Localizing Transcriptional Regulatory Elements at the Mouse Dlk1 Locus

Much effort has focused recently on determining the mechanisms that control the allele-specific expression of genes subject to genomic imprinting, yet imprinting regulation is only one aspect of configuring appropriate expression of these genes. Imprinting control mechanisms must interact with those regulating the tissue-specific expression pattern of each imprinted gene in a cluster. Proper expression of the imprinted Delta-like 1 (Dlk1) - Maternally expressed gene 3 (Meg3) gene pair is required for normal fetal development in mammals, yet the mechanisms that control tissue-specific expression of these genes are unknown. We have used a combination of in vivo and in vitro expression assays to localize cis-regulatory elements that may regulate Dlk1 expression in the mouse embryo. A bacterial artificial chromosome transgene encompassing the Dlk1 gene and 77 kb of flanking sequence conferred expression in most endogenous Dlk1-expressing tissues. In combination with previous transgenic data, these experiments localize the majority of Dlk1 cis-regulatory elements to a 41 kb region upstream of the gene. Cross-species sequence conservation was used to further define potential regulatory elements, several of which functioned as enhancers in a luciferase expression assay. Two of these elements were able to drive expression of a lacZ reporter transgene in Dlk1-expressing tissues in the mouse embryo. The sequence proximal to Dlk1 therefore contains at least two discrete regions that may regulate tissue-specificity of Dlk1 expression

A Soft Budget Constraint Explanation for the Venture Capital Cycle

We explore why venture capital funds limit the amount of capital they raise and do not reinvest the proceeds. This structure is puzzling because it leads to a succession of several funds financing each new venture which multiplies the well known agency problems. We argue that an inside investor cannot provide a hard budget constraint while a less well informed outsider can. Therefore, the venture capitalist delegates the continuation decision to the outsider by ex ante restricting the amount of capital he has under management. The soft budget constraint problem becomes the more important the higher the entrepreneur’s private benefits are and the higher the probability of failure of a project is

Immortalized myogenic cells from congenital muscular dystrophy type1A patients recapitulate aberrant caspase activation in pathogenesis: a new tool for MDC1A research

BACKGROUND: Congenital muscular dystrophy Type 1A (MDC1A) is a severe, recessive disease of childhood onset that is caused by mutations in the LAMA2 gene encoding laminin-alpha2. Studies with both mouse models and primary cultures of human MDC1A myogenic cells suggest that aberrant activation of cell death is a significant contributor to pathogenesis in laminin-alpha2-deficiency. METHODS: To overcome the limited population doublings of primary cultures, we generated immortalized, clonal lines of human MDC1A myogenic cells via overexpression of both CDK4 and the telomerase catalytic component (human telomerase reverse transcriptase (hTERT)). RESULTS: The immortalized MDC1A myogenic cells proliferated indefinitely when cultured at low density in high serum growth medium, but retained the capacity to form multinucleate myotubes and express muscle-specific proteins when switched to low serum medium. When cultured in the absence of laminin, myotubes formed from immortalized MDC1A myoblasts, but not those formed from immortalized healthy or disease control human myoblasts, showed significantly increased activation of caspase-3. This pattern of aberrant caspase-3 activation in the immortalized cultures was similar to that found previously in primary MDC1A cultures and laminin-alpha2-deficient mice. CONCLUSIONS: Immortalized MDC1A myogenic cells provide a new resource for studies of pathogenetic mechanisms and for screening possible therapeutic approaches in laminin-alpha2-deficiency

Insight from PREFACE & AWA on Tropical Atlantic Tuna ecology and effects on western African fisheries economies

International audienc

Analysis of the Type IIn Supernova 1998S: Effects of Circumstellar Interaction on Observed Spectra

We present spectral analysis of early observations of the Type IIn supernova 1998S using the general non-local thermodynamic equilibrium atmosphere code \tt PHOENIX}. We model both the underlying supernova spectrum and the overlying circumstellar interaction region and produce spectra in good agreement with observations. The early spectra are well fit by lines produced primarily in the circumstellar region itself, and later spectra are due primarily to the supernova ejecta. Intermediate spectra are affected by both regions. A mass-loss rate of order $\dot M \sim 0.0001-0.001$\msol yr$^{-1}$ is inferred for a wind speed of 100-1000 \kmps. We discuss how future self-consistent models will better clarify the underlying progenitor structure.Comment: to appear in ApJ, 2001, 54

New Low Accretion-Rate Magnetic Binary Systems and their Significance for the Evolution of Cataclysmic Variables

Discoveries of two new white dwarf plus M star binaries with striking optical cyclotron emission features from the Sloan Digital Sky Survey (SDSS) brings to six the total number of X-ray faint, magnetic accretion binaries that accrete at rates < 10^{-13} Msun/yr, or <1% of the values normally encountered in cataclysmic variables. This fact, coupled with donor stars that underfill their Roche lobes and very cool white dwarfs, brand the binaries as post common-envelope systems whose orbits have not yet decayed to the point of Roche-lobe contact. They are pre-magnetic CVs, or pre-Polars. The systems exhibit spin/orbit synchronism and apparently accrete by efficient capture of the stellar wind from the secondary star, a process that has been dubbed a ``magnetic siphon''. Because of this, period evolution of the binaries will occur solely by gravitational radiation, which is very slow for periods >3 hr. Optical surveys for the cyclotron harmonics appear to be the only means of discovery, so the space density of pre-Polars could rival that of Polars, and the binaries provide an important channel of progenitors (in addition to the asynchronous Intermediate Polars). Both physical and SDSS observational selection effects are identified that may help to explain the clumping of all six systems in a narrow range of magnetic field strength around 60 MG.Comment: 25 pages, 13 figures, Accepted to Ap

In situ epitaxial MgB2 thin films for superconducting electronics

A thin film technology compatible with multilayer device fabrication is critical for exploring the potential of the 39-K superconductor magnesium diboride for superconducting electronics. Using a Hybrid Physical-Chemical Vapor Deposition (HPCVD) process, it is shown that the high Mg vapor pressure necessary to keep the MgB$_2$ phase thermodynamically stable can be achieved for the {\it in situ} growth of MgB$_2$ thin films. The films grow epitaxially on (0001) sapphire and (0001) 4H-SiC substrates and show a bulk-like $T_c$ of 39 K, a $J_c$(4.2K) of $1.2 \times 10^7$ A/cm$^2$ in zero field, and a $H_{c2}(0)$ of 29.2 T in parallel magnetic field. The surface is smooth with a root-mean-square roughness of 2.5 nm for MgB$_2$ films on SiC. This deposition method opens tremendous opportunities for superconducting electronics using MgB$_2$

Variation in Tropical Reef Symbiont Metagenomes Defined by Secondary Metabolism

The complex evolution of secondary metabolism is important in biology, drug development, and synthetic biology. To examine this problem at a fine scale, we compared the genomes and chemistry of 24 strains of uncultivated cyanobacteria, Prochloron didemni, that live symbiotically with tropical ascidians and that produce natural products isolated from the animals. Although several animal species were obtained along a >5500 km transect of the Pacific Ocean, P. didemni strains are >97% identical across much of their genomes, with only a few exceptions concentrated in secondary metabolism. Secondary metabolic gene clusters were sporadically present or absent in identical genomic locations with no consistent pattern of co-occurrence. Discrete mutations were observed, leading to new chemicals that we isolated from animals. Functional cassettes encoding diverse chemicals are exchanged among a single population of symbiotic P. didemni that spans the tropical Pacific, providing the host animals with a varying arsenal of secondary metabolites

Skyrmions and edge spin excitations in quantum Hall droplets

We present an analysis of spin-textures in Quantum Hall droplets, for filling factors $\nu \simeq 1$. Analytical wavefunctions with well defined quantum numbers are given for the low-lying states of the system which result to be either bulk skyrmions or edge spin excitations. We compute dispersion relations and study how skyrmions become ground states of the Quantum Hall droplet at $\nu \gtrsim 1$. A Hartree-Fock approximation is recovered and discussed for those spin textures.Comment: RevTeX, four postscript figures appende