309 research outputs found
Focal Adhesion Kinase-mediated Phosphorylation of Beclin1 Protein Suppresses Cardiomyocyte Autophagy and Initiates Hypertrophic Growth
Autophagy is an evolutionarily conserved intracellular degradation/recycling system that is essential for cellular homeostasis but is dysregulated in a number of diseases, including myocardial hypertrophy. Although it is clear that limiting or accelerating autophagic flux can result in pathological cardiac remodeling, the physiological signaling pathways that fine-tune cardiac autophagy are poorly understood. Herein, we demonstrated that stimulation of cardiomyocytes with phenylephrine (PE), a well known hypertrophic agonist, suppresses autophagy and that activation of focal adhesion kinase (FAK) is necessary for PE-stimulated autophagy suppression and subsequent initiation of hypertrophic growth. Mechanistically, we showed that FAK phosphorylates Beclin1, a core autophagy protein, on Tyr-233 and that this post-translational modification limits Beclin1 association with Atg14L and reduces Beclin1-dependent autophagosome formation. Remarkably, although ectopic expression of wild-type Beclin1 promoted cardiomyocyte atrophy, expression of a Y233E phosphomimetic variant of Beclin1 failed to affect cardiomyocyte size. Moreover, genetic depletion of Beclin1 attenuated PE-mediated/FAK-dependent initiation of myocyte hypertrophy in vivo. Collectively, these findings identify FAK as a novel negative regulator of Beclin1-mediated autophagy and indicate that this pathway can facilitate the promotion of compensatory hypertrophic growth. This novel mechanism to limit Beclin1 activity has important implications for treating a variety of pathologies associated with altered autophagic flux
Conformal Maxwell theory as a singleton field theory on AdS_5, IIB three-branes and duality
We examine the boundary conditions associated with extended supersymmetric
Maxwell theory in 5-dimensional anti-De Sitter space. Excitations on the
boundary are identical to those of ordinary 4-dimensional conformal invariant
super electrodynammics. Extrapolations of these excitations give rise to a
5-dimensional topological gauge theory of the singleton type. The possibility
of a connection of this phenomenon to the world volume theory of 3-branes in
IIB string theory is discussed.Comment: 19 pages, TeX, no figures; v2: misprints corrected, references added,
discussion on Chern-Simons couplings revised. v3: References added, misprints
corrected and a discussion in section 2 revised. v4: Typos corrected and
reference adde
In search of dying radio sources in the local universe
Up till now very few dying sources were known, presumably because the dying
phase is short at centimeter wavelengths. We therefore have tried to improve
the statistics on sources that have ceased to be active, or are intermittently
active. The latter sources would partly consist of a fossil radio plasma left
over from an earlier phase of activity, plus a recently restarted core and
radio jets. Improving the statistics of dying sources will give us a better
handle on the evolution of radio sources, in particular the frequency and time
scales of radio activity. We have used the WENSS and NVSS surveys, in order to
find sources with steep spectral indices, associated with nearby elliptical
galaxies. In the cross correlation we presently used only unresolved sources,
with flux densities at 1.4 GHz larger than 10 mJy. The eleven candidates thus
obtained were observed with the VLA in various configurations, in order to
confirm the steepness of the spectra, and to check whether active structures
like flat-spectrum cores and jets are present, perhaps at low levels. We
estimated the duration of the active and relic phases by modelling the
integrated radio spectra using the standard models of spectral evolution. We
have found six dying sources and three restarted sources, while the remaining
two candidates remain unresolved also with the new VLA data and may be Compact
Steep Spectrum sources, with an unusually steep spectrum. The typical age of
the active phase, as derived by spectral fits, is in the range 10^7 - 10^8
years. For our sample of dying sources, the age of the relic phase is on
average shorter by an order of magnitude than the active phase.Comment: 21 pages, 17 figures, accepted by A&A. For a version with high
quality figures, see http://erg.ca.astro.it/preprints/dying2007
Identification of beryllium-dependent peptides recognized by CD4+ T cells in chronic beryllium disease
Chronic beryllium disease (CBD) is a granulomatous disorder characterized by an influx of beryllium (Be)-specific CD4+ T cells into the lung. The vast majority of these T cells recognize Be in an HLA-DP–restricted manner, and peptide is required for T cell recognition. However, the peptides that stimulate Be-specific T cells are unknown. Using positional scanning libraries and fibroblasts expressing HLA-DP2, the most prevalent HLA-DP molecule linked to disease, we identified mimotopes and endogenous self-peptides that bind to MHCII and Be, forming a complex recognized by pathogenic CD4+ T cells in CBD. These peptides possess aspartic and glutamic acid residues at p4 and p7, respectively, that surround the putative Be-binding site and cooperate with HLA-DP2 in Be coordination. Endogenous plexin A peptides and proteins, which share the core motif and are expressed in lung, also stimulate these TCRs. Be-loaded HLA-DP2–mimotope and HLA-DP2–plexin A4 tetramers detected high frequencies of CD4+ T cells specific for these ligands in all HLA-DP2+ CBD patients tested. Thus, our findings identify the first ligand for a CD4+ T cell involved in metal-induced hypersensitivity and suggest a unique role of these peptides in metal ion coordination and the generation of a common antigen specificity in CBD
The Amborella genome: an evolutionary reference for plant biology
The nuclear genome sequence of Amborella trichopoda, the sister species to all other extant angiosperms, will be an exceptional resource for plant genomics
Comparison of next generation sequencing technologies for transcriptome characterization
<p>Abstract</p> <p>Background</p> <p>We have developed a simulation approach to help determine the optimal mixture of sequencing methods for most complete and cost effective transcriptome sequencing. We compared simulation results for traditional capillary sequencing with "Next Generation" (NG) ultra high-throughput technologies. The simulation model was parameterized using mappings of 130,000 cDNA sequence reads to the <it>Arabidopsis </it>genome (NCBI Accession SRA008180.19). We also generated 454-GS20 sequences and <it>de novo </it>assemblies for the basal eudicot California poppy (<it>Eschscholzia californica</it>) and the magnoliid avocado (<it>Persea americana</it>) using a variety of methods for cDNA synthesis.</p> <p>Results</p> <p>The <it>Arabidopsis </it>reads tagged more than 15,000 genes, including new splice variants and extended UTR regions. Of the total 134,791 reads (13.8 MB), 119,518 (88.7%) mapped exactly to known exons, while 1,117 (0.8%) mapped to introns, 11,524 (8.6%) spanned annotated intron/exon boundaries, and 3,066 (2.3%) extended beyond the end of annotated UTRs. Sequence-based inference of relative gene expression levels correlated significantly with microarray data. As expected, NG sequencing of normalized libraries tagged more genes than non-normalized libraries, although non-normalized libraries yielded more full-length cDNA sequences. The <it>Arabidopsis </it>data were used to simulate additional rounds of NG and traditional EST sequencing, and various combinations of each. Our simulations suggest a combination of FLX and Solexa sequencing for optimal transcriptome coverage at modest cost. We have also developed ESTcalc <url>http://fgp.huck.psu.edu/NG_Sims/ngsim.pl</url>, an online webtool, which allows users to explore the results of this study by specifying individualized costs and sequencing characteristics.</p> <p>Conclusion</p> <p>NG sequencing technologies are a highly flexible set of platforms that can be scaled to suit different project goals. In terms of sequence coverage alone, the NG sequencing is a dramatic advance over capillary-based sequencing, but NG sequencing also presents significant challenges in assembly and sequence accuracy due to short read lengths, method-specific sequencing errors, and the absence of physical clones. These problems may be overcome by hybrid sequencing strategies using a mixture of sequencing methodologies, by new assemblers, and by sequencing more deeply. Sequencing and microarray outcomes from multiple experiments suggest that our simulator will be useful for guiding NG transcriptome sequencing projects in a wide range of organisms.</p
Noncommutative Sp(2,R) Gauge Theories - A Field Theory Approach to Two-Time Physics
Phase-space and its relativistic extension is a natural space for realizing
Sp(2,R) symmetry through canonical transformations. On a Dx2 dimensional
covariant phase-space, we formulate noncommutative field theories, where
Sp(2,R) plays a role as either a global or a gauge symmetry group. In both
cases these field theories have potential applications, including certain
aspects of string theories, M-theory, as well as quantum field theories. If
interpreted as living in lower dimensions, these theories realize Poincare'
symmetry linearly in a way consistent with causality and unitarity. In case
Sp(2,R) is a gauge symmetry, we show that the spacetime signature is determined
dynamically as (D-2,2). The resulting noncommutative Sp(2,R) gauge theory is
proposed as a field theoretical formulation of two-time physics: classical
field dynamics contains all known results of `two-time physics', including the
reduction of physical spacetime from D to (D-2) dimensions, with the associated
`holography' and `duality' properties. In particular, we show that the solution
space of classical noncommutative field equations put all massless scalar,
gauge, gravitational, and higher-spin fields in (D-2) dimensions on
equal-footing, reminiscent of string excitations at zero and infinite tension
limits.Comment: 32 pages, LaTe
Superconformal symmetry and maximal supergravity in various dimensions
In this paper we explore the relation between conformal superalgebras with 64
supercharges and maximal supergravity theories in three, four and six
dimensions using twistorial oscillator techniques. The massless fields of N=8
supergravity in four dimensions were shown to fit into a CPT-self-conjugate
doubleton supermultiplet of the conformal superalgebra SU(2,2|8) a long time
ago. We show that the fields of maximal supergravity in three dimensions can
similarly be fitted into the super singleton multiplet of the conformal
superalgebra OSp(16|4,R), which is related to the doubleton supermultiplet of
SU(2,2|8) by dimensional reduction. Moreover, we construct the ultra-short
supermultiplet of the six-dimensional conformal superalgebra OSp(8*|8) and show
that its component fields can be organized in an on-shell superfield. The
ultra-short OSp(8*|8) multiplet reduces to the doubleton supermultiplet of
SU(2,2|8) upon dimensional reduction. We discuss the possibility of a chiral
maximal (4,0) six-dimensional supergravity theory with USp(8) R-symmetry that
reduces to maximal supergravity in four dimensions and is different from
six-dimensional (2,2) maximal supergravity, whose fields cannot be fitted into
a unitary supermultiplet of a simple conformal superalgebra. Such an
interacting theory would be the gravitational analog of the (2,0) theory.Comment: 54 pages, PDFLaTeX, Section 5 and several references added. Version
accepted for publication in JHE
- …