151 research outputs found
Search for CP violation in D+âÏÏ+ and D+sâK0SÏ+ decays
A search for CP violation in D + â ÏÏ + decays is performed using data collected in 2011 by the LHCb experiment corresponding to an integrated luminosity of 1.0 fbâ1 at a centre of mass energy of 7 TeV. The CP -violating asymmetry is measured to be (â0.04 ± 0.14 ± 0.14)% for candidates with K â K + mass within 20 MeV/c 2 of the Ï meson mass. A search for a CP -violating asymmetry that varies across the Ï mass region of the D + â K â K + Ï + Dalitz plot is also performed, and no evidence for CP violation is found. In addition, the CP asymmetry in the D+sâK0SÏ+ decay is measured to be (0.61 ± 0.83 ± 0.14)%
The Toll-Like Receptor Gene Family Is Integrated into Human DNA Damage and p53 Networks
In recent years the functions that the p53 tumor suppressor plays in human biology have been greatly extended beyond âguardian of the genome.â Our studies of promoter response element sequences targeted by the p53 master regulatory transcription factor suggest a general role for this DNA damage and stress-responsive regulator in the control of human Toll-like receptor (TLR) gene expression. The TLR gene family mediates innate immunity to a wide variety of pathogenic threats through recognition of conserved pathogen-associated molecular motifs. Using primary human immune cells, we have examined expression of the entire TLR gene family following exposure to anti-cancer agents that induce the p53 network. Expression of all TLR genes, TLR1 to TLR10, in blood lymphocytes and alveolar macrophages from healthy volunteers can be induced by DNA metabolic stressors. However, there is considerable inter-individual variability. Most of the TLR genes respond to p53 via canonical as well as noncanonical promoter binding sites. Importantly, the integration of the TLR gene family into the p53 network is unique to primates, a recurrent theme raised for other gene families in our previous studies. Furthermore, a polymorphism in a TLR8 response element provides the first human example of a p53 target sequence specifically responsible for endogenous gene induction. These findingsâdemonstrating that the human innate immune system, including downstream induction of cytokines, can be modulated by DNA metabolic stressâhave many implications for health and disease, as well as for understanding the evolution of damage and p53 responsive networks
Autophagy Impairment Induces Premature Senescence in Primary Human Fibroblasts
BACKGROUND:Recent studies have demonstrated that activation of autophagy increases the lifespan of organisms from yeast to flies. In contrast to the lifespan extension effect in lower organisms, it has been reported that overexpression of unc-51-like kinase 3 (ULK3), the mammalian homolog of autophagy-specific gene 1 (ATG1), induces premature senescence in human fibroblasts. Therefore, we assessed whether the activation of autophagy would genuinely induce premature senescence in human cells. METHODOLOGY/PRINCIPAL FINDINGS:Depletion of ATG7, ATG12, or lysosomal-associated membrane protein 2 (Lamp2) by transfecting siRNA or infecting cells with a virus containing gene-specific shRNA resulted in a senescence-like state in two strains of primary human fibroblasts. Prematurely senescent cells induced by autophagy impairment exhibited the senescent phenotypes, similar to the replicatively senescent cells, such as increased senescence associated ÎČ-galactosidase (SA-ÎČ-gal) activity, reactive oxygen species (ROS) generation, and accumulation of lipofuscin. In addition, expression levels of ribosomal protein S6 kinase1 (S6K1), p-S6K1, p-S6, and eukaryotic translation initiation factor 4E (eIF4E) binding protein 1 (4E-BP1) in the mammalian target of rapamycin (mTOR) pathway and beclin-1, ATG7, ATG12-ATG5 conjugate, and the sequestosome 1 (SQSTM1/p62) monomer in the autophagy pathway were decreased in both the replicatively and the autophagy impairment-induced prematurely senescent cells. Furthermore, it was found that ROS scavenging by N-acetylcysteine (NAC) and inhibition of p53 activation by pifithrin-α or knockdown of p53 using siRNA, respectively, delayed autophagy impairment-induced premature senescence and restored the expression levels of components in the mTOR and autophagy pathways. CONCLUSION:Taken together, we concluded that autophagy impairment induces premature senescence through a ROS- and p53-dependent manner in primary human fibroblasts
The cyclin-dependent kinase inhibitor 5, 6-dichloro-1-beta-D-ribofuranosylbenzimidazole induces nongenotoxic, DNA replication-independent apoptosis of normal and leukemic cells, regardless of their p53 status
<p>Abstract</p> <p>Background</p> <p>Current chemotherapy of human cancers focuses on the DNA damage pathway to induce a p53-mediated cellular response leading to either G1 arrest or apoptosis. However, genotoxic treatments may induce mutations and translocations that result in secondary malignancies or recurrent disease. In addition, about 50% of human cancers are associated with mutations in the <it>p53 </it>gene. Nongenotoxic activation of apoptosis by targeting specific molecular pathways thus provides an attractive therapeutic approach.</p> <p>Methods</p> <p>Normal and leukemic cells were evaluated for their sensitivity to 5, 6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) through cell viability and caspase activation tests. The apoptotic pathway induced by DRB was analysed by immunfluorescence and immunoblot analysis. H2AX phosphorylation and cell cycle analysis were performed to study the dependance of apoptosis on DNA damage and DNA replication, respectively. To investigate the role of p53 in DRB-induced apoptosis, specific p53 inhibitors were used. Statistical analysis on cell survival was performed with the test of independence.</p> <p>Results</p> <p>Here we report that DRB, an inhibitor of the transcriptional cyclin-dependent kinases (CDKs) 7 and 9, triggers DNA replication-independent apoptosis in normal and leukemic human cells regardless of their p53 status and without inducing DNA damage. Our data indicate that (i) in p53-competent cells, apoptosis induced by DRB relies on a cytosolic accumulation of p53 and subsequent Bax activation, (ii) in the absence of p53, it may rely on p73, and (iii) it is independent of ATM and NBS1 proteins. Notably, even apoptosis-resistant leukemic cells such as Raji were sensitive to DRB.</p> <p>Conclusion</p> <p>Our results indicate that DRB represents a potentially useful cancer chemotherapeutic strategy that employs both the p53-dependent and -independent apoptotic pathways without inducing genotoxic stress, thereby decreasing the risk of secondary malignancies.</p
Updated measurements of exclusive J/Ï and Ï(2S) production cross-sections in pp collisions at âs = 7 TeV
The differential cross-section as a function of rapidity has been measured for the exclusive production of J/Ï and Ï(2S) mesons in protonâproton collisions at âs = 7 TeV, using data collected by the LHCb experiment, corresponding to an integrated luminosity of 930 pbâ1. The cross-sections times branching fractions to two muons having pseudorapidities between 2.0 and 4.5 are measured to be where the first uncertainty is statistical and the second is systematic. The measurements agree with next-to-leading order QCD predictions as well as with models that include saturation effects
Measurement of the Îb0, Îb-, and Ωb- Baryon Masses
Bottom baryons decaying to a J/Ï meson and a hyperon are reconstructed using 1.0ââfb-1 of data collected in 2011 with the LHCb detector. Significant Îb0âJ/ÏÎ, Îb-âJ/ÏÎ- and Ωb-âJ/ÏΩ- signals are observed and the corresponding masses are measured to be M(Îb0)=5619.53±0.13(stat.)±0.45(syst.)ââMeV/c2, M(Îb-)=5795.8±0.9(stat.)±0.4(syst.)ââMeV/c2, M(Ωb-)=6046.0±2.2(stat.)±0.5(syst.)ââMeV/c2, while the differences with respect to the Îb0 mass are M(Îb-)-M(Îb0)=176.2±0.9(stat.)±0.1(syst.)ââMeV/c2, M(Ωb-)-M(Îb0)=426.4±2.2(stat.)±0.4(syst.)ââMeV/c2. These are the most precise mass measurements of the Îb0, Îb- and Ωb- baryons to date. Averaging the above Îb0 mass measurement with that published by LHCb using 35ââpb-1 of data collected in 2010 yields M(Îb0)=5619.44±0.13(stat.)±0.38(syst.)ââMeV/c2
Studies of beauty baryon decays to D0phâ and Î+châ final states
Decays of beauty baryons to the D0phâ and Î+châ final states (where h indicates a pion or a kaon) are studied using a data sample of pp collisions, corresponding to an integrated luminosity of 1.0ââfbâ1, collected by the LHCb detector. The Cabibbo-suppressed decays Î0bâD0pKâ and Î0bâÎ+cKâ are observed, and their branching fractions are measured with respect to the decays Î0bâD0pÏâ and Î0bâÎ+cÏâ. In addition, the first observation is reported of the decay of the neutral beauty-strange baryon Î0b to the D0pKâ final state, and a measurement of the Î0b mass is performed. Evidence of the Î0bâÎ+cKâ decay is also reported
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