759 research outputs found

    The connexin43 mimetic peptide Gap19 inhibits hemichannels without altering gap junctional communication in astrocytes

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    In the brain, astrocytes represent the cellular population that expresses the highest amount of connexins (Cxs). This family of membrane proteins is the molecular constituent of gap junction channels and hemichannels that provide pathways for direct cytoplasm-to-cytoplasm and inside-out exchange, respectively. Both types of Cx channels are permeable to ions and small signaling molecules allowing astrocytes to establish dynamic interactions with neurons. So far, most pharmacological approaches currently available do not distinguish between these two channel functions, stressing the need to develop new specific molecular tools. In astrocytes two major Cxs are expressed, Cx43 and Cx30, and there is now evidence indicating that at least Cx43 operates as a gap junction channel as well as a hemichannel in these cells. Based on studies in primary cultures as well as in acute hippocampal slices, we report here that Gap 19, a nonapeptide derived from the cytoplasmic loop of Cx43, inhibits astroglial Cx43 hemichannels in a dose-dependent manner, without affecting gap junction channels. This peptide, which not only selectively inhibits hemichannels but is also specific for Cx43, can be delivered in vivo in mice as TAT-Gap19, and displays penetration into the brain parenchyma. As a result, Gap 19 combined with other tools opens up new avenues to decipher the role of Cx43 hemichannels in interactions between astrocytes and neurons in physiological as well as pathological situations

    Atmospheric phase correction using CARMA-PACS: high angular resolution observations of the FU Orionis star PP 13S*

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    We present 0".15 resolution observations of the 227 GHz continuum emission from the circumstellar disk around the FU Orionis star PP 13S*. The data were obtained with the Combined Array for Research in Millimeter-wave Astronomy (CARMA) Paired Antenna Calibration System (C-PACS), which measures and corrects the atmospheric delay fluctuations on the longest baselines of the array in order to improve the sensitivity and angular resolution of the observations. A description of the C-PACS technique and the data reduction procedures are presented. C-PACS was applied to CARMA observations of PP 13S*, which led to a factor of 1.6 increase in the observed peak flux of the source, a 36% reduction in the noise of the image, and a 52% decrease in the measured size of the source major axis. The calibrated complex visibilities were fitted with a theoretical disk model to constrain the disk surface density. The total disk mass from the best-fit model corresponds to 0.06 M_⊙, which is larger than the median mass of a disk around a classical T Tauri star. The disk is optically thick at a wavelength of 1.3 mm for orbital radii less than 48 AU. At larger radii, the inferred surface density of the PP 13S* disk is an order of magnitude lower than that needed to develop a gravitational instability

    A Resolved Ring of Debris Dust around the Solar Analog HD 107146

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    We present resolved images of the dust continuum emission from the debris disk around the young (80-200 Myr) solar-type star HD 107146 with CARMA at λ = 1.3 mm and the CSO at λ = 350 μ. Both images show that the dust emission extends over an approximately 10" diameter region. The high-resolution (3") CARMA image further reveals that the dust is distributed in a partial ring with significant decrease in a flux inward of 97 AU. Two prominent emission peaks appear within the ring separated by ~140° in the position angle. The morphology of the dust emission is suggestive of dust captured into a mean motion resonance, which would imply the presence of a planet at an orbital radius of ~45-75 AU

    Targeting MAPK phosphorylation of Connexin43 provides neuroprotection in stroke

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    Connexin43 (Cx43) function is influenced by kinases that phosphorylate specific serine sites located near its C-terminus. Stroke is a powerful inducer of kinase activity, but its effect on Cx43 is unknown. We investigated the impact of wild-type (WT) and knock-in Cx43 with serine to alanine mutations at the protein kinase C (PKC) site Cx43(S368A), the casein kinase 1 (CK1) sites Cx43(S325A/328Y/330A), and the mitogen-activated protein kinase (MAPK) sites Cx43(S255/262/279/282A) (MK4) on a permanent middle cerebral artery occlusion (pMCAO) stroke model. We demonstrate that MK4 transgenic animals exhibit a significant decrease in infarct volume that was associated with improvement in behavioral performance. An increase in astrocyte reactivity with a concomitant decrease in microglial reactivity was observed in MK4 mice. In contrast to WT, MK4 astrocytes displayed reduced Cx43 hemichannel activity. Pharmacological blockade of Cx43 hemichannels with TAT-Gap19 also significantly decreased infarct volume in WT animals. This study provides novel molecular insights and charts new avenues for therapeutic intervention associated with Cx43 function

    Cytoprotective Activated Protein C Averts Nlrp3 Inflammasome–Induced Ischemia-Reperfusion Injury Via Mtorc1 Inhibition

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    Cytoprotection by activated protein C (aPC) after ischemia-reperfusion injury (IRI) is associated with apoptosis inhibition. However, IRI is hallmarked by inflammation, and hence, cell-death forms disjunct from immunologically silent apoptosis are, in theory, more likely to be relevant. Because pyroptosis (ie, cell death resulting from inflammasome activation) is typically observed in IRI, we speculated that aPC ameliorates IRI by inhibiting inflammasome activation. Here we analyzed the impact of aPC on inflammasome activity in myocardial and renal IRIs. aPC treatment before or after myocardial IRI reduced infarct size and Nlrp3 inflammasome activation in mice. Kinetic in vivo analyses revealed that Nlrp3 inflammasome activation preceded myocardial injury and apoptosis, corroborating a pathogenic role of the Nlrp3 inflammasome. The constitutively active Nlrp3A350V mutation abolished the protective effect of aPC, demonstrating that Nlrp3 suppression is required for aPC-mediated protection from IRI. In vitro aPC inhibited inflammasome activation in macrophages, cardiomyocytes, and cardiac fibroblasts via proteinase-activated receptor 1 (PAR-1) and mammalian target of rapamycin complex 1 (mTORC1) signaling. Accordingly, inhibiting PAR-1 signaling, but not the anticoagulant properties of aPC, abolished the ability of aPC to restrict Nlrp3 inflammasome activity and tissue damage in myocardial IRI. Targeting biased PAR-1 signaling via parmodulin-2 restricted mTORC1 and Nlrp3 inflammasome activation and limited myocardial IRI as efficiently as aPC. The relevance of aPC-mediated Nlrp3 inflammasome suppression after IRI was corroborated in renal IRI, where the tissue protective effect of aPC was likewise dependent on Nlrp3 inflammasome suppression. These studies reveal that aPC protects from IRI by restricting mTORC1-dependent inflammasome activation and that mimicking biased aPC PAR-1 signaling using parmodulins may be a feasible therapeutic approach to combat IRI

    CMB polarimetry with BICEP: instrument characterization, calibration, and performance

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    BICEP is a ground-based millimeter-wave bolometric array designed to target the primordial gravity wave signature on the polarization of the cosmic microwave background (CMB) at degree angular scales. Currently in its third year of operation at the South Pole, BICEP is measuring the CMB polarization with unprecedented sensitivity at 100 and 150 GHz in the cleanest available 2% of the sky, as well as deriving independent constraints on the diffuse polarized foregrounds with select observations on and off the Galactic plane. Instrument calibrations are discussed in the context of rigorous control of systematic errors, and the performance during the first two years of the experiment is reviewed.Comment: 12 pages, 15 figures, updated version of a paper accepted for Millimeter and Submillimeter Detectors and Instrumentation for Astronomy IV, Proceedings of SPIE, 7020, 200

    Co-catalytic absorption layers for controlled laser-induced chemical vapor deposition of carbon nanotubes.

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    The concept of co-catalytic layer structures for controlled laser-induced chemical vapor deposition of carbon nanotubes is established, in which a thin Ta support layer chemically aids the initial Fe catalyst reduction. This enables a significant reduction in laser power, preventing detrimental positive optical feedback and allowing improved growth control. Systematic study of experimental parameters combined with simple thermostatic modeling establishes general guidelines for the effective design of such catalyst/absorption layer combinations. Local growth of vertically aligned carbon nanotube forests directly on flexible polyimide substrates is demonstrated, opening up new routes for nanodevice design and fabrication.This document is the unedited Author's version of a Submitted Work that was subsequently accepted for publication in ACS Applied Materials and Interfaces, copyright © American Chemical Society after peer review. To access the final edited and published work see [insert ACS Articles on Request author-directed link to Published Work, see http://pubs.acs.org/page/policy/articlesonrequest/index.html]
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