MAPK phosphorylation of connexin 43 promotes binding of cyclin E and smooth muscle cell proliferation

<p>Rationale: Dedifferentiation of vascular smooth muscle cells (VSMC) leading to a proliferative cell phenotype significantly contributes to the development of atherosclerosis. Mitogen-activated protein kinase (MAPK) phosphorylation of proteins including connexin 43 (Cx43) has been associated with VSMC proliferation in atherosclerosis.</p> <p>Objective: To investigate whether MAPK phosphorylation of Cx43 is directly involved in VSMC proliferation.</p> <p>Methods and Results: We show in vivo that MAPK-phosphorylated Cx43 forms complexes with the cell cycle control proteins cyclin E and cyclin-dependent kinase 2 (CDK2) in carotids of apolipoprotein-E receptor null (ApoE−/−) mice and in C57Bl/6 mice treated with platelet-derived growth factor–BB (PDGF). We tested the involvement of Cx43 MAPK phosphorylation in vitro using constructs for full-length Cx43 (Cx43) or the Cx43 C-terminus (Cx43CT) and produced null phosphorylation Ser>Ala (Cx43MK4A/Cx43CTMK4A) and phospho-mimetic Ser>Asp (Cx43MK4D/Cx43CTMK4D) mutations. Coimmunoprecipitation studies in primary VSMC isolated from Cx43 wild-type (Cx43+/+) and Cx43 null (Cx43−/−) mice and analytic size exclusion studies of purified proteins identify that interactions between cyclin E and Cx43 requires Cx43 MAPK phosphorylation. We further demonstrate that Cx43 MAPK phosphorylation is required for PDGF-mediated VSMC proliferation. Finally, using a novel knock-in mouse containing Cx43-MK4A mutation, we show in vivo that interactions between Cx43 and cyclin E are lost and VSMC proliferation does not occur after treatment of carotids with PDGF and that neointima formation is significantly reduced in carotids after injury.</p> <p>Conclusions: We identify MAPK-phosphorylated Cx43 as a novel interacting partner of cyclin E in VSMC and show that this interaction is critical for VSMC proliferation. This novel interaction may be important in the development of atherosclerotic lesions.</p&gt

Bi2Fe4O9 thin films as novel visible-light-active photoanodes for solar water splitting

We report the chemical solution deposition (CSD) of a phase-pure Bi2Fe4O9 thin film for use as a photoanode in photoelectrochemical (PEC) water splitting. The energy levels of Bi2Fe4O9 films have been measured and n-type characteristics have been confirmed. With band gaps determined as 2.05 eV (indirect) and 2.80 eV (direct) and valence and conduction bands straddling the water oxidation and reduction potentials, this material is highly promising as a photocatalyst for solar water splitting. The photocurrent of a planar photoanode reached 0.1 mA cm−2 at 1.23 VNHE under AM1.5G illumination. The addition of H2O2 as a hole scavenger increased the photocurrent to 0.25 mA cm−2, indicating hole injection is one limiting factor to the performance. The performance was enhanced by nearly 5-fold when the Bi2Fe4O9 photoanode is coupled to a Co–Pi surface co-catalyst. The photoanode also shows excellent stability with no change in photocurrent over three hours of continuous illumination. These results indicate that this material represents a promising addition to the growing selection of low-cost, stable photocatalysts for use in solar water splitting

Sensitivity of hydrological performance assessment analysis to variations in material properties, conceptual models, and ventilation models

The Yucca Mountain Site Characterization Project is studying Yucca Mountain in southwestern Nevada as a potential site for a high-level nuclear waste repository. Site characterization includes surface- based and underground testing. Analyses have been performed to support the design of an Exploratory Studies Facility (ESF) and the design of the tests performed as part of the characterization process, in order to ascertain that they have minimal impact on the natural ability of the site to isolate waste. The information in this report pertains to sensitivity studies evaluating previous hydrological performance assessment analyses to variation in the material properties, conceptual models, and ventilation models, and the implications of this sensitivity on previous recommendations supporting ESF design. This document contains information that has been used in preparing recommendations for Appendix I of the Exploratory Studies Facility Design Requirements document

Stimulant Medication and Reading Performance

The study examined the sustained effects of methylphenidate on reading performance in a sample of 42 boys, ages 8 to 11, with attention deficit-hyperactivity disorder (ADHD). Two subgroups were formed based on the presence or absence of co-occurring conduct disorders. Subjects were selected on the basis of their positive response to methylphenidate as determined in a series of original medication trials (Forness, Cantwell, Swanson, Hanna, & Youpa, 1991). For the purpose of this study, subjects were placed on their optimal dose of medication for a 6-week period and then tested on measures of oral reading and reading comprehension equivalent to those used in the original trials, retested after a week without medication (placebo), then tested again the following week after return to medication. Only the subgroup with conduct disorders responded, and this response was limited to reading comprehension improvement in only those subjects who also demonstrated improvement in oral reading on original trials. No response differences were found between subjects with or without learning disabilities.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68569/2/10.1177_002221949202500205.pd

Multiwavelength studies of MHD waves in the solar chromosphere: An overview of recent results

The chromosphere is a thin layer of the solar atmosphere that bridges the relatively cool photosphere and the intensely heated transition region and corona. Compressible and incompressible waves propagating through the chromosphere can supply significant amounts of energy to the interface region and corona. In recent years an abundance of high-resolution observations from state-of-the-art facilities have provided new and exciting ways of disentangling the characteristics of oscillatory phenomena propagating through the dynamic chromosphere. Coupled with rapid advancements in magnetohydrodynamic wave theory, we are now in an ideal position to thoroughly investigate the role waves play in supplying energy to sustain chromospheric and coronal heating. Here, we review the recent progress made in characterising, categorising and interpreting oscillations manifesting in the solar chromosphere, with an impetus placed on their intrinsic energetics.Comment: 48 pages, 25 figures, accepted into Space Science Review

B7-H3-redirected chimeric antigen receptor T cells target glioblastoma and neurospheres

Background: The dismal survival of glioblastoma (GBM) patients urgently calls for the development of new treatments. Chimeric antigen receptor T (CAR-T) cells are an attractive strategy, but preclinical and clinical studies in GBM have shown that heterogeneous expression of the antigens targeted so far causes tumor escape, highlighting the need for the identification of new targets. We explored if B7-H3 is a valuable target for CAR-T cells in GBM. Methods: We compared mRNA expression of antigens in GBM using TCGA data, and validated B7-H3 expression by immunohistochemistry. We then tested the antitumor activity of B7-H3-redirected CAR-T cells against GBM cell lines and patient-derived GBM neurospheres in vitro and in xenograft murine models. Findings: B7-H3 mRNA and protein are overexpressed in GBM relative to normal brain in all GBM subtypes. Of the 46 specimens analyzed by immunohistochemistry, 76% showed high B7-H3 expression, 22% had detectable, but low B7-H3 expression and 2% were negative, as was normal brain. All 20 patient-derived neurospheres showed ubiquitous B7-H3 expression. B7-H3-redirected CAR-T cells effectively targeted GBM cell lines and neurospheres in vitro and in vivo. No significant differences were found between CD28 and 4-1BB co-stimulation, although CD28-co-stimulated CAR-T cells released more inflammatory cytokines. Interpretation: We demonstrated that B7-H3 is highly expressed in GBM specimens and neurospheres that contain putative cancer stem cells, and that B7-H3-redirected CAR-T cells can effectively control tumor growth. Therefore, B7-H3 represents a promising target in GBM. Fund: Alex's Lemonade Stand Foundation; Il Fondo di Gio Onlus; National Cancer Institute; Burroughs Wellcome Fund

Spectroscopic Coronal Observations during the Total Solar Eclipse of 11 July 2010

The flash spectrum of the solar chromosphere and corona was measured with a slitless spectrograph before, after, and during the totality of the solar eclipse, of 11 July 2010, at Easter Island, Chile. This eclipse took place at the beginning of the Solar Cycle 24, after an extended minimum of solar activity. The spectra taken during the eclipse show a different intensity ratio of the red and green coronal lines compared with those taken during the total solar eclipse of 1 August 2008, which took place towards the end of the Solar Cycle 23. The characteristic coronal forbidden emission line of forbidden Fe XIV (5303 {\AA}) was observed on the east and west solar limbs in four areas relatively symmetrically located with respect to the solar rotation axis. Subtraction of the continuum flash-spectrum background led to the identification of several extremely weak emission lines, including forbidden Ca XV (5694 {\AA}), which is normally detected only in regions of very high excitation, e.g., during flares or above large sunspots. The height of the chromosphere was measured spectrophotometrically, using spectral lines from light elements and compared with the equivalent height of the lower chromosphere measured using spectral lines from heavy elements.Comment: 14 pages, 8 figures, 1 table; Solar Physics, 2012, Februar