A structure-activity relationship study of dorsomorphin, a previously identified inhibitor of SMAD 1/5/8 phosphorylation by bone morphogenetic protein (BMP) type 1 receptors ALK2, 3, and 6, revealed that increased inhibitory activity could be accomplished by replacing the pendent 4-pyridine ring with 4-quinoline. The activity contributions of various nitrogen atoms in the core pyrazolo [1,5-a]pyrimidine ring were also examined by preparing and evaluating pyrrolo[1,2-a]pyrimidine and pyrazolo [1,5-a]pyridine derivatives. In addition, increased mouse liver microsome stability was achieved by replacing the ether substituent on the pendent phenyl ring with piperazine. Finally, an optimized compound 13 (LDN-193189 or DM-3189) demonstrated moderate pharmacokinetic characteristics (e.g. plasma t 1/2 = 1.6 h) following intraperitoneal administration in mice. These studies provide useful molecular probes for examining the in vivo pharmacology of BMP signaling inhibition.Bone morphogenetic proteins (BMPs) are a group of > 25 protein ligands that comprise a subset of the transforming growth factor β (TGF-β) family. BMPs modulate a multitude of biological processes, including bone and cartilage formation during embryogenesis. 1a However, they are also intimately involved with numerous nonosteogenic developmental and physiological processes throughout adulthood as well as several pathological conditions. BMPs bind to two classes of cell surface bone morphogenetic protein receptors (BMPR-I and BMPRII). 1a The BMPR-I receptor class consists of three receptor types, activin receptor-like kinase-2 (ALK-2 or ActR-IA), ALK-3 (BMPR-IA) and ALK-6 (BMPR-IB). The BMPR-II receptor class is comprised of three receptor types, BMPR-II, ActR-IIA and ActR-IIB. Binding of BMPs results in the formation of heterotetrameric complexes containing two type I and two *To whom correspondence should be addressed: Phone: 617-768-8640, Fax: 617-768-8606, E-mail: gcuny@rics.bwh.harvard.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Recently, dorsomorphin, 1, 7a, 11, 12 was discovered as an inhibitor of SMAD 1/5/8 phosphorylation by BMP type 1 receptors (ALK2, 3, and 6) utilizing a phenotypic screen to identify compounds that perturb embryonic dorsoventral axis formation. Furthermore, this inhibition was shown to decrease BMP-regulated hepatic hepcidin gene transcription, leading to increased iron levels in vivo. 7a However, 1 only demonstrated moderate inhibition of SMAD 1/5/8 phosphorylation by BMPR-I with an IC50 ~ 0.5 µM and lacks metabolic stability. Herein, we describe the results of a structu...

X-ray observations have revealed in other galaxies a class of extranuclear X-ray point sources with X-ray luminosities of 10 39 -10 41 ergs s À1 , exceeding the Eddington luminosity for stellar mass X-ray binaries. These ultraluminous X-ray sources (ULXs) may be powered by intermediate-mass black holes of a few thousand M or stellar mass black holes with special radiation processes. In this paper, we present a survey of ULXs in 313 nearby galaxies with D 25 > 1 0 within 40 Mpc with 467 ROSAT High Resolution Imager (HRI) archival observations. The HRI observations are reduced with uniform procedures, refined by simulations that help define the point source detection algorithm employed in this survey. A sample of 562 extragalactic X-ray point sources with L X ¼ 10 38 10 43 ergs s À1 is extracted from 173 survey galaxies, including 106 ULX candidates within the D 25 isophotes of 63 galaxies and 110 ULX candidates between 1D 25 and 2D 25 of 64 galaxies, from which a clean sample of 109 ULXs is constructed to minimize the contamination from foreground or background objects. The strong connection between ULXs and star formation is confirmed based on the striking preference of ULXs to occur in late-type galaxies, especially in star-forming regions such as spiral arms. ULXs are variable on timescales over days to years and exhibit a variety of long term variability patterns. The identifications of ULXs in the clean sample show some ULXs identified as supernovae (remnants), H ii regions/nebulae, or young massive stars in star-forming regions, and a few other ULXs identified as old globular clusters. In a subsequent paper, the statistic properties of the survey will be studied to calculate the occurrence frequencies and luminosity functions for ULXs in different types of galaxies to shed light on the nature of these enigmatic sources.

Flare events are mainly due to magnetic reconnection and thus are indicative of stellar activity. The Kepler Space Observatory records numerous stellar activities with unprecedented high photometric precision in flux measurements. It is perfectly suitable for carrying out a statistical study of flares. Here we present 540 M dwarfs with flare events discovered using Kepler long-cadence data. The normalized flare energy, as defined by the ratio to bolometric stellar luminosity, L L flare bol , is used to indicate the flare activity. We find that, similar to the X-ray luminosity relation, the L L flare bol versus P rot relation can also be described with three phases, supersaturation, saturation, and exponential decay, corresponding to an ultra-short period, a short period, and a long period. The flare activity and the number fraction of flaring stars in M dwarfs rise steeply near M4, which is consistent with the prediction of a turbulent dynamo. The size of starspots are positively correlated with flare activity. The L L flare bol ratio has a power-law dependence on L L H bol a , a parameter indicative of stellar chromosphere activity. According to this relation, a small enhancement in chromosphere activity may cause a huge rise in flare energy, which suggests that superflares or hyperflares may not need an extra excitation mechanism. Through a comparison study, we suggest that flare activity is a more suitable indicator for stellar activity, especially in the boundary region. However, contrary to what is expected, some M dwarfs with strong flares do not show any light variation caused by starspots. Follow-up observations are needed to investigate this problem.

The first extragalactic X-ray binary, LMC X-1, was discovered in 1969. In the 1980s, its compact primary was established as the fourth dynamical black hole candidate. Recently, we published accurate values for the mass of the black hole and the orbital inclination angle of the binary system. Building on these results, we have analyzed 53 X-ray spectra obtained by RXTE and, using a selected sample of 18 of these spectra, we have determined the dimensionless spin parameter of the black hole to be a * = 0.92 +0.05 −0.07 . This result takes into account all sources of observational and model-parameter uncertainties. The standard deviation around the mean value of a * for these 18 X-ray spectra, which were obtained over a span of several years, is only Δa * = 0.02. When we consider our complete sample of 53 RXTE spectra, we find a somewhat higher value of the spin parameter and a larger standard deviation. Finally, we show that our results based on RXTE data are confirmed by our analyses of selected X-ray spectra obtained by the XMM-Newton, BeppoSAX, and Ginga missions.

This paper reports the demonstration of optically pumped GeSn edge-emitting lasers grown on Si substrates. The whole device structures were grown by an industry standard chemical vapor deposition reactor using the low cost commercially available precursors SnCl4 and GeH4 in a single run epitaxy process. Temperature-dependent characteristics of laser-output versus pumping-laser-input showed lasing operation up to 110 K. The 10 K lasing threshold and wavelength were measured as 68 kW/cm2 and 2476 nm, respectively. Lasing characteristic temperature (T0) was extracted as 65 K.

All stellar mass black holes have hitherto been identified by X-rays emitted by gas that is accreting onto the black hole from a companion star. These systems are all binaries with black holes below 30 M ⊙ 1-4. Theory predicts, however, that X-ray emitting systems form a minority of the total population of star-black hole binaries 5, 6. When the black hole is not accreting gas, it can be found through radial velocity measurements of the motion of the companion star. Here we report radial velocity measurements of a Galactic star, LB-1, which is a B-type star, taken over two years. We find that the motion of the B-star and an accompanying Hα emission line require the presence of a dark companion with a mass of

The Chandra data archive is a treasure for various studies, and in this paper we exploit this valuable resource to study the X-ray point source populations in nearby galaxies. By 2007 December 14, 383 galaxies within 40 Mpc with isophotal major axis above 1 arcmin had been observed by 626 public ACIS observations, most of which were for the first time analyzed by this survey to study the X-ray point sources. Uniform data analysis procedures are applied to the 626 ACIS observations and lead to the detection of 28,099 point sources, which belong to 17,599 independent sources. These include 8700 sources observed twice or more and 1000 sources observed 10 times or more, providing us a wealth of data to study the long-term variability of these X-ray sources. Cross-correlation of these sources with galaxy isophotes led to 8519 sources within the D 25 isophotes of 351 galaxies, 3305 sources between the D 25 and 2D 25 isophotes of 309 galaxies, and additionally 5735 sources outside 2D 25 isophotes of galaxies. This survey has produced a uniform catalog, by far the largest, of 11,824 X-ray point sources within 2D 25 isophotes of 380 galaxies. Contamination analysis using the log N-log S relation shows that 74% of sources within 2D 25 isophotes above 10 39 erg s −1 , 71% of sources above 10 38 erg s −1 , 63% of sources above 10 37 erg s −1 , and 56% of all sources are truly associated with galaxies. Meticulous efforts have identified 234 X-ray sources with galactic nuclei of nearby galaxies. This archival survey leads to 300 ultraluminous X-ray sources (ULXs) with L X (0.3-8 keV) 2 × 10 39 erg s −1 within D 25 isophotes, 179 ULXs between D 25 and 2D 25 isophotes, and a total of 479 ULXs within 188 host galaxies, with about 324 ULXs truly associated with host galaxies based on the contamination analysis. About 4% of the sources exhibited at least one supersoft phase, and 70 sources are classified as ultraluminous supersoft sources with L X (0.3-8 keV)2 × 10 38 erg s −1 . With a uniform data set and good statistics, this survey enables future works on various topics, such as X-ray luminosity functions for the ordinary X-ray binary populations in different types of galaxies, and X-ray properties of galactic nuclei.

Ultraluminous X-ray (ULX) sources are extranuclear point sources in external galaxies with L X ¼ 10 39 10 41 ergs s À1 and are among the most poorly understood X-ray sources. To help understand their nature, we are trying to identify their optical counterparts by combining images from the Hubble Space Telescope (HST ) and the Chandra X-Ray Observatory. Here we report on the optical counterpart for the ULX in NGC 5204, which has average X-ray luminosity of $3 Â 10 39 ergs s À1 and has varied by a factor of 50% over the last 10 years. A unique optical counterpart to this ULX is found by carefully comparing the Chandra ACIS images and HST WFPC2 and ACS/HRC images. The spectral energy distribution and the HST/STIS far-ultraviolet (FUV) spectrum of this object show that it is a B0 Ib supergiant star with peculiarities, including the N v k1240 emission line, which is uncommon in B stellar spectra but has been predicted for X-ray-illuminated accretion disks and seen in some X-ray binaries. Study of its FUV spectrum leads to a binary model for this ULX in which the B0 Ib supergiant is overflowing its Roche lobe and accreting onto the compact primary, probably a black hole. This picture predicts an orbital period of $10 days for different black hole masses, which can be tested by future observations.