all major components including muscle, neurons and ICC. Severe symptoms can occur in the absence of these changes, however and may reflect vagal, central or hormonal influences. Gastroparesis is therefore likely to be a heterogeneous disorder. Careful molecular and pathological analysis may allow more precise phenotypic differentiation and shed insight into the underlying mechanisms as well as identify novel therapeutic targets.</p
A Detection of Cosmological 21 cm Emission from CHIME in Cross-correlation with eBOSS Measurements of the Lyman- Forest
We report the detection of 21 cm emission at an average redshift in the cross-correlation of data from the Canadian Hydrogen Intensity
Mapping Experiment (CHIME) with measurements of the Lyman- forest from
eBOSS. Data collected by CHIME over 88 days in the ~MHz frequency band
() are formed into maps of the sky and high-pass delay filtered
to suppress the foreground power, corresponding to removing cosmological scales
with at the average redshift.
Line-of-sight spectra to the eBOSS background quasar locations are extracted
from the CHIME maps and combined with the Lyman- forest flux
transmission spectra to estimate the 21 cm-Lyman- cross-correlation
function. Fitting a simulation-derived template function to this measurement
results in a detection significance. The coherent accumulation of the
signal through cross-correlation is sufficient to enable a detection despite
excess variance from foreground residuals times brighter than the
expected thermal noise level in the correlation function. These results are the
highest-redshift measurement of \tcm emission to date, and set the stage for
future 21 cm intensity mapping analyses at
Gastric stimulation: influence of electrical parameters on gastric emptying in control and diabetic rats
BACKGROUND: The aim of this study was to test the effect of different pulse frequencies and amplitudes during gastric stimulation (GS) on gastric emptying in the rat. METHODS: GS was performed in 2 groups of laparotomized rats: healthy control animals, and rats with acute diabetes. The effects of four pulse frequencies (0.5, 1, 10, 20 Hz) and three pulse amplitudes (5, 20, 40 mA) were tested. The volumes emptied from the stomach after the oro-gastric instillation of a nutrient solution were compared to those obtained in animals without GS. Intragastric pH values were assessed under basal conditions and after GS. RESULTS: In both groups, GS increased emptied volumes compared to conditions without stimulation (p < 0.05) for pulse frequencies above 0.5 Hz. Increases in pulse frequencies accelerated gastric emptying (p < 0.01) with a plateau at around 10 Hz. The increase in pulse amplitudes resulted in larger emptied volumes only when the pulse frequency was 1 Hz (p < 0.04) while the opposite effect was observed at 20 Hz (p < 0.04). The most effective combinations to enhance gastric emptying compared to baseline conditions were 10 Hz with 5 or 20 mA. The overall effect of GS on gastric emptying compared to baseline conditions without stimulation, was greater in diabetic than in controls rats (p < 0.05). During stimulation, intragastric pH values were not different from basal conditions during fasting or after a meal in control and diabetic rats. CONCLUSIONS: Although both pulse frequency and amplitude should be considered during GS, frequency appears to be the most critical point. The possibility of increasing gastric emptying by electrical stimulation in diabetic rats suggests potential clinical applications for this method
IVSPlat 1.0: an integrated virtual screening platform with a molecular graphical interface
<p>Abstract</p> <p>Background</p> <p>The virtual screening (VS) of lead compounds using molecular docking and pharmacophore detection is now an important tool in drug discovery. VS tasks typically require a combination of several software tools and a molecular graphics system. Thus, the integration of all the requisite tools in a single operating environment could reduce the complexity of running VS experiments. However, only a few freely available integrated software platforms have been developed.</p> <p>Results</p> <p>A free open-source platform, IVSPlat 1.0, was developed in this study for the management and automation of VS tasks. We integrated several VS-related programs into a molecular graphics system to provide a comprehensive platform for the solution of VS tasks based on molecular docking, pharmacophore detection, and a combination of both methods. This tool can be used to visualize intermediate and final results of the VS execution, while also providing a clustering tool for the analysis of VS results. A case study was conducted to demonstrate the applicability of this platform.</p> <p>Conclusions</p> <p>IVSPlat 1.0 provides a plug-in-based solution for the management, automation, and visualization of VS tasks. IVSPlat 1.0 is an open framework that allows the integration of extra software to extend its functionality and modified versions can be freely distributed. The open source code and documentation are available at <url>http://kyc.nenu.edu.cn/IVSPlat/.</url></p
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