Dorsomorphin, a Selective Small Molecule Inhibitor of BMP Signaling, Promotes Cardiomyogenesis in Embryonic Stem Cells

Background: Pluripotent embryonic stem (ES) cells, which have the capacity to give rise to all tissue types in the body, show great promise as a versatile source of cells for regenerative therapy. However, the basic mechanisms of lineage specification of pluripotent stem cells are largely unknown, and generating sufficient quantities of desired cell types remains a formidable challenge. Small molecules, particularly those that modulate key developmental pathways like the bone morphogenetic protein (BMP) signaling cascade, hold promise as tools to study in vitro lineage specification and to direct differentiation of stem cells toward particular cell types. Methodology/Principal Findings: We describe the use of dorsomorphin, a selective small molecule inhibitor of BMP signaling, to induce myocardial differentiation in mouse ES cells. Cardiac induction is very robust, increasing the yield of spontaneously beating cardiomyocytes by at least 20 fold. Dorsomorphin, unlike the endogenous BMP antagonist Noggin, robustly induces cardiomyogenesis when treatment is limited to the initial 24-hours of ES cell differentiation. Quantitative-PCR analyses of differentiating ES cells indicate that pharmacological inhibition of BMP signaling during the early critical stage promotes the development of the cardiomyocyte lineage, but reduces the differentiation of endothelial, smooth muscle, and hematopoietic cells. Conclusions/Significance: Administration of a selective small molecule BMP inhibitor during the initial stages of ES cell differentiation substantially promotes the differentiation of primitive pluripotent cells toward the cardiomyocytic lineage, apparently at the expense of other mesodermal lineages. Small molecule modulators of developmental pathways like dorsomorphin could become versatile pharmacological tools for stem cell research and regenerative medicine

Detecting the orientation of magnetic fields in galaxy clusters

Clusters of galaxies, filled with hot magnetized plasma, are the largest bound objects in existence and an important touchstone in understanding the formation of structures in our Universe. In such clusters, thermal conduction follows field lines, so magnetic fields strongly shape the cluster's thermal history; that some have not since cooled and collapsed is a mystery. In a seemingly unrelated puzzle, recent observations of Virgo cluster spiral galaxies imply ridges of strong, coherent magnetic fields offset from their centre. Here we demonstrate, using three-dimensional magnetohydrodynamical simulations, that such ridges are easily explained by galaxies sweeping up field lines as they orbit inside the cluster. This magnetic drape is then lit up with cosmic rays from the galaxies' stars, generating coherent polarized emission at the galaxies' leading edges. This immediately presents a technique for probing local orientations and characteristic length scales of cluster magnetic fields. The first application of this technique, mapping the field of the Virgo cluster, gives a startling result: outside a central region, the magnetic field is preferentially oriented radially as predicted by the magnetothermal instability. Our results strongly suggest a mechanism for maintaining some clusters in a 'non-cooling-core' state.Comment: 48 pages, 21 figures, revised version to match published article in Nature Physics, high-resolution version available at http://www.cita.utoronto.ca/~pfrommer/Publications/pfrommer-dursi.pd

Effectiveness of a Regional Prepregnancy Care Program in Women With Type 1 and Type 2 Diabetes: Benefits beyond glycemic control

OBJECTIVE: To implement and evaluate a regional prepregnancy care program in women with type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS: Prepregnancy care was promoted among patients and health professionals and delivered across 10 regional maternity units. A prospective cohort study of 680 pregnancies in women with type 1 and type 2 diabetes was performed. Primary outcomes were adverse pregnancy outcome (congenital malformation, stillbirth, or neonatal death), congenital malformation, and indicators of pregnancy preparation (5 mg folic acid, gestational age, and A1C). Comparisons were made with a historical cohort (n = 613 pregnancies) from the same units during 1999-2004. RESULTS: A total of 181 (27%) women attended, and 499 women (73%) did not attend prepregnancy care. Women with prepregnancy care presented earlier (6.7 vs. 7.7 weeks; P < 0.001), were more likely to take 5 mg preconception folic acid (88.2 vs. 26.7%; P < 0.0001) and had lower A1C levels (A1C 6.9 vs. 7.6%; P < 0.0001). They had fewer adverse pregnancy outcomes (1.3 vs. 7.8%; P = 0.009). Multivariate logistic regression confirmed that in addition to glycemic control, lack of prepregnancy care was independently associated with adverse outcome (odds ratio 0.2 [95% CI 0.05-0.89]; P = 0.03). Compared with 1999-2004, folic acid supplementation increased (40.7 vs. 32.5%; P = 0.006) and congenital malformations decreased (4.3 vs. 7.3%; P = 0.04). CONCLUSIONS: Regional prepregnancy care was associated with improved pregnancy preparation and reduced risk of adverse pregnancy outcome in type 1 and type 2 diabetes. Prepregnancy care had benefits beyond improved glycemic control and was a stronger predictor of pregnancy outcome than maternal obesity, ethnicity, or social disadvantage

Mass and Charge in Brane-World and Non-Compact Kaluza-Klein Theories in 5 Dim

In classical Kaluza-Klein theory, with compactified extra dimensions and without scalar field, the rest mass as well as the electric charge of test particles are constants of motion. We show that in the case of a large extra dimension this is no longer so. We propose the Hamilton-Jacobi formalism, instead of the geodesic equation, for the study of test particles moving in a five-dimensional background metric. This formalism has a number of advantages: (i) it provides a clear and invariant definition of rest mass, without the ambiguities associated with the choice of the parameters used along the motion in 5D and 4D, (ii) the electromagnetic field can be easily incorporated in the discussion, and (iii) we avoid the difficulties associated with the "splitting" of the geodesic equation. For particles moving in a general 5D metric, we show how the effective rest mass, as measured by an observer in 4D, varies as a consequence of the large extra dimension. Also, the fifth component of the momentum changes along the motion. This component can be identified with the electric charge of test particles. With this interpretation, both the rest mass and the charge vary along the trajectory. The constant of motion is now a combination of these quantities. We study the cosmological variations of charge and rest mass in a five-dimensional bulk metric which is used to embed the standard k = 0 FRW universes. The time variations in the fine structure "constant" and the Thomson cross section are also discussed.Comment: V2: References added, discussion extended. V3 is identical to V2, references updated. To appear in General Relativity and Gravitatio

Massive Spin-2 States as the Origin of the Top Quark Forward-Backward Asymmetry

We show that the anomalously large top quark forward-backward asymmetry observed by CDF and D\O\, can naturally be accommodated in models with flavor-violating couplings of a new massive spin-2 state to quarks. Regardless of its origin, the lowest-order couplings of a spin-2 boson to fermions are analogous to the coupling of the graviton to energy/momentum, leading to strong sensitivity of the effects associated with its virtual exchange to the energy scales at hand. Precisely due to this fact, the observed dependence of the asymmetry on the $t\bar t$ invariant mass fits nicely into the proposed framework. In particular, we find a vast parameter space which can lead to the central value for the observed forward-backward asymmetry in the high mass bin, while being in accord with all of the existing experimental constraints.Comment: added discussion of differential observables at the LHC, matches version accepted for publication in JHE

VAST: An ASKAP Survey for Variables and Slow Transients

The Australian Square Kilometre Array Pathfinder (ASKAP) will give us an unprecedented opportunity to investigate the transient sky at radio wavelengths. In this paper we present VAST, an ASKAP survey for Variables and Slow Transients. VAST will exploit the wide-field survey capabilities of ASKAP to enable the discovery and investigation of variable and transient phenomena from the local to the cosmological, including flare stars, intermittent pulsars, X-ray binaries, magnetars, extreme scattering events, interstellar scintillation, radio supernovae and orphan afterglows of gamma ray bursts. In addition, it will allow us to probe unexplored regions of parameter space where new classes of transient sources may be detected. In this paper we review the known radio transient and variable populations and the current results from blind radio surveys. We outline a comprehensive program based on a multi-tiered survey strategy to characterise the radio transient sky through detection and monitoring of transient and variable sources on the ASKAP imaging timescales of five seconds and greater. We also present an analysis of the expected source populations that we will be able to detect with VAST.Comment: 29 pages, 8 figures. Submitted for publication in Pub. Astron. Soc. Australi

The Raychaudhuri equations: a brief review

We present a brief review on the Raychaudhuri equations. Beginning with a summary of the essential features of the original article by Raychaudhuri and subsequent work of numerous authors, we move on to a discussion of the equations in the context of alternate non--Riemannian spacetimes as well as other theories of gravity, with a special mention on the equations in spacetimes with torsion (Einstein--Cartan--Sciama--Kibble theory). Finally, we give an overview of some recent applications of these equations in General Relativity, Quantum Field Theory, String Theory and the theory of relativisitic membranes. We conclude with a summary and provide our own perspectives on directions of future research.Comment: 35 pages, two figures, to appear in the special issue of Pramana dedicated to the memory of A. K. Raychaudhur

The Phase II Murchison Widefield Array: Design overview

We describe the motivation and design details of the "Phase II" upgrade of the Murchison Widefield Array (MWA) radio telescope. The expansion doubles to 256 the number of antenna tiles deployed in the array. The new antenna tiles enhance the capabilities of the MWA in several key science areas. Seventy-two of the new tiles are deployed in a regular configuration near the existing MWA core. These new tiles enhance the surface brightness sensitivity of the MWA and will improve the ability of the MWA to estimate the slope of the Epoch of Reionisation power spectrum by a factor of ~3.5. The remaining 56 tiles are deployed on long baselines, doubling the maximum baseline of the array and improving the array u,v coverage. The improved imaging capabilities will provide an order of magnitude improvement in the noise floor of MWA continuum images. The upgrade retains all of the features that have underpinned the MWA's success (large field-of-view, snapshot image quality, pointing agility) and boosts the scientific potential with enhanced imaging capabilities and by enabling new calibration strategies