834 research outputs found
Inflammation-induced DNA damage and damage-induced inflammation: a vicious cycle
Inflammation is the ultimate response to the constant challenges of the immune system by microbes, irritants or injury. The inflammatory cascade initiates with the recognition of microorganism-derived pathogen associated molecular patterns (PAMPs) and host cell-derived damage associated molecular patterns (DAMPs) by the pattern recognition receptors (PRRs). DNA as a molecular PAMP or DAMP is sensed directly or via specific binding proteins to instigate pro-inflammatory response. Some of these DNA binding proteins also participate in canonical DNA repair pathways and recognise damaged DNA to initiate DNA damage response. In this review we aim to capture the essence of the complex interplay between DNA damage response and the pro-inflammatory signalling through representative examples
Expression of DDX3 Is Directly Modulated by Hypoxia Inducible Factor-1 Alpha in Breast Epithelial Cells
DEAD box protein, DDX3, is aberrantly expressed in breast cancer cells ranging from weakly invasive to aggressive phenotypes and functions as an important regulator of cancer cell growth and survival. Here, we demonstrate that hypoxia inducible factor-1Îą is a transcriptional activator of DDX3 in breast cancer cells. Within the promoter region of the human DDX3 gene, we identified three putative hypoxia inducible factor-1 responsive elements. By luciferase reporter assays in combination with mutated hypoxia inducible factor-1 responsive elements, we determined that the hypoxia inducible factor-1 responsive element at position -153 relative to the translation start site is essential for transcriptional activation of DDX3 under hypoxic conditions. We also demonstrated that hypoxia inducible factor-1 binds to the DDX3 promoter and that the binding is specific, as revealed by siRNA against hypoxia inducible factor-1 and chromatin immunoprecipitation assays. Thus, the activation of DDX3 expression during hypoxia is due to the direct binding of hypoxia inducible factor-1 to hypoxia responsive elements in the DDX3 promoter. In addition, we observed a significant overlap in the protein expression pattern of hypoxia inducible factor-1Îą and DDX3 in MDA-MB-231 xenograft tumors. Taken together, our results demonstrate, for the first time, the role of DDX3 as a hypoxia-inducible gene that exhibits enhanced expression through the interaction of hypoxia inducible factor-1 with hypoxia inducible factor-1 responsive elements in its promoter region
A search for the decay modes B+/- to h+/- tau l
We present a search for the lepton flavor violating decay modes B+/- to h+/-
tau l (h= K,pi; l= e,mu) using the BaBar data sample, which corresponds to 472
million BBbar pairs. The search uses events where one B meson is fully
reconstructed in one of several hadronic final states. Using the momenta of the
reconstructed B, h, and l candidates, we are able to fully determine the tau
four-momentum. The resulting tau candidate mass is our main discriminant
against combinatorial background. We see no evidence for B+/- to h+/- tau l
decays and set a 90% confidence level upper limit on each branching fraction at
the level of a few times 10^-5.Comment: 15 pages, 7 figures, submitted to Phys. Rev.
Evidence for an excess of B -> D(*) Tau Nu decays
Based on the full BaBar data sample, we report improved measurements of the
ratios R(D(*)) = B(B -> D(*) Tau Nu)/B(B -> D(*) l Nu), where l is either e or
mu. These ratios are sensitive to new physics contributions in the form of a
charged Higgs boson. We measure R(D) = 0.440 +- 0.058 +- 0.042 and R(D*) =
0.332 +- 0.024 +- 0.018, which exceed the Standard Model expectations by 2.0
sigma and 2.7 sigma, respectively. Taken together, our results disagree with
these expectations at the 3.4 sigma level. This excess cannot be explained by a
charged Higgs boson in the type II two-Higgs-doublet model. We also report the
observation of the decay B -> D Tau Nu, with a significance of 6.8 sigma.Comment: Expanded section on systematics, text corrections, improved the
format of Figure 2 and included the effect of the change of the Tau
polarization due to the charged Higg
Search for the decay modes D^0 â e^+e^-, D^0 â Îź^+Îź^-, and D^0 â e^¹Οâ
We present searches for the rare decay modes D^0âe^+e^-, D^0âÎź^+Îź^-, and D^0âe^¹Ο^â in continuum e^+e^-âcc events recorded by the BABAR detector in a data sample that corresponds to an integrated luminosity of 468ââfb^(-1). These decays are highly GlashowâIliopoulosâMaiani suppressed but may be enhanced in several extensions of the standard model. Our observed event yields are consistent with the expected backgrounds. An excess is seen in the D^0âÎź^+Îź^- channel, although the observed yield is consistent with an upward background fluctuation at the 5% level. Using the FeldmanâCousins method, we set the following 90% confidence level intervals on the branching fractions: B(D^0âe^+e^-)<1.7Ă10^(-7), B(D^0âÎź^+Îź^-) within [0.6,8.1]Ă10^(-7), and B(D^0âe^¹Ο^â)<3.3Ă10^(-7)
Study of the reaction e^{+}e^{-} -->J/psi\pi^{+}\pi^{-} via initial-state radiation at BaBar
We study the process with
initial-state-radiation events produced at the PEP-II asymmetric-energy
collider. The data were recorded with the BaBar detector at center-of-mass
energies 10.58 and 10.54 GeV, and correspond to an integrated luminosity of 454
. We investigate the mass
distribution in the region from 3.5 to 5.5 . Below 3.7
the signal dominates, and above 4
there is a significant peak due to the Y(4260). A fit to
the data in the range 3.74 -- 5.50 yields a mass value
(stat) (syst) and a width value (stat)(syst) for this state. We do not
confirm the report from the Belle collaboration of a broad structure at 4.01
. In addition, we investigate the system
which results from Y(4260) decay
Search for rare quark-annihilation decays, B --> Ds(*) Phi
We report on searches for B- --> Ds- Phi and B- --> Ds*- Phi. In the context
of the Standard Model, these decays are expected to be highly suppressed since
they proceed through annihilation of the b and u-bar quarks in the B- meson.
Our results are based on 234 million Upsilon(4S) --> B Bbar decays collected
with the BABAR detector at SLAC. We find no evidence for these decays, and we
set Bayesian 90% confidence level upper limits on the branching fractions BF(B-
--> Ds- Phi) Ds*- Phi)<1.2x10^(-5). These results
are consistent with Standard Model expectations.Comment: 8 pages, 3 postscript figues, submitted to Phys. Rev. D (Rapid
Communications
Calcineurin Interacts with PERK and Dephosphorylates Calnexin to Relieve ER Stress in Mammals and Frogs
Background: The accumulation of misfolded proteins within the endoplasmic reticulum (ER) triggers a cellular process known as the Unfolded Protein Response (UPR). One of the earliest responses is the attenuation of protein translation. Little is known about the role that Ca 2+ mobilization plays in the early UPR. Work from our group has shown that cytosolic phosphorylation of calnexin (CLNX) controls Ca 2+ uptake into the ER via the sarco-endoplasmic reticulum Ca 2+-ATPase (SERCA) 2b. Methodology/Principal Findings: Here, we demonstrate that calcineurin (CN), a Ca 2+ dependent phosphatase, associates with the (PKR)-like ER kinase (PERK), and promotes PERK auto-phosphorylation. This association, in turn, increases the phosphorylation level of eukaryotic initiation factor-2 a (eIF2-a) and attenuates protein translation. Data supporting these conclusions were obtained from co-immunoprecipitations, pull-down assays, in-vitro kinase assays, siRNA treatments and [ 35 S]-methionine incorporation measurements. The interaction of CN with PERK was facilitated at elevated cytosolic Ca 2+ concentrations and involved the cytosolic domain of PERK. CN levels were rapidly increased by ER stressors, which could be blocked by siRNA treatments for CN-Aa in cultured astrocytes. Downregulation of CN blocked subsequent ER-stress-induced increases in phosphorylated elF2-a. CN knockdown in Xenopus oocytes predisposed them to induction of apoptosis. We also found that CLNX was dephosphorylated by CN when Ca 2+ increased. These data were obtained from [c 32 P]-CLN
X-ray emission from the Sombrero galaxy: discrete sources
We present a study of discrete X-ray sources in and around the
bulge-dominated, massive Sa galaxy, Sombrero (M104), based on new and archival
Chandra observations with a total exposure of ~200 ks. With a detection limit
of L_X = 1E37 erg/s and a field of view covering a galactocentric radius of ~30
kpc (11.5 arcminute), 383 sources are detected. Cross-correlation with Spitler
et al.'s catalogue of Sombrero globular clusters (GCs) identified from HST/ACS
observations reveals 41 X-rays sources in GCs, presumably low-mass X-ray
binaries (LMXBs). We quantify the differential luminosity functions (LFs) for
both the detected GC and field LMXBs, whose power-low indices (~1.1 for the
GC-LF and ~1.6 for field-LF) are consistent with previous studies for
elliptical galaxies. With precise sky positions of the GCs without a detected
X-ray source, we further quantify, through a fluctuation analysis, the GC LF at
fainter luminosities down to 1E35 erg/s. The derived index rules out a
faint-end slope flatter than 1.1 at a 2 sigma significance, contrary to recent
findings in several elliptical galaxies and the bulge of M31. On the other
hand, the 2-6 keV unresolved emission places a tight constraint on the field
LF, implying a flattened index of ~1.0 below 1E37 erg/s. We also detect 101
sources in the halo of Sombrero. The presence of these sources cannot be
interpreted as galactic LMXBs whose spatial distribution empirically follows
the starlight. Their number is also higher than the expected number of cosmic
AGNs (52+/-11 [1 sigma]) whose surface density is constrained by deep X-ray
surveys. We suggest that either the cosmic X-ray background is unusually high
in the direction of Sombrero, or a distinct population of X-ray sources is
present in the halo of Sombrero.Comment: 11 figures, 5 tables, ApJ in pres
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