Downregulation of genes with a function in axon outgrowth and synapse formation in motor neurones of the VEGF(delta/delta) mouse model of amyotrophic lateral sclerosis

Background: Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen that stimulates vasculogenesis. It has also been shown to act as a neurotrophic factor in vitro and in vivo. Deletion of the hypoxia response element of the promoter region of the gene encoding VEGF in mice causes a reduction in neural VEGF expression, and results in adult-onset motor neurone degeneration that resembles amyotrophic lateral sclerosis (ALS). Investigating the molecular pathways to neurodegeneration in the VEGF(delta/delta) mouse model of ALS may improve understanding of the mechanisms of motor neurone death in the human disease. Results: Microarray analysis was used to determine the transcriptional profile of laser captured spinal motor neurones of transgenic and wild-type littermates at 3 time points of disease. 324 genes were significantly differentially expressed in motor neurones of presymptomatic VEGF(delta/delta) mice, 382 at disease onset, and 689 at late stage disease. Massive transcriptional downregulation occurred with disease progression, associated with downregulation of genes involved in RNA processing at late stage disease. VEGF(delta/delta) mice showed reduction in expression, from symptom onset, of the cholesterol synthesis pathway, and genes involved in nervous system development, including axonogenesis, synapse formation, growth factor signalling pathways, cell adhesion and microtubule-based processes. These changes may reflect a reduced capacity of VEGF(delta/delta) mice for maintenance and remodelling of neuronal processes in the face of demands of neural plasticity. The findings are supported by the demonstration that in primary motor neurone cultures from VEGF(delta/delta) mice, axon outgrowth is significantly reduced compared to wild-type littermates. Conclusions: Downregulation of these genes involved in axon outgrowth and synapse formation in adult mice suggests a hitherto unrecognized role of VEGF in the maintenance of neuronal circuitry. Dysregulation of VEGF may lead to neurodegeneration through synaptic regression and dying-back axonopathy

Conformal regularization of Einstein's field equations

To study asymptotic structures, we regularize Einstein's field equations by means of conformal transformations. The conformal factor is chosen so that it carries a dimensional scale that captures crucial asymptotic features. By choosing a conformal orthonormal frame we obtain a coupled system of differential equations for a set of dimensionless variables, associated with the conformal dimensionless metric, where the variables describe ratios with respect to the chosen asymptotic scale structure. As examples, we describe some explicit choices of conformal factors and coordinates appropriate for the situation of a timelike congruence approaching a singularity. One choice is shown to just slightly modify the so-called Hubble-normalized approach, and one leads to dimensionless first order symmetric hyperbolic equations. We also discuss differences and similarities with other conformal approaches in the literature, as regards, e.g., isotropic singularities.Comment: New title plus corrections and text added. To appear in CQ

Hubble Space Telescope WFPC2 Imaging of SN 1979C and Its Environment

The locations of supernovae in the local stellar and gaseous environment in galaxies contain important clues to their progenitor stars. As part of a program to study the environments of supernovae using Hubble Space Telescope (HST) imaging data, we have examined the environment of the Type II-L SN 1979C in NGC 4321 (M100). We place more rigorous constraints on the mass of the SN progenitor, which may have had a mass M \approx 17--18 M_sun. Moreover, we have recovered and measured the brightness of SN 1979C, m=23.37 in F439W (~B; m_B(max) = 11.6), 17 years after explosion. .Comment: 18 pages, 8 figures, submitted to PAS

Dynamical systems approach to G2 cosmology

In this paper we present a new approach for studying the dynamics of spatially inhomogeneous cosmological models with one spatial degree of freedom. By introducing suitable scale-invariant dependent variables we write the evolution equations of the Einstein field equations as a system of autonomous partial differential equations in first-order symmetric hyperbolic format, whose explicit form depends on the choice of gauge. As a first application, we show that the asymptotic behaviour near the cosmological initial singularity can be given a simple geometrical description in terms of the local past attractor on the boundary of the scale-invariant dynamical state space. The analysis suggests the name ``asymptotic silence'' to describe the evolution of the gravitational field near the cosmological initial singularity.Comment: 28 pages, 3 tables, 1 *.eps figure, LaTeX2e (10pt), matches version accepted for publication by Classical and Quantum Gravit

A new proof of the Bianchi type IX attractor theorem

We consider the dynamics towards the initial singularity of Bianchi type IX vacuum and orthogonal perfect fluid models with a linear equation of state. The `Bianchi type IX attractor theorem' states that the past asymptotic behavior of generic type IX solutions is governed by Bianchi type I and II vacuum states (Mixmaster attractor). We give a comparatively short and self-contained new proof of this theorem. The proof we give is interesting in itself, but more importantly it illustrates and emphasizes that type IX is special, and to some extent misleading when one considers the broader context of generic models without symmetries.Comment: 26 pages, 5 figure

SIGNALS FOR MINIMAL SUPERGRAVITY AT THE CERN LARGE HADRON COLLIDER: MULTI-JET PLUS MISSING ENERGY CHANNEL,

We use ISAJET to perform a detailed study of the missing transverse energy \eslt plus multi-jet signal expected from superparticle production at the CERN LHC. Our analysis is performed within the framework of the minimal supergravity model with gauge coupling unification and radiative electroweak symmetry breaking. We delineate the region of parameter space where the \eslt supersymmetry signal should be observable at the LHC and compare it to the regions explorable via searches for sleptons and for chargino/neutralino production. We confirm that, given a data sample of 10~\fb^{-1}, $m_{\tg}\sim 1300$ GeV can be explored if m_{\tq}\gg m_{\tg}, while $m_{\tg}\sim 2000$ GeV can be probed if m_{\tq}\simeq m_{\tg}. We further examine what information can be gleaned from scrutinizing this event sample. For instance, the multi-jet multiplicity yields information on whether squark production makes a significant contribution to the observed \eslt sample. Furthermore, reconstructing hemispheric masses may yield a measure of $m_{\tg}$ to $\sim 15-25\%$. Finally, for favourable ranges of parameters, by reconstructing masses of tagged $b\bar{b}$ jet pairs, it may be possible to detect Higgs bosons produced via sparticle cascade decay chains.Comment: 22 pages (REVTEX); a PS text file (etmiss.ps) and 12 figures (etlhc.uu or etlhc.ps) can be obtained via anonymous ftp at ftp://hep.fsu.edu/anonymous.bae

Observations of the Crab Nebula and its pulsar in the far-ultraviolet and in the optical

We present HST/STIS far-UV observations of the Crab nebula and its pulsar. Broad, blueshifted absorption arising in the nebula is seen in C IV 1550, reaching about 2500 km/s. This can be interpreted as evidence for a fast outer shell, and we adopt a spherically symmetric model to constrain the properties of this. We find that the density appears to decrease outward in the shell. A lower limit to the mass is 0.3 solar masses with an accompanying kinetic energy of 1.5EE{49} ergs. A massive 10^{51} erg shell cannot be excluded, but is less likely if the density profile is much steeper than R^{-4} and the velocity is <6000 km/s. The observations cover the region 1140-1720 A. With the time-tag mode of the spectrograph we obtain the pulse profile. It is similar to that in the near-UV, although the primary peak is marginally narrower. Together with the near-UV data, and new optical data from NOT, our spectrum of the pulsar covers the entire region from 1140-9250 A. Dereddening the spectrum gives a flat spectrum for E(B-V)=0.52, R=3.1. This dereddened spectrum of the Crab pulsar can be fitted by a power law with spectral index alpha_{\nu} = 0.11 +/- 0.04. The main uncertainty is the amount and characteristics of the interstel- lar reddening, and we have investigated the dependence of \alpha_{\nu} on E(B-V) and R. In the extended emission covered by our 25" x 0.5" slit in the far-UV, we detect C IV 1550 and He II 1640 emission lines from the Crab nebula. Several interstellar absorption lines are detected toward the pulsar. The Ly alpha absorption indicates a column density of 3.0+/-0.5\EE{21} cm^{-2} of neutral hydrogen, which agrees well with our estimate of E(B-V)=0.52 mag. Other lines show no evidence of severe depletion of metals in atomic gas.Comment: 18 pages emulateapj style, including 10 figures. ApJ, accepte

Spike Oscillations

According to Belinskii, Khalatnikov and Lifshitz (BKL), a generic spacelike singularity is characterized by asymptotic locality: Asymptotically, toward the singularity, each spatial point evolves independently from its neighbors, in an oscillatory manner that is represented by a sequence of Bianchi type I and II vacuum models. Recent investigations support a modified conjecture: The formation of spatial structures (`spikes') breaks asymptotic locality. The complete description of a generic spacelike singularity involves spike oscillations, which are described by sequences of Bianchi type I and certain inhomogeneous vacuum models. In this paper we describe how BKL and spike oscillations arise from concatenations of exact solutions in a Hubble-normalized state space setting, suggesting the existence of hidden symmetries and showing that the results of BKL are part of a greater picture.Comment: 38 pages, 14 figure

Asymptotic silence-breaking singularities

We discuss three complementary aspects of scalar curvature singularities: asymptotic causal properties, asymptotic Ricci and Weyl curvature, and asymptotic spatial properties. We divide scalar curvature singularities into two classes: so-called asymptotically silent singularities and non-generic singularities that break asymptotic silence. The emphasis in this paper is on the latter class which have not been previously discussed. We illustrate the above aspects and concepts by describing the singularities of a number of representative explicit perfect fluid solutions.Comment: 25 pages, 6 figure

Increased chromosomal radiosensitivity in asymptomatic carriers of a heterozygous BRCA1 mutation

Background: Breast cancer risk increases drastically in individuals carrying a germline BRCA1 mutation. The exposure to ionizing radiation for diagnostic or therapeutic purposes of BRCA1 mutation carriers is counterintuitive, since BRCA1 is active in the DNA damage response pathway. The aim of this study was to investigate whether healthy BRCA1 mutations carriers demonstrate an increased radiosensitivity compared with healthy individuals. Methods: We defined a novel radiosensitivity indicator (RIND) based on two endpoints measured by the G2 micronucleus assay, reflecting defects in DNA repair and G2 arrest capacity after exposure to doses of 2 or 4 Gy. We investigated if a correlation between the RIND score and nonsense-mediated decay (NMD) could be established. Results: We found significantly increased radiosensitivity in the cohort of healthy BRCA1 mutation carriers compared with healthy controls. In addition, our analysis showed a significantly different distribution over the RIND scores (p = 0.034, Fisher’s exact test) for healthy BRCA1 mutation carriers compared with non-carriers: 72 % of mutation carriers showed a radiosensitive phenotype (RIND score 1–4), whereas 72 % of the healthy volunteers showed no radiosensitivity (RIND score 0). Furthermore, 28 % of BRCA1 mutation carriers had a RIND score of 3 or 4 (not observed in control subjects). The radiosensitive phenotype was similar for relatives within several families, but not for unrelated individuals carrying the same mutation. The median RIND score was higher in patients with a mutation leading to a premature termination codon (PTC) located in the central part of the gene than in patients with a germline mutation in the 5′ end of the gene. Conclusions: We show that BRCA1 mutations are associated with a radiosensitive phenotype related to a compromised DNA repair and G2 arrest capacity after exposure to either 2 or 4 Gy. Our study confirms that haploinsufficiency is the mechanism involved in radiosensitivity in patients with a PTC allele, but it suggests that further research is needed to evaluate alternative mechanisms for mutations not subjected to NMD