The Guanylate Cyclase C-cGMP Signaling Axis Opposes Intestinal Epithelial Injury and Neoplasia.

Guanylate cyclase C (GUCY2C) is a transmembrane receptor expressed on the luminal aspect of the intestinal epithelium. Its ligands include bacterial heat-stable enterotoxins responsible for traveler\u27s diarrhea, the endogenous peptide hormones uroguanylin and guanylin, and the synthetic agents, linaclotide, plecanatide, and dolcanatide. Ligand-activated GUCY2C catalyzes the synthesis of intracellular cyclic GMP (cGMP), initiating signaling cascades underlying homeostasis of the intestinal epithelium. Mouse models of GUCY2C ablation, and recently, human populations harboring GUCY2C mutations, have revealed the diverse contributions of this signaling axis to epithelial health, including regulating fluid secretion, microbiome composition, intestinal barrier integrity, epithelial renewal, cell cycle progression, responses to DNA damage, epithelial-mesenchymal cross-talk, cell migration, and cellular metabolic status. Because of these wide-ranging roles, dysregulation of the GUCY2C-cGMP signaling axis has been implicated in the pathogenesis of bowel transit disorders, inflammatory bowel disease, and colorectal cancer. This review explores the current understanding of cGMP signaling in the intestinal epithelium and mechanisms by which it opposes intestinal injury. Particular focus will be applied to its emerging role in tumor suppression. In colorectal tumors, endogenous GUCY2C ligand expression is lost by a yet undefined mechanism conserved in mice and humans. Further, reconstitution of GUCY2C signaling through genetic or oral ligand replacement opposes tumorigenesis in mice. Taken together, these findings suggest an intriguing hypothesis that colorectal cancer arises in a microenvironment of functional GUCY2C inactivation, which can be repaired by oral ligand replacement. Hence, the GUCY2C signaling axis represents a novel therapeutic target for preventing colorectal cancer

APC-β-catenin-TCF signaling silences the intestinal guanylin-GUCY2C tumor suppressor axis.

Sporadic colorectal cancer initiates with mutations in APC or its degradation target β-catenin, producing TCF-dependent nuclear transcription driving tumorigenesis. The intestinal epithelial receptor, GUCY2C, with its canonical paracrine hormone guanylin, regulates homeostatic signaling along the crypt-surface axis opposing tumorigenesis. Here, we reveal that expression of the guanylin hormone, but not the GUCY2C receptor, is lost at the earliest stages of transformation in APC-dependent tumors in humans and mice. Hormone loss, which silences GUCY2C signaling, reflects transcriptional repression mediated by mutant APC-β-catenin-TCF programs in the nucleus. These studies support a pathophysiological model of intestinal tumorigenesis in which mutant APC-β-catenin-TCF transcriptional regulation eliminates guanylin expression at tumor initiation, silencing GUCY2C signaling which, in turn, dysregulates intestinal homeostatic mechanisms contributing to tumor progression. They expand the mechanistic paradigm for colorectal cancer from a disease of irreversible mutations in APC and β-catenin to one of guanylin hormone loss whose replacement, and reconstitution of GUCY2C signaling, could prevent tumorigenesis

X-Ray And Optical Flux Ratio Anomalies In Quadruply Lensed Quasars. II. Mapping the Dark Matter Content in Elliptical Galaxies

We present a microlensing analysis of 61 Chandra observations of 14 quadruply lensed quasars. X-ray flux measurements of the individual quasar images give a clean determination of the microlensing effects in the lensing galaxy and thus offer a direct assessment of the local fraction of stellar matter making up the total integrated mass along the lines of sight through the lensing galaxy. A Bayesian analysis of the ensemble of lensing galaxies gives a most likely local stellar fraction of 7%, with the other 93% in a smooth, dark matter component, at an average impact parameter R_c of 6.6 kpc from the center of the lensing galaxy. We divide the systems into smaller ensembles based on R_c and find that the most likely local stellar fraction varies qualitatively and quantitatively as expected, decreasing as a function of R_c.Comment: 13 pages, published in ApJ, 744:111, 2012 January 1

Refined Neutron-Star Mass Determinations for Six Eclipsing X-Ray Pulsar Binaries

We present an improved method for determining the mass of neutron stars in eclipsing X-ray pulsar binaries and apply the method to six systems, namely Vela X-1, 4U 1538-52, SMC X-1, LMC X-4, Cen X-3, and Her X-1. In previous studies to determine neutron star mass, the X-ray eclipse duration has been approximated analytically by assuming the companion star is spherical with an effective Roche lobe radius. We use a numerical code based on Roche geometry with various optimizers to analyze the published data for these systems, which we supplement with new spectroscopic and photometric data for 4U 1538-52. This allows us to model the eclipse duration more accurately and thus calculate an improved value for the neutron star mass. The derived neutron star mass also depends on the assumed Roche lobe filling factor beta of the companion star, where beta = 1 indicates a completely filled Roche lobe. In previous work a range of beta between 0.9 and 1.0 was usually adopted. We use optical ellipsoidal lightcurve data to constrain beta. We find neutron star masses of 1.77 +/- 0.08 M_{sun} for Vela X-1, 0.87 +/- 0.07 M_{sun} for 4U 1538-52 (eccentric orbit), 1.00 +/- 0.10 M_{sun} for 4U 1538-52 (circular orbit), 1.04 +/- 0.09 M_{sun} for SMC X-1, 1.29 +/- 0.05 M_{sun} for LMC X-4, 1.49 +/- 0.08 M_{sun} for Cen X-3, and 1.07 +/- 0.36 M_{sun} for Her X-1. We discuss the limits of the approximations that were used to derive the earlier mass determinations, and we comment on the implications our new masses have for observationally refining the upper and lower bounds of the neutron star mass distribution.Comment: 10 figures, accepted for publication in The Astrophysical Journa

Kepler Eclipsing Binary Stars. VI. Identification of Eclipsing Binaries in the K2 Campaign 0 Data-set

The original {\it Kepler} mission observed and characterized over 2400 eclipsing binaries in addition to its prolific exoplanet detections. Despite the mechanical malfunction and subsequent non-recovery of two reaction wheels used to stabilize the instrument, the {\it Kepler} satellite continues collecting data in its repurposed {\it K2} mission surveying a series of fields along the ecliptic plane. Here we present an analysis of the first full baseline {\it K2} data release: the Campaign 0 data-set. In the 7761 light curves, we have identified a total of 207 eclipsing binaries. Of these, 97 are new discoveries that were not previously identified. Our pixel-level analysis of these objects has also resulted in identification of several false positives (observed targets contaminated by neighboring eclipsing binaries), as well as the serendipitous discovery of two short period exoplanet candidates. We provide catalog cross-matched source identifications, orbital periods, morphologies and ephemerides for these eclipsing systems. We also describe the incorporation of the K2 sample into the Kepler Eclipsing Binary Catalog\footnote{\url{keplerebs.villanova.edu/k2}}, present spectroscopic follow-up observations for a limited selection of nine systems, and discuss prospects for upcoming {\it K2} campaigns.Comment: Accepted for publication in MNRAS. 51 pages [20 figures, 8 tables]. Results available online in the Kepler Eclipsing Binary Star Catalog http://keplerebs.villanova.edu/k

Sizes and Temperature Profiles of Quasar Accretion Disks from Chromatic Microlensing

Microlensing perturbations to the flux ratios of gravitationally lensed quasar images can vary with wavelength because of the chromatic dependence of the accretion disk's apparent size. Multiwavelength observations of microlensed quasars can thus constrain the temperature profiles of their accretion disks, a fundamental test of an important astrophysical process which is not currently possible using any other method. We present single-epoch broadband flux ratios for 12 quadruply lensed quasars in eight bands ranging from 0.36 to 2.2 microns, as well as Chandra 0.5--8 keV flux ratios for five of them. We combine the optical/IR and X-ray ratios, together with X-ray ratios from the literature, using a Bayesian approach to constrain the half-light radii of the quasars in each filter. Comparing the overall disk sizes and wavelength slopes to those predicted by the standard thin accretion disk model, we find that on average the disks are larger than predicted by nearly an order of magnitude, with sizes that grow with wavelength with an average slope of ~0.2 rather than the slope of 4/3 predicted by the standard thin disk theory. Though the error bars on the slope are large for individual quasars, the large sample size lends weight to the overall result. Our results present severe difficulties for a standard thin accretion disk as the main source of UV/optical radiation from quasars.Comment: 21 pages, 9 tables, 10 figures. Fairly significant changes made to match published version, including the addition of an extra table, and extra figure, and some explanatory tex

A 15.65 solar mass black hole in an eclipsing binary in the nearby spiral galaxy Messier 33

Stellar-mass black holes are discovered in X-ray emitting binary systems, where their mass can be determined from the dynamics of their companion stars. Models of stellar evolution have difficulty producing black holes in close binaries with masses >10 solar masses, which is consistent with the fact that the most massive stellar black holes known so all have masses within 1 sigma of 10 solar masses. Here we report a mass of 15.65 +/- 1.45 solar masses for the black hole in the recently discovered system M33 X-7, which is located in the nearby galaxy Messier 33 (M33) and is the only known black hole that is in an eclipsing binary. In order to produce such a massive black hole, the progenitor star must have retained much of its outer envelope until after helium fusion in the core was completed. On the other hand, in order for the black hole to be in its present 3.45 day orbit about its 70.0 +/- 6.9 solar mass companion, there must have been a ``common envelope'' phase of evolution in which a significant amount of mass was lost from the system. We find the common envelope phase could not have occured in M33 X-7 unless the amount of mass lost from the progenitor during its evolution was an order of magnitude less than what is usually assumed in evolutionary models of massive stars.Comment: To appear in Nature October 18, 2007. Four figures (one color figure degraded). Differs slightly from published version. Supplementary Information follows in a separate postin

Masses, radii, and orbits of small Kepler planets : The transition from gaseous to rocky planets

We report on the masses, sizes, and orbits of the planets orbiting 22 Kepler stars. There are 49 planet candidates around these stars, including 42 detected through transits and 7 revealed by precise Doppler measurements of the host stars. Based on an analysis of the Kepler brightness measurements, along with high-resolution imaging and spectroscopy, Doppler spectroscopy, and (for 11 stars) asteroseismology, we establish low false-positive probabilities (FPPs) for all of the transiting planets (41 of 42 have an FPP under 1%), and we constrain their sizes and masses. Most of the transiting planets are smaller than three times the size of Earth. For 16 planets, the Doppler signal was securely detected, providing a direct measurement of the planet's mass. For the other 26 planets we provide either marginal mass measurements or upper limits to their masses and densities; in many cases we can rule out a rocky composition. We identify six planets with densities above 5 g cm-3, suggesting a mostly rocky interior for them. Indeed, the only planets that are compatible with a purely rocky composition are smaller than 2 R ⊕. Larger planets evidently contain a larger fraction of low-density material (H, He, and H2O).Peer reviewedFinal Accepted Versio

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations