The Fat-like Cadherin CDH-4 Acts Cell-Non-Autonomously in Anterior-Posterior Neuroblast Migration

Directed migration of neurons is critical in the normal and pathological development of the brain and central nervous system. In C. elegans, the bilateral Q neuroblasts, QR on the right and QL on the left, migrate anteriorly and posteriorly, respectively. Initial protrusion and migration of the Q neuroblasts is autonomously controlled by the transmembrane proteins UNC-40/DCC, PTP-3/LAR, and MIG-21. As QL migrates posteriorly, it encounters and EGL-20/Wnt signal that induces MAB-5/Hox expression that drives QL descendant posterior migration. QR migrates anteriorly away from EGL-20/Wnt and does not activate MAB-5/Hox, resulting in anterior QR descendant migration. A forward genetic screen for new mutations affecting initial Q migrations identified alleles of cdh-4, which caused defects in both QL and QR directional migration similar to unc-40, ptp-3, and mig-21. Previous studies showed that in QL, PTP-3/LAR and MIG-21 act in a pathway in parallel to UNC-40/DCC to drive posterior QL migration. Here we show genetic evidence that CDH-4 acts in the PTP-3/MIG-21 pathway in parallel to UNC-40/DCC to direct posterior QL migration. In QR, the PTP-3/MIG-21 and UNC-40/DCC pathways mutually inhibit each other, allowing anterior QR migration. We report here that CDH-4 acts in both the PTP-3/MIG-21 and UNC-40/DCC pathways in mutual inhibition in QR, and that CDH-4 acts cell-non-autonomously. Interaction of CDH-4 with UNC-40/DCC in QR but not QL represents an inherent left-right asymmetry in the Q cells, the nature of which is not understood. We conclude that CDH-4 might act as a permissive signal for each Q neuroblast to respond differently to anterior-posterior guidance information based upon inherent left-right asymmetries in the Q neuroblasts

The Fat-like Cadherin CDH-4 Acts Cell-Non-Autonomously in Anterior-Posterior Neuroblast Migration

Directed migration of neurons is critical in the normal and pathological development of the brain and central nervous system. In C. elegans, the bilateral Q neuroblasts, QR on the right and QL on the left, migrate anteriorly and posteriorly, respectively. Initial protrusion and migration of the Q neuroblasts is autonomously controlled by the transmembrane proteins UNC-40/DCC, PTP-3/LAR, and MIG-21. As QL migrates posteriorly, it encounters and EGL-20/Wnt signal that induces MAB-5/Hox expression that drives QL descendant posterior migration. QR migrates anteriorly away from EGL-20/Wnt and does not activate MAB-5/Hox, resulting in anterior QR descendant migration. A forward genetic screen for new mutations affecting initial Q migrations identified alleles of cdh-4, which caused defects in both QL and QR directional migration similar to unc-40, ptp-3, and mig-21. Previous studies showed that in QL, PTP-3/LAR and MIG-21 act in a pathway in parallel to UNC-40/DCC to drive posterior QL migration. Here we show genetic evidence that CDH-4 acts in the PTP-3/MIG-21 pathway in parallel to UNC-40/DCC to direct posterior QL migration. In QR, the PTP-3/MIG-21 and UNC-40/DCC pathways mutually inhibit each other, allowing anterior QR migration. We report here that CDH-4 acts in both the PTP-3/MIG-21 and UNC-40/DCC pathways in mutual inhibition in QR, and that CDH-4 acts cell-non-autonomously. Interaction of CDH-4 with UNC-40/DCC in QR but not QL represents an inherent left-right asymmetry in the Q cells, the nature of which is not understood. We conclude that CDH-4 might act as a permissive signal for each Q neuroblast to respond differently to anterior-posterior guidance information based upon inherent left-right asymmetries in the Q neuroblasts

MEF2C regulates outflow tract alignment and transcriptional control of Tdgf1

Congenital heart defects are the most common birth defects in humans, and those that affect the proper alignment of the outflow tracts and septation of the ventricles are a highly significant cause of morbidity and mortality in infants. A late differentiating population of cardiac progenitors, referred to as the anterior second heart field (AHF), gives rise to the outflow tract and the majority of the right ventricle and provides an embryological context for understanding cardiac outflow tract alignment and membranous ventricular septal defects. However, the transcriptional pathways controlling AHF development and their roles in congenital heart defects remain incompletely elucidated. Here, we inactivated the gene encoding the transcription factor MEF2C in the AHF in mice. Loss of Mef2c function in the AHF results in a spectrum of outflow tract alignment defects ranging from overriding aorta to double-outlet right ventricle and dextro-transposition of the great arteries. We identify Tdgf1, which encodes a Nodal co-receptor (also known as Cripto), as a direct transcriptional target of MEF2C in the outflow tract via an AHFrestricted Tdgf1 enhancer. Importantly, both the MEF2C and TDGF1 genes are associated with congenital heart defects in humans. Thus, these studies establish a direct transcriptional pathway between the core cardiac transcription factor MEF2C and the human congenital heart disease gene TDGF1. Moreover, we found a range of outflow tract alignment defects resulting from a single genetic lesion, supporting the idea that AHF-derived outflow tract alignment defects may constitute an embryological spectrum rather than distinct anomalies

SN1997cy/GRB970514 - A New Piece in the GRB Puzzle?

We present observations of SN1997cy, a supernova discovered as part of the Mount Stromlo Abell Cluster SN Search, which does not easily fit into the traditional classification scheme for supernovae. This object's extraordinary optical properties and coincidence with GRB970514, a short duration gamma ray burst, suggest a second case, after SN1998bw/GRB980425, for a SN-GRB association. SN1997cy is among the most luminous SNe yet discovered and has a peculiar spectrum. We present evidence that SN1997cy ejected approximately 2 solar masses of 56Ni, supported by its late-time light curve, and FeII/[FeIII] lines in its spectrum, although it is possible that both these observations can be explained via circumstellar interaction. While SN1998bw and SN1997cy appear to be very different objects with respect to both their gamma ray and optical properties, SN1997cy and the optical transient associated with GRB970508 have roughly similar late-time optical behavior. This similarity may indicate that the late-time optical output of these two intrinsically bright transient events have a common physical process. Although the connection between GRB970514 and SN1997cy is suggestive, it is not conclusive. However, if this association is real, followup of short duration GRBs detected with BATSE or HETE2 should reveal objects similar to SN1997cy.Comment: 26 pages including 6 postscript figures and 3 tables. Submitted to ApJ. Re-calibrated photometry - objects are about 0.3mags brighter than in original versio

Temporal relationship between instantaneous pressure gradients and peak‐to‐peak systolic ejection gradient in congenital aortic stenosis

ObjectiveWe sought to identify a time during cardiac ejection when the instantaneous pressure gradient (IPG) correlated best, and near unity, with peak‐to‐peak systolic ejection gradient (PPSG) in patients with congenital aortic stenosis. Noninvasive echocardiographic measurement of IPG has limited correlation with cardiac catheterization measured PPSG across the spectrum of disease severity of congenital aortic stenosis. A major contributor is the observation that these measures are inherently different with a variable relationship dependent on the degree of stenosis.DesignHemodynamic data from cardiac catheterizations utilizing simultaneous pressure measurements from the left ventricle (LV) and ascending aorta (AAo) in patients with congenital valvar aortic stenosis was retrospectively reviewed over the past 5 years. The cardiac cycle was standardized for all patients using the percentage of total LV ejection time (ET). Instantaneous gradient at 5% intervals of ET were compared to PPSG using linear regression and Bland‐Altman analysis.ResultsA total of 22 patients underwent catheterization at a median age of 13.7 years (interquartile range [IQR] 10.3‐18.0) and median weight of 51.1 kg (IQR 34.2‐71.6). The PPSG was 46.5 ± 12.6 mm Hg (mean ± SD) and correlated suboptimally with the maximum and mean IPG. The midsystolic IPG (occurring at 50% of ET) had the strongest correlation with the PPSG (PPSG = 0.97(IPG50%)–1.12, R2 = 0.88), while the IPG at 55% of ET was closest to unity (PPSG = 0.997(IPG55%)–1.17, R2 = 0.87).ConclusionsThe commonly measured maximum and mean IPG are suboptimal estimates of the PPSG in congenital aortic stenosis. Using catheter‐based data, IPG at 50%–55% of ejection correlates well with PPSG. This may allow for a more accurate estimation of PPSG via noninvasive assessment of IPG.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140042/1/chd12514.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/140042/2/chd12514_am.pd

Radio Observations of the Hubble Deep Field South region: I. Survey Description and Initial Results

This paper is the first of a series describing the results of the Australia Telescope Hubble Deep Field South (ATHDFS) radio survey. The survey was conducted at four wavelengths - 20, 11, 6, and 3 cm, over a 4-year period, and achieves an rms sensitivity of about 10 microJy at each wavelength. We describe the observations and data reduction processes, and present data on radio sources close to the centre of the HDF-S. We discuss in detail the properties of a subset of these sources. The sources include both starburst galaxies and galaxies powered by an active galactic nucleus, and range in redshift from 0.1 to 2.2. Some of them are characterised by unusually high radio-to-optical luminosities, presumably caused by dust extinction.Comment: Accepted by AJ. 32 pages, 4 tables, 3 figures. PDF with full-resolution figures is on http://www.atnf.csiro.au/people/rnorris/N197.pd

Glucocorticoids associate with cardiometabolic risk factors in black South Africans

Circulating glucocorticoids are associated with metabolic syndrome and related cardiometabolic risk factors in non-Africans. This study investigated these associations in Africans, whose metabolic phenotype reportedly differs from Europeans. Adiposity, blood pressure, glycaemia, insulin resistance, and lipid profile, were measured in 316 African men and 788 African women living in Soweto, Johannesburg. The 2009 harmonized criteria were used to define metabolic syndrome. Serum glucocorticoids were measured using liquid chromatography-mass spectrometry. Cortisol was associated with greater odds presenting with metabolic syndrome (odds ratio (95% CI) =1.50 (1.04, 2.17) and higher systolic (beta coefficient, β (95% CI) =0.04 (0.01, 0.08)) and diastolic (0.05 (0.02, 0.09)) blood pressure, but higher HDL (0.10 (0.02, 0.19)) and lower LDL (−0.14 (−0.24, −0.03)) cholesterol concentrations, in the combined sample of men and women. In contrast, corticosterone was only associated with higher insulin sensitivity (Matsuda index; 0.22 (0.03, 0.41)), but this was not independent of BMI. Sex-specific associations were observed, such that both cortisol and corticosterone were associated with higher fasting glucose (standardized β (95% CI): 0.24 (0.12, 0.36) for cortisol and 0.12 (0.01, 0.23) for corticosterone) and HbA1c (0.13 (0.01, 0.25) for cortisol and 0.12 (0.01, 0.24) for corticosterone) in men only, but lower HbA1c (0.10 (−0.20, −0.01) for cortisol and −0.09 (−0.18, −0.03) for corticosterone) in women only. Our study reports for the first time that associations between circulating glucocorticoid concentrations and key cardiometabolic risk factors exhibit both glucocorticoid- and sex-specificity in Africans

Carbon-Enhanced Metal-Poor Stars. III. Main-Sequence Turn-Off Stars from the SDSS/SEGUE Sample

The chemical compositions of seven Carbon-Enhanced Metal-Poor (CEMP) turn-off stars are determined from high-resolution spectroscopy. Five of them are selected from the SDSS/SEGUE sample of metal-poor stars. The effective temperatures of these objects are all higher than 6000 K, while their metallicities, parametrized by [Fe/H], are all below -2. Six of our program objects exhibit high abundance ratios of barium ([Ba/H]> +1), suggesting large contributions of the products of former AGB companions via mass transfer across binary systems. Combining our results with previous studies provides a total of 20 CEMP main-sequence turn-off stars for which the abundances of carbon and at least some neutron-capture elements are determined. Inspection of the [C/H] ratios for this sample of CEMP turn-off stars show that they are generally higher than those of CEMP giants; their dispersion in this ratio is also smaller. We take these results to indicate that the carbon-enhanced material provided from the companion AGB star is preserved at the surface of turn-off stars with no significant dilution. In contrast, a large dispersion in the observed [Ba/H] is found for the sample of CEMP turn-off stars, suggesting that the efficiency of the s-process in very metal-poor AGB stars may differ greatly from star to star. Four of the six stars from the SDSS/SEGUE sample exhibit kinematics that are associated with membership in the outer-halo population, a remarkably high fraction.Comment: 45 pages, 10 figures, 10 tables, Astrophysical Journal, in pres

Two Stellar Components in the Halo of the Milky Way

The halo of the Milky Way provides unique elemental abundance and kinematic information on the first objects to form in the Universe, which can be used to tightly constrain models of galaxy formation and evolution. Although the halo was once considered a single component, evidence for its dichotomy has slowly emerged in recent years from inspection of small samples of halo objects. Here we show that the halo is indeed clearly divisible into two broadly overlapping structural components -- an inner and an outer halo -- that exhibit different spatial density profiles, stellar orbits and stellar metallicities (abundances of elements heavier than helium). The inner halo has a modest net prograde rotation, whereas the outer halo exhibits a net retrograde rotation and a peak metallicity one-third that of the inner halo. These properties indicate that the individual halo components probably formed in fundamentally different ways, through successive dissipational (inner) and dissipationless (outer) mergers and tidal disruption of proto-Galactic clumps.Comment: Two stand-alone files in manuscript, concatenated together. The first is for the main paper, the second for supplementary information. The version is consistent with the version published in Natur