Peroxisome proliferator-activated receptor -β/δ, -γ Agonists and resveratrol modulate hypoxia induced changes in nuclear receptor activators of muscle oxidative metabolism

PPAR-α, PPAR-β, and PPAR-γ, and RXR in conjunction with PGC-1α and SIRT1, activate oxidative metabolism genes determining insulin sensitivity. In utero, hypoxia is commonly observed in Intrauterine Growth Restriction (IUGR), and reduced insulin sensitivity is often observed in these infants as adults. We sought to investigate how changes in oxygen tension might directly impact muscle PPAR regulation of oxidative genes. Following eight days in culture at 1 oxygen, C2C12 muscle myoblasts displayed a reduction of PGC-1α, PPAR-α, and RXR-α mRNA, as well as CPT-1b and UCP-2 mRNA. SIRT1 and PGC-1α protein was reduced, and PPAR-γ protein increased. The addition of a PPAR-β agonist (L165,041) for the final 24 hours of 1 treatment resulted in increased levels of UCP-2 mRNA and protein whereas Rosiglitazone induced SIRT1, PGC-1α, RXR-α, PPAR-γ, CPT-1b, and UCP-2 mRNA and SIRT1 protein. Under hypoxia, Resveratrol induced SIRT1, RXR-, PPAR- mRNA, and PPAR- and UCP-2 protein. These findings demonstrate that hypoxia alters the components of the PPAR pathway involved in muscle fatty acid oxidative gene transcription and translation. These results have implications for understanding selective hypoxia adaptation and how it might impact long-term muscle oxidative metabolism and insulin sensitivity. Copyright © 2010 Timothy R. H. Regnault et al

Fate of Z(N) walls in hot holographic QCD

We first study Z(N) walls in a deconfined phase of Witten's D4-brane background of pure SU(N) Yang-Mills theory, motivated by a recent work in the case of N=4 SYM. Similarly to it, we propose that for a large wall charge k ~ N, it is described by k D2-branes blown up into a NS5-brane wrapping S^3 inside S^4 via Myers effect, and we calculate the tension by suitable U-duality. We find a precise Casimir scaling for the tension formula. We then study the fate of Z(N)-vacua in a presence of fundamental flavors in quenched approximation via gauge/gravity correspondence. In the case of D3/D7 system where one can vary the mass m_q of flavors, we show that there is a phase transition at T_c ~ m_q, below which the Z(N)-vacua survive while they are lifted above the critical temperature. We analytically calculate the energy lift of k'th vacua in the massless case, both in the D3/D7 system and in the Sakai-Sugimoto model.Comment: 24 pages, v2: references updated, v3: A clarification on the meaning of Z(N) walls in Euclidean space added, citations update

Thermodynamics of AdS/QCD

We study finite temperature properties of four dimensional QCD-like gauge theories in the gauge theory/gravity duality picture. The gravity dual contains two deformed 5d AdS metrics, with and without a black hole, and a dilaton. We study the thermodynamics of the 4d boundary theory and constrain the two metrics so that they correspond to a high and a low temperature phase separated by a first order phase transition. The equation of state has the standard form for the pressure of a strongly coupled fluid modified by a vacuum energy, a bag constant. We determine the parameters of the deformation by using QCD results for $T_c$ and the hadron spectrum. With these parameters, we show that the phase transition in the 4d boundary theory and the 5d bulk Hawking-Page transition agree. We probe the dynamics of the two phases by computing the quark-antiquark free energy in them and confirm that the transition corresponds to confinement-deconfinement transition.Comment: 1+19 pages, 6 figures, references added, section 3 improve

The dynamics of quark-gluon plasma and AdS/CFT

In these pedagogical lectures, we present the techniques of the AdS/CFT correspondence which can be applied to the study of real time dynamics of a strongly coupled plasma system. These methods are based on solving gravitational Einstein's equations on the string/gravity side of the AdS/CFT correspondence. We illustrate these techniques with applications to the boost-invariant expansion of a plasma system. We emphasize the common underlying AdS/CFT description both in the large proper time regime where hydrodynamic dynamics dominates, and in the small proper time regime where the dynamics is far from equilibrium. These AdS/CFT methods provide a fascinating arena interrelating General Relativity phenomenae with strongly coupled gauge theory physics.Comment: 35 pages, 3 figures. Lectures at the 5th Aegean summer school, `From gravity to thermal gauge theories: the AdS/CFT correspondence'. To appear in the proceedings in `Lecture Notes in Physics

Particle Acceleration in Pulsar Wind Nebulae: PIC modelling

We discuss the role of particle-in-cell (PIC) simulations in unveiling the origin of the emitting particles in PWNe. After describing the basics of the PIC technique, we summarize its implications for the quiescent and the flaring emission of the Crab Nebula, as a prototype of PWNe. A consensus seems to be emerging that, in addition to the standard scenario of particle acceleration via the Fermi process at the termination shock of the pulsar wind, magnetic reconnection in the wind, at the termination shock and in the Nebula plays a major role in powering the multi-wavelength signatures of PWNe.Comment: 32 pages, 16 figures, to appear in the book "Modelling Nebulae" edited by D. Torres for Springer, based on the invited contributions to the workshop held in Sant Cugat (Barcelona), June 14-17, 201

Holographic nonlinear hydrodynamics from AdS/CFT with multiple/non-Abelian symmetries

We study viscous hydrodynamics of hot conformal field theory plasma with multiple/non-Abelian symmetries in the framework of AdS/CFT correspondence, using a recently proposed method of directly solving bulk gravity in derivative expansion of local plasma parameters. Our motivation is to better describe the real QCD plasma produced at RHIC, incorporating its U(1)^Nf flavor symmetry as well as SU(2)_I non-Abelian iso-spin symmetry. As concrete examples, we choose to study the STU model for multiple U(1)^3 symmetries, which is a sub-sector of 5D N=4 gauged SUGRA dual to N=4 Super Yang-Mills theory, capturing Cartan U(1)^3 dynamics inside the full R-symmetry. For SU(2), we analyze the minimal 4D N=3 gauged SUGRA whose bosonic action is simply an Einstein-Yang-Mills system, which corresponds to SU(2) R-symmetry dynamics on M2-branes at a Hyper-Kahler cone. By generalizing the bosonic action to arbitrary dimensions and Lie groups, we present our analysis and results for any non-Abelian plasma in arbitrary dimensions.Comment: 37 pages, v3: errors corrected, reference added, JHEP versio

Anomalous Transport from Kubo Formulae

Chiral anomalies have profound impact on the transport properties of relativistic fluids. In four dimensions there are different types of anomalies, pure gauge and mixed gauge-gravitational anomalies. They give rise to two new non-dissipative transport coefficients, the chiral magnetic conductivity and the chiral vortical conductivity. They can be calculated from the microscopic degrees of freedom with the help of Kubo formulae. We review the calculation of the anomalous transport coefficients via Kubo formulae with a particular emphasis on the contribution of the mixed gauge-gravitational anomaly.Comment: 36 pages, 4 figures, 1 table; to appear in Lect. Notes Phys. "Strongly interacting matter in magnetic fields" (Springer), edited by D. Kharzeev, K. Landsteiner, A. Schmitt, H.-U. Yee; v2 small changes in introduction, added references; v3 corrected eq. (21) and added eq. (77), added reference

Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk

No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing.

BACKGROUND: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. METHODS: We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. RESULTS: The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). CONCLUSIONS: These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.The COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 - HEALTH-F2-2009-223175). BCAC is funded by Cancer Research UK [C1287/A10118, C1287/A12014] and by the European Community´s Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 16 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defense (W81XWH-10-1- 0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. This study made use of data generated by the Wellcome Trust Case Control consortium. Funding for the project was provided by the Wellcome Trust under award 076113. The results published here are in part based upon data generated by The Cancer Genome Atlas Project established by the National Cancer Institute and National Human Genome Research Institute.This is the author accepted manuscript. The final version is available from BMJ Group at http://dx.doi.org/10.1136/jmedgenet-2015-103529