721 research outputs found
CPT and Lorentz-invariance violation
The largest gap in our understanding of nature at the fundamental level is
perhaps a unified description of gravity and quantum theory. Although there are
currently a variety of theoretical approaches to this question, experimental
research in this field is inhibited by the expected Planck-scale suppression of
quantum-gravity effects. However, the breakdown of spacetime symmetries has
recently been identified as a promising signal in this context: a number of
models for underlying physics can accommodate minuscule Lorentz and CPT
violation, and such effects are amenable to ultrahigh-precision tests. This
presentation will give an overview of the subject. Topics such as motivations,
the SME test framework, mechanisms for relativity breakdown, and experimental
tests will be reviewed. Emphasis is given to observations involving antimatter.Comment: 6 page
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DNA damage-induced S and G2/M cell cycle arrest requires mTORC2-dependent regulation of Chk1.
mTOR signalling is commonly dysregulated in cancer. Concordantly, mTOR inhibitors have demonstrated efficacy in a subset of tumors and are in clinical trials as combination therapies. Although mTOR is associated with promoting cell survival after DNA damage, the exact mechanisms are not well understood. Moreover, since mTOR exists as two complexes, mTORC1 and mTORC2, the role of mTORC2 in cancer and in the DNA damage response is less well explored. Here, we report that mTOR protein levels and kinase activity are transiently increased by DNA damage in an ATM and ATR-dependent manner. We show that inactivation of mTOR with siRNA or pharmacological inhibition of mTORC1/2 kinase prevents etoposide-induced S and G2/M cell cycle arrest. Further results show that Chk1, a key regulator of the cell cycle arrest, is important for this since ablation of mTOR prevents DNA damage-induced Chk1 phosphorylation and decreases Chk1 protein production. Furthermore, mTORC2 was essential and mTORC1 dispensable, for this role. Importantly, we show that mTORC1/2 inhibition sensitizes breast cancer cells to chemotherapy. Taken together, these results suggest that breast cancer cells may rely on mTORC2-Chk1 pathway for survival and provide evidence that mTOR kinase inhibitors may overcome resistance to DNA-damage based therapies in breast cancer
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Oxygen therapy in premature low birth weight infants is associated with capillary loss and increases in blood pressure: a pilot study
Low birth weight (LBW) and premature birth are known risk factors for future cardiovascular disease and in particular essential hypertension (EH). Capillary rarefaction (CR) is an established hallmark of EH and is known to occur in individuals with a history of LBW. We previously reported that LBW infants do not have CR at birth but rather increased capillary density (CD). We hypothesized that LBW infants undergo a process of accelerated CR in early life, triggered in part by oxygen therapy. We studied 26 LBW infants, of whom 10 infants received oxygen therapy, and compared them to 14 normal birth weight (NBW) infants. We measured CD at 1, 5 and 10 days after birth and again after 40 weeks adjusted gestational age equivalent to birth at full term. We confirmed that LBW infants had higher CD at birth compared to NBW infants and found that significant structural CR occurred at term age in LBW infants who had received oxygen therapy (mean difference −22 capillaries/field, p = 0.007) and in those who did not receive oxygen therapy (mean difference −29 capillaries/field, p < 0.001) compared to baseline at birth. Both LBW groups showed a significant rise in BP at 40 weeks adjusted term age and the rise in systolic (mean difference 24 mm Hg, p < 0.0001) and diastolic BP (mean difference 14 mm Hg, p < 0.001) was more pronounced in the oxygen treated group compared to the nonoxygen group (mean difference 14 mm Hg, p = 0.043 and mean difference = 9 mm Hg p = 0.056 respectively). In conclusion, oxygen therapy in premature LBW infants may induce significant increases in their BP in early life
Chemotherapy-mediated p53-dependent DNA damage response in clear cell renal cell carcinoma: role of the mTORC1/2 and hypoxia-inducible factor pathways.
The DNA-damaging agent camptothecin (CPT) and its analogs demonstrate clinical utility for the treatment of advanced solid tumors, and CPT-based nanopharmaceuticals are currently in clinical trials for advanced kidney cancer; however, little is known regarding the effects of CPT on hypoxia-inducible factor-2α (HIF-2α) accumulation and activity in clear cell renal cell carcinoma (ccRCC). Here we assessed the effects of CPT on the HIF/p53 pathway. CPT demonstrated striking inhibition of both HIF-1α and HIF-2α accumulation in von Hippel-Lindau (VHL)-defective ccRCC cells, but surprisingly failed to inhibit protein levels of HIF-2α-dependent target genes (VEGF, PAI-1, ET-1, cyclin D1). Instead, CPT induced DNA damage-dependent apoptosis that was augmented in the presence of pVHL. Further analysis revealed CPT regulated endothelin-1 (ET-1) in a p53-dependent manner: CPT increased ET-1 mRNA abundance in VHL-defective ccRCC cell lines that was significantly augmented in their VHL-expressing counterparts that displayed increased phosphorylation and accumulation of p53; p53 siRNA suppressed CPT-induced increase in ET-1 mRNA, as did an inhibitor of ataxia telangiectasia mutated (ATM) signaling, suggesting a role for ATM-dependent phosphorylation of p53 in the induction of ET-1. Finally, we demonstrate that p53 phosphorylation and accumulation is partially dependent on mTOR activity in ccRCC. Consistent with this result, pharmacological inhibition of mTORC1/2 kinase inhibited CPT-mediated ET-1 upregulation, and p53-dependent responses in ccRCC. Collectively, these data provide mechanistic insight into the action of CPT in ccRCC, identify ET-1 as a p53-regulated gene and demonstrate a requirement of mTOR for p53-mediated responses in this tumor type
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HIF-mediated suppression of DEPTOR confers resistance to mTOR kinase inhibition in renal cancer
Mechanistic target of rapamycin (mTOR) is a fundamental regulator of cell growth, proliferation, and metabolism. mTOR is activated in renal cancer and accelerates tumor progression. Here, we report that the mTOR inhibitor, DEP domain-containing mTOR-interacting protein (DEPTOR), is strikingly suppressed in clear cell renal cell carcinoma (ccRCC) tumors and cell lines. We demonstrate that DEPTOR is repressed by both hypoxia-inducible factors, HIF-1 and HIF-2, which occurs through activation of the HIF-target gene and transcriptional repressor, BHLHe40/DEC1/Stra13. Restoration of DEPTOR- and CRISPR/Cas9-mediated knockout experiments demonstrate that DEPTOR is growth inhibitory in ccRCC. Furthermore, loss of DEPTOR confers resistance to second-generation mTOR kinase inhibitors through deregulated mTORC1 feedback to IRS-2/PI3K/Akt. This work reveals a hitherto unknown mechanism of resistance to mTOR kinase targeted therapy that is mediated by HIF-dependent reprograming of mTOR/DEPTOR networks and suggests that restoration of DEPTOR in ccRCC will confer sensitivity to mTOR kinase therapeutics
Cosmological Birefringence: an Astrophysical test of Fundamental Physics
We review the methods used to test for the existence of cosmological
birefringence, i.e. a rotation of the plane of linear polarization for
electromagnetic radiation traveling over cosmological distances, which might
arise in a number of important contexts involving the violation of fundamental
physical principles. The main methods use: (1) the radio polarization of radio
galaxies and quasars, (2) the ultraviolet polarization of radio galaxies, and
(3) the cosmic microwave background polarization. We discuss the main results
obtained so far, the advantages and disadvantages of each method, and future
prospects.Comment: To appear in the Proceedings of the JENAM 2010 Symposium "From
Varying Couplings to Fundamental Physics", held in Lisbon, 6-10 Sept. 201
Effective Theory Approach to the Spontaneous Breakdown of Lorentz Invariance
We generalize the coset construction of Callan, Coleman, Wess and Zumino to
theories in which the Lorentz group is spontaneously broken down to one of its
subgroups. This allows us to write down the most general low-energy effective
Lagrangian in which Lorentz invariance is non-linearly realized, and to explore
the consequences of broken Lorentz symmetry without having to make any
assumptions about the mechanism that triggers the breaking. We carry out the
construction both in flat space, in which the Lorentz group is a global
spacetime symmetry, and in a generally covariant theory, in which the Lorentz
group can be treated as a local internal symmetry. As an illustration of this
formalism, we construct the most general effective field theory in which the
rotation group remains unbroken, and show that the latter is just the
Einstein-aether theory.Comment: 45 pages, no figures
Transmutation operators boundary value problems
Transmutation operators method is used to solve and study boundary value problems. In this paper several ways to obtain transformation operators are considered: the finite integral transforms, Neumann series, the Fourier transforms, and reflection techniques. The finite integral transform technique leads to solution in the form of a composition of the Fourier sine transform and inverse finite integral transfor
Lorentz Violation in Warped Extra Dimensions
Higher dimensional theories which address some of the problematic issues of
the Standard Model(SM) naturally involve some form of -dimensional
Lorentz invariance violation (LIV). In such models the fundamental physics
which leads to, e.g., field localization, orbifolding, the existence of brane
terms and the compactification process all can introduce LIV in the higher
dimensional theory while still preserving 4-d Lorentz invariance. In this
paper, attempting to capture some of this physics, we extend our previous
analysis of LIV in 5-d UED-type models to those with 5-d warped extra
dimensions. To be specific, we employ the 5-d analog of the SM Extension of
Kostelecky et. al. ~which incorporates a complete set of operators arising from
spontaneous LIV. We show that while the response of the bulk scalar, fermion
and gauge fields to the addition of LIV operators in warped models is
qualitatively similar to what happens in the flat 5-d UED case, the gravity
sector of these models reacts very differently than in flat space.
Specifically, we show that LIV in this warped case leads to a non-zero bulk
mass for the 5-d graviton and so the would-be zero mode, which we identify as
the usual 4-d graviton, must necessarily become massive. The origin of this
mass term is the simultaneous existence of the constant non-zero
curvature and the loss of general co-ordinate invariance via LIV in the 5-d
theory. Thus warped 5-d models with LIV in the gravity sector are not
phenomenologically viable.Comment: 14 pages, 4 figs; discussion added, algebra repaire
Constraining noncommutative field theories with holography
An important window to quantum gravity phenomena in low energy noncommutative
(NC) quantum field theories (QFTs) gets represented by a specific form of UV/IR
mixing. Yet another important window to quantum gravity, a holography,
manifests itself in effective QFTs as a distinct UV/IR connection. In matching
these two principles, a useful relationship connecting the UV cutoff
, the IR cutoff and the scale of
noncommutativity , can be obtained. We show that an effective
QFT endowed with both principles may not be capable to fit disparate
experimental bounds simultaneously, like the muon and the masslessness of
the photon. Also, the constraints from the muon preclude any possibility
to observe the birefringence of the vacuum coming from objects at cosmological
distances. On the other hand, in NC theories without the UV completion, where
the perturbative aspect of the theory (obtained by truncating a power series in
) becomes important, a heuristic estimate of the region
where the perturbative expansion is well-defined , gets affected when holography is applied by providing the energy of the
system a -dependent lower limit. This may affect models
which try to infer the scale by using data from low-energy
experiments.Comment: 4 pages, version to be published in JHE
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