Epac and the high affinity rolipram binding conformer of PDE4 modulate neurite outgrowth and myelination using an in vitro spinal cord injury model

<b>Background and Purpose</b><p></p> cAMP and pharmacological inhibition of PDE4, which degrades it, are promising therapeutic targets for the treatment of spinal cord injury (SCI). Using our previously described in vitro SCI model, we studied the mechanisms by which cAMP modulators promote neurite outgrowth and myelination using enantiomers of the PDE4-specific inhibitor rolipram and other modulators of downstream signalling effectors.<p></p> <b>Experimental Approach</b><p></p> Rat mixed neural cell myelinating cultures were cut with a scalpel and treated with enantiomers of the PDE4-specific inhibitor rolipram, Epac agonists and PKA antagonists. Neurite outgrowth, density and myelination were assessed by immunocytochemistry and cytokine levels analysed by qPCR.<p></p> <b>Key Results</b><p></p> Inhibition of the high-affinity rolipram-binding state (HARBS), rather than the low-affinity rolipram binding state (LARBS) PDE4 conformer promoted neurite outgrowth and myelination. These effects were mediated through the activation of Epac and not through PKA. Expression of the chemokine CXCL10, known to inhibit myelination, was markedly elevated in astrocytes after Rho inhibition and this was blocked by inhibition of Rho kinase or PDE4.<p></p> <b>Conclusions and Implications</b><p></p> PDE4 inhibitors targeted at the HARBS conformer or Epac agonists may provide promising novel targets for the treatment of SCI. Our study demonstrates the differential mechanisms of action of these compounds, as well as the benefit of a combined pharmacological approach and highlighting potential promising targets for the treatment of SCI. These findings need to be confirmed in vivo

Radiosondes for Characterizing the Martian Atmosphere

The National Weather Service (NWS) releases approximately 75,000 radiosondes each year to measure pressure, altitude, temperature, relative humidity, wind and cosmic radiation [1]. The data obtained from these measurements have led to a more thorough understanding of the Earth s lower atmosphere. On the contrary, there have been only six fully successful landings on Mars, and there is much less known about the variations in winds, density, etc., in the mid-regions of the Martian atmosphere (see Fig. 1). This data is vital to understanding Martian weather and the development of Mars landers for larger payloads [2,3,4]. Mars has too much atmosphere to land like is done on the moon, and too little atmosphere to land like is done on Earth. It is suggested that radiosondes could be added as secondary payloads on Mars missions and used to map physical properties in the different regions of the Martian atmosphere

The Assembly of the Red Sequence at z ~ 1: The Color and Spectral Properties of Galaxies in the Cl1604 Supercluster

We investigate the properties of the 525 spectroscopically confirmed members of the Cl1604 supercluster at z ~ 0.9 as part of the Observations of Redshift Evolution in Large Scale Environments survey. In particular, we focus on the photometric, stellar mass, morphological, and spectral properties of the 305 member galaxies of the eight clusters and groups that comprise the Cl1604 supercluster. Using an extensive Keck Low-Resolution Imaging Spectrometer (LRIS)/DEep Imaging Multi-Object Spectrograph (DEIMOS) spectroscopic database in conjunction with ten-band ground-based, Spitzer, and Hubble Space Telescope imaging, we investigate the buildup of the red sequence in groups and clusters at high redshift. Nearly all of the brightest and most massive red-sequence galaxies present in the supercluster environment are found to lie within the bounds of the cluster and group systems, with a surprisingly large number of such galaxies present in low-mass group systems. Despite the prevalence of these red-sequence galaxies, we find that the average cluster galaxy has a spectrum indicative of a star-forming galaxy, with a star formation rate between those of z ~ 1 field galaxies and moderate-redshift cluster galaxies. The average group galaxy is even more active, exhibiting spectral properties indicative of a starburst. The presence of massive, red galaxies and the high fraction of starbursting galaxies present in the group environment suggest that significant processing is occurring in group environments at z ~ 1 and earlier. There is a deficit of low-luminosity red-sequence galaxies in all Cl1604 clusters and groups, suggesting that such galaxies transition to the red sequence at later times. Extremely massive (~10^(12)M_☉) red-sequence galaxies routinely observed in rich clusters at z ~ 0 are also absent from the Cl1604 clusters and groups. We suggest that such galaxies form at later times through merging processes. There are significant populations of transition galaxies at intermediate stellar masses (log(M_*)=10.25-10.75) present in the group and cluster environments, suggesting that this range is important for the buildup of the red-sequence mass function at z ~ 1. Through a comparison of the transitional populations present in the Cl1604 cluster and group systems, we find evidence that massive blue-cloud galaxies are quenched earliest in the most dynamically relaxed systems and at progressively later times in dynamically unrelaxed systems

Load fluctuations drive actin network growth

The growth of actin filament networks is a fundamental biological process that drives a variety of cellular and intracellular motions. During motility, eukaryotic cells and intracellular pathogens are propelled by actin networks organized by nucleation-promoting factors, which trigger the formation of nascent filaments off the side of existing filaments in the network. A Brownian ratchet (BR) mechanism has been proposed to couple actin polymerization to cellular movements, whereby thermal motions are rectified by the addition of actin monomers at the end of growing filaments. Here, by following actin--propelled microspheres using three--dimensional laser tracking, we find that beads adhered to the growing network move via an object--fluctuating BR. Velocity varies with the amplitude of thermal fluctuation and inversely with viscosity as predicted for a BR. In addition, motion is saltatory with a broad distribution of step sizes that is correlated in time. These data point to a model in which thermal fluctuations of the microsphere or entire actin network, and not individual filaments, govern motility. This conclusion is supported by Monte Carlo simulations of an adhesion--based BR and suggests an important role for membrane tension in the control of actin--based cellular protrusions.Comment: To be published in PNA

Adsorption of Xe and Ar on Quasicrystalline Al-Ni-Co

An interaction potential energy between and adsorbate (Xe and Ar) and the 10-fold Al-Ni-Co quasicrystal is computed by summing over all adsorbate-substrate interatomic interactions. The quasicrystal atoms' coordinates are obtained from LEED experiments and the Lennard-Jones parameters of Xe-Al, Xe-Ni and Xe-Co are found using semiempirical combining rules. The resulting potential energy function of position is highly corrugated. Monolayer adsorption of Xe and Ar on the quasicrystal surface is investigated in two cases: 1) in the limit of low coverage (Henry's law regime), and 2) at somewhat larger coverage, when interactions between adatoms are considered through the second virial coefficient, C_{AAS}. A comparison with adsorption on a flat surface indicates that the corrugation enhances the effect on Xe-Xe (Ar-Ar) interactions. The theoretical results for the low coverage adsorption regime are compared to experimental (LEED isobar) data.Comment: 12 pages, 8figure

Pseudomorphic Growth of a Single Element Quasiperiodic Ultrathin Film on a Quasicrystal Substrate

An ultrathin film with a periodic interlayer spacing was grown by the deposition of Cu atoms on thefivefold surface of the icosahedral Al70 Pd21 Mn9 quasicrystal. For coverages from 5 to 25 monolayers, a distinctive quasiperiodic low-energy electron diffraction pattern is observed. Scanning tunneling microscopy images show that the in-plane structure comprises rows having separations of S = 4.5 �0.2 �A and L = 7.3 0.3 A, whose ratio equals � =1.618... within experimental error. The sequences of such row separations form segments of terms of the Fibonacci sequence, indicative of the formation of a pseudomorphic Cu film

A tandem duplication within the fibrillin 1 gene is associated with the mouse tight skin mutation.

Mice carrying the Tight skin (Tsk) mutation have thickened skin and visceral fibrosis resulting from an accumulation of extracellular matrix molecules. These and other connective tissue abnormalities have made Tskl + mice models for scleroderma, hereditary emphysema, and myocardial hypertrophy. Previously we localized Tsk to mouse chromosome 2 in a region syntenic with human chromosome 15. The microfibrillar glycoprotein gene, fibrillin 1 (FBN1), on human chromosome 15q, provided a candidate for the Tsk mutation. We now demonstrate that the Tsk chromosome harbors a 30- to 40-kb genomic duplication within the Fbn1 gene that results in a larger than normal in-frame Fbn1 transcript. These findings provide hypotheses to explain some of the phenotypic characteristics of Tskl + mice and the lethality of Tsk/Tsk embryos