542 research outputs found
dATF4 regulation of mitochondrial folate-mediated one-carbon metabolism is neuroprotective.
Neurons rely on mitochondria as their preferred source of energy. Mutations in PINK1 and PARKIN cause neuronal death in early-onset Parkinson's disease (PD), thought to be due to mitochondrial dysfunction. In Drosophila pink1 and parkin mutants, mitochondrial defects lead to the compensatory upregulation of the mitochondrial one-carbon cycle metabolism genes by an unknown mechanism. Here we uncover that this branch is triggered by the activating transcription factor 4 (ATF4). We show that ATF4 regulates the expression of one-carbon metabolism genes SHMT2 and NMDMC as a protective response to mitochondrial toxicity. Suppressing Shmt2 or Nmdmc caused motor impairment and mitochondrial defects in flies. Epistatic analyses showed that suppressing the upregulation of Shmt2 or Nmdmc deteriorates the phenotype of pink1 or parkin mutants. Conversely, the genetic enhancement of these one-carbon metabolism genes in pink1 or parkin mutants was neuroprotective. We conclude that mitochondrial dysfunction caused by mutations in the Pink1/Parkin pathway engages ATF4-dependent activation of one-carbon metabolism as a protective response. Our findings show a central contribution of ATF4 signalling to PD that may represent a new therapeutic strategy. A video abstract for this article is available at https://youtu.be/cFJJm2YZKKM
Soft branes in supersymmetry-breaking backgrounds
We revisit the analysis of effective field theories resulting from
non-supersymmetric perturbations to supersymmetric flux compactifications of
the type-IIB superstring with an eye towards those resulting from the
backreaction of a small number of anti-D3-branes. Independently of the
background, we show that the low-energy Lagrangian describing the fluctuations
of a stack of probe D3-branes exhibits soft supersymmetry breaking, despite
perturbations to marginal operators that were not fully considered in some
previous treatments. We take this as an indication that the breaking of
supersymmetry by anti-D3-branes or other sources may be spontaneous rather than
explicit. In support of this, we consider the action of an anti-D3-brane
probing an otherwise supersymmetric configuration and identify a candidate for
the corresponding goldstino.Comment: 36+5 pages. References added, minor typos correcte
Stationary Black Holes: Uniqueness and Beyond
The spectrum of known black-hole solutions to the stationary Einstein
equations has been steadily increasing, sometimes in unexpected ways. In
particular, it has turned out that not all black-hole-equilibrium
configurations are characterized by their mass, angular momentum and global
charges. Moreover, the high degree of symmetry displayed by vacuum and
electro-vacuum black-hole spacetimes ceases to exist in self-gravitating
non-linear field theories. This text aims to review some developments in the
subject and to discuss them in light of the uniqueness theorem for the
Einstein-Maxwell system.Comment: Major update of the original version by Markus Heusler from 1998.
Piotr T. Chru\'sciel and Jo\~ao Lopes Costa succeeded to this review's
authorship. Significantly restructured and updated all sections; changes are
too numerous to be usefully described here. The number of references
increased from 186 to 32
Differential effects of cytokines and corticosteroids on Toll-like receptor 2 expression and activity in human airway epithelia
<p>Abstract</p> <p>Background</p> <p>The recognition of microbial molecular patterns via Toll-like receptors (TLRs) is critical for mucosal defenses.</p> <p>Methods</p> <p>Using well-differentiated primary cultures of human airway epithelia, we investigated the effects of exposure of the cells to cytokines (TNF-α and IFN-γ) and dexamethasone (dex) on responsiveness to the TLR2/TLR1 ligand Pam3CSK4. Production of IL-8, CCL20, and airway surface liquid antimicrobial activity were used as endpoints.</p> <p>Results</p> <p>Microarray expression profiling in human airway epithelia revealed that first response cytokines markedly induced TLR2 expression. Real-time PCR confirmed that cytokines (TNF-α and IFN-γ), dexamethasone (dex), or cytokines + dex increased TLR2 mRNA abundance. A synergistic increase was seen with cytokines + dex. To assess TLR2 function, epithelia pre-treated with cytokines ± dex were exposed to the TLR2/TLR1 ligand Pam3CSK4 for 24 hours. While cells pre-treated with cytokines alone exhibited significantly enhanced IL-8 and CCL20 secretion following Pam3CSK4, mean IL-8 and CCL20 release decreased in Pam3CSK4 stimulated cells following cytokines + dex pre-treatment. This marked increase in inflammatory gene expression seen after treatment with cytokines followed by the TLR2 ligand did not correlate well with NF-κB, Stat1, or p38 MAP kinase pathway activation. Cytokines also enhanced TLR2 agonist-induced beta-defensin 2 mRNA expression and increased the antimicrobial activity of airway surface liquid. Dex blocked these effects.</p> <p>Conclusion</p> <p>While dex treatment enhanced TLR2 expression, co-administration of dex with cytokines inhibited airway epithelial cell responsiveness to TLR2/TLR1 ligand over cytokines alone. Enhanced functional TLR2 expression following exposure to TNF-α and IFN-γ may serve as a dynamic means to amplify epithelial innate immune responses during infectious or inflammatory pulmonary diseases.</p
Improved Measurement of the Pseudoscalar Decay Constant
We present a new determination of the Ds decay constant, f_{Ds} using 5
million continuum charm events obtained with the CLEO II detector. Our value is
derived from our new measured ratio of widths for Ds -> mu nu/Ds -> phi pi of
0.173+/- 0.021 +/- 0.031. Taking the branching ratio for Ds -> phi pi as (3.6
+/- 0.9)% from the PDG, we extract f_{Ds} = (280 +/- 17 +/- 25 +/- 34){MeV}. We
compare this result with various model calculations.Comment: 23 page postscript file, postscript file also available through
http://w4.lns.cornell.edu/public/CLN
First Observation of and Decays
We have observed new channels for decays with an in the final
state. We study 3-prong tau decays, using the and
\eta\to 3\piz decay modes and 1-prong decays with two \piz's using the
channel. The measured branching fractions are
\B(\tau^{-}\to \pi^{-}\pi^{-}\pi^{+}\eta\nu_{\tau})
=(3.4^{+0.6}_{-0.5}\pm0.6)\times10^{-4} and \B(\tau^{-}\to
\pi^{-}2\piz\eta\nu_{\tau}
=(1.4\pm0.6\pm0.3)\times10^{-4}. We observe clear evidence for
substructure and measure \B(\tau^{-}\to
f_1\pi^{-}\nu_{\tau})=(5.8^{+1.4}_{-1.3}\pm1.8)\times10^{-4}. We have also
searched for production and obtain 90% CL upper limits
\B(\tau^{-}\to \pi^{-}\eta'\nu_\tau)<7.4\times10^{-5} and \B(\tau^{-}\to
\pi^{-}\piz\eta'\nu_\tau)<8.0\times10^{-5}.Comment: 11 page postscript file, postscript file also available through
http://w4.lns.cornell.edu/public/CLN
Search for the Decays B^0 -> D^{(*)+} D^{(*)-}
Using the CLEO-II data set we have searched for the Cabibbo-suppressed decays
B^0 -> D^{(*)+} D^{(*)-}. For the decay B^0 -> D^{*+} D^{*-}, we observe one
candidate signal event, with an expected background of 0.022 +/- 0.011 events.
This yield corresponds to a branching fraction of Br(B^0 -> D^{*+} D^{*-}) =
(5.3^{+7.1}_{-3.7}(stat) +/- 1.0(syst)) x 10^{-4} and an upper limit of Br(B^0
-> D^{*+} D^{*-}) D^{*\pm} D^\mp and
B^0 -> D^+ D^-, no significant excess of signal above the expected background
level is seen, and we calculate the 90% CL upper limits on the branching
fractions to be Br(B^0 -> D^{*\pm} D^\mp) D^+
D^-) < 1.2 x 10^{-3}.Comment: 12 page postscript file also available through
http://w4.lns.cornell.edu/public/CLNS, submitted to Physical Review Letter
Production in Two-Photon Interactions at CLEO
Using the CLEO detector at the Cornell storage ring, CESR, we study
the two-photon production of , making the first
observation of . We present the
cross-section for as a function of
the center of mass energy and compare it to that predicted by
the quark-diquark model.Comment: 10 pages, postscript file also available through
http://w4.lns.cornell.edu/public/CLN
Observation of the Decay
Using e+e- annihilation data collected by the CLEO~II detector at CESR, we
have observed the decay Ds+ to omega pi+. This final state may be produced
through the annihilation decay of the Ds+, or through final state interactions.
We find a branching ratio of [Gamma(Ds+ to omega pi+)/Gamma(Ds+ to eta
pi+)]=0.16+-0.04+-0.03, where the first error is statistical and the second is
systematic.Comment: 9 pages, postscript file also available through
http://w4.lns.cornell.edu/public/CLN
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