The cardiomyocyte "redox rheostat": Redox signalling via the AMPK-mTOR axis and regulation of gene and protein expression balancing survival and death.

Reactive oxygen species (ROS) play a key role in development of heart failure but, at a cellular level, their effects range from cytoprotection to induction of cell death. Understanding how this is regulated is crucial to develop novel strategies to ameliorate only the detrimental effects. Here, we revisited the fundamental hypothesis that the level of ROS per se is a key factor in the cellular response by applying different concentrations of H2O2 to cardiomyocytes. High concentrations rapidly reduced intracellular ATP and inhibited protein synthesis. This was associated with activation of AMPK which phosphorylated and inhibited Raptor, a crucial component of mTOR complex-1 that regulates protein synthesis. Inhibition of protein synthesis by high concentrations of H2O2 prevents synthesis of immediate early gene products required for downstream gene expression, and such mRNAs (many encoding proteins required to deal with oxidant stress) were only induced by lower concentrations. Lower concentrations of H2O2 promoted mTOR phosphorylation, associated with differential recruitment of some mRNAs to the polysomes for translation. Some of the upregulated genes induced by low H2O2 levels are cytoprotective. We identified p21Cip1/WAF1 as one such protein, and preventing its upregulation enhanced the rate of cardiomyocyte apoptosis. The data support the concept of a "redox rheostat" in which different degrees of ROS influence cell energetics and intracellular signalling pathways to regulate mRNA and protein expression. This sliding scale determines cell fate, modulating survival vs death

Neuromedin U partially mediates leptin-induced hypothalamo-pituitary adrenal (HPA) stimulation and has a physiological role in the regulation of the HPA axis in the rat.

Intracerebroventricular (ICV) administration of the hypothalamic neuropeptide neuromedin U (NMU) or the adipostat hormone leptin increases plasma ACTH and corticosterone. The relationship between leptin and NMU in the regulation of the hypothalamo-pituitary adrenal (HPA) axis is currently unknown. In this study, leptin (1 nM) significantly increased the release of CRH from ex vivo hypothalamic explants by 207 ± 8.4% (P < 0.05 vs. basal), an effect blocked by the administration of anti-NMU IgG. The ICV administration of leptin (10 μg, 0.625 nmol) increased plasma ACTH and corticosterone 20 min after injection [plasma ACTH (picograms per milliliter): vehicle, 63 ± 20, leptin, 135 ± 36, P < 0.05; plasma corticosterone (nanograms per milliliter): vehicle, 285 ± 39, leptin, 452 ± 44, P < 0.01]. These effects were partially attenuated by the prior administration of anti-NMU IgG. Peripheral leptin also stimulated ACTH release, an effect attenuated by prior ICV administration of anti-NMU IgG. We examined the diurnal pattern of hypothalamic NMU mRNA expression and peptide content, plasma leptin, and plasma corticosterone. The diurnal changes in hypothalamic NMU mRNA expression were positively correlated with hypothalamic NMU peptide content, plasma corticosterone, and plasma leptin. The ICV administration of anti-NMU IgG significantly attenuated the dark phase rise in corticosterone [corticosterone (nanograms per milliliter): vehicle, 493 ± 38; NMU IgG, 342 ± 47 (P < 0.05)]. These studies suggest that NMU may play a role in the regulation of the HPA axis and partially mediate leptin-induced HPA stimulation. Copyright © 2006 by The Endocrine Society

Structure of wavefunctions in (1+2)-body random matrix ensembles

Abstrtact: Random matrix ensembles defined by a mean-field one-body plus a chaos generating random two-body interaction (called embedded ensembles of (1+2)-body interactions) predict for wavefunctions, in the chaotic domain, an essentially one parameter Gaussian forms for the energy dependence of the number of principal components NPC and the localization length {\boldmath l}_H (defined by information entropy), which are two important measures of chaos in finite interacting many particle systems. Numerical embedded ensemble calculations and nuclear shell model results, for NPC and {\boldmath l}_H, are compared with the theory. These analysis clearly point out that for realistic finite interacting many particle systems, in the chaotic domain, wavefunction structure is given by (1+2)-body embedded random matrix ensembles.Comment: 20 pages, 3 figures (1a-c, 2a-b, 3a-c), prepared for the invited talk given in the international conference on `Perspectives in Theoretical Physics', held at Physical Research Laboratory, Ahmedabad during January 8-12, 200

Renormalization group flow of SU(3) lattice gauge theory - Numerical studies in a two coupling space

We investigate the renormalization group (RG) flow of SU(3) lattice gauge theory in a two coupling space with couplings $\beta_{11}$ and $\beta_{12}$ corresponding to $1\times 1$ and $1\times 2$ loops respectively. Extensive numerical calculations of the RG flow are made in the fourth quadrant of this coupling space, i.e., $\beta_{11}>0$ and $\beta_{12}<0$. Swendsen's factor two blocking and the Schwinger-Dyson method are used to find an effective action for the blocked gauge field. The resulting renormalization group flow runs quickly towards an attractive stream which has an approximate line shape. This is numerical evidence of a renormalized trajectory which locates close to the two coupling space. A model flow equation which incorporates a marginal coupling (asymptotic scaling term), an irrelevant coupling and a non-perturbative attraction towards the strong coupling limit reproduces qualitatively the observed features. We further examine the scaling properties of an action which is closer to the attractive stream than the currently used improved actions. It is found that this action shows excellent restoration of rotational symmetry even for coarse lattices with $a \sim 0.3$ fm.Comment: 18 pages with 9 eps figures psfig.sty, typos correcte

Zeeman smearing of the Coulomb blockade

Charge fluctuations of a large quantum dot coupled to a two-dimensional lead via a single-mode good Quantum Point Contact (QPC) and capacitively coupled to a back-gate, are investigated in the presence of a parallel magnetic field. The Zeeman term induces an asymmetry between transmission probabilities for the spin-up and spin-down channels at the QPC, producing noticeable effects on the quantization of the grain charge already at low magnetic fields. Performing a quantitative analysis, I show that the capacitance between the gate and the lead exhibits - instead of a logarithmic singularity - a reduced peak as a function of gate voltage. Experimental applicability is discussed.Comment: 5 pages, 3 figures (Final version

Elevated expression of artemis in human fibroblast cells is associated with cellular radiosensitivity and increased apoptosis

Copyright @ 2012 Nature Publishing GroupThis article has been made available through the Brunel Open Access Publishing Fund.Background: The objective of this study was to determine the molecular mechanism(s) responsible for cellular radiosensitivity in two human fibroblast cell lines 84BR and 175BR derived from two cancer patients. Methods: Clonogenic assays were performed following exposure to increasing doses of gamma radiation to confirm radiosensitivity. γ-H2AX foci assays were used to determine the efficiency of DNA double strand break (DSB) repair in cells. Quantitative-PCR (Q-PCR) established the expression levels of key DNA DSB repair proteins. Imaging flow cytometry using Annexin V-FITC was used to compare artemis expression and apoptosis in cells. Results: Clonogenic cellular hypersensitivity in the 84BR and 175BR cell lines was associated with a defect in DNA DSB repair measured by the γ-H2AX foci assay. Q-PCR analysis and imaging flow cytometry revealed a two-fold overexpression of the artemis DNA repair gene which was associated with an increased level of apoptosis in the cells before and after radiation exposure. Over-expression of normal artemis protein in a normal immortalised fibroblast cell line NB1-Tert resulted in increased radiosensitivity and apoptosis. Conclusion: We conclude elevated expression of artemis is associated with higher levels of DNA DSB, radiosensitivity and elevated apoptosis in two radio-hypersensitive cell lines. These data reveal a potentially novel mechanism responsible for radiosensitivity and show that increased artemis expression in cells can result in either radiation resistance or enhanced sensitivity.This work was supported in part by The Vidal Sassoon Foundation USA. This article is made available through the Brunel Open Access Publishing Fund

Ground-State Magnetization for Interacting Fermions in a Disordered Potential : Kinetic Energy, Exchange Interaction and Off-Diagonal Fluctuations

We study a model of interacting fermions in a disordered potential, which is assumed to generate uniformly fluctuating interaction matrix elements. We show that the ground state magnetization is systematically decreased by off-diagonal fluctuations of the interaction matrix elements. This effect is neglected in the Stoner picture of itinerant ferromagnetism in which the ground-state magnetization is simply determined by the balance between ferromagnetic exchange and kinetic energy, and increasing the interaction strength always favors ferromagnetism. The physical origin of the demagnetizing effect of interaction fluctuations is the larger number of final states available for interaction-induced scattering in the lower spin sectors of the Hilbert space. We analyze the energetic role played by these fluctuations in the limits of small and large interaction $U$. In the small $U$ limit we do second-order perturbation theory and identify explicitly transitions which are allowed for minimal spin and forbidden for higher spin. These transitions then on average lower the energy of the minimal spin ground state with respect to higher spin. For large interactions $U$ we amplify on our earlier work [Ph. Jacquod and A.D. Stone, Phys. Rev. Lett. 84, 3938 (2000)] which showed that minimal spin is favored due to a larger broadening of the many-body density of states in the low-spin sectors. Numerical results are presented in both limits.Comment: 35 pages, 24 figures - final, shortened version, to appear in Physical Review

Efficacy of temsirolimus in metastatic chromophobe renal cell carcinoma

&lt;p&gt;Background: Renal cell carcinoma (RCC) is a histopathologically and molecularly heterogeneous disease with the chromophobe subtype (chRCC) accounting for approximately 5% of all cases. The median overall survival of advanced RCC has improved significantly since the advent of tyrosine kinase inhibitors and mammalian target of rapamycin (mTOR) inhibitors. However, high-quality evidence for the use of new generation tyrosine kinase inhibitors in patients with advanced chRCC is lacking. Few published case reports have highlighted the use of temsirolimus in chRCC.&lt;/p&gt; &lt;p&gt;Case presentation: Here, we report the case of a 36-year-old Caucasian woman with metastatic chRCC with predominantly skeletal metastases who was refractory to sunitinib who demonstrated a durable clinical response to temsirolimus lasting 20 months. We review the available evidence pertaining to the use of new generation molecularly targeted agents, in particular mTOR inhibitors in chRCC and discuss their emerging role in the management of this disease which would aid the oncologists faced with the challenge of treating this rare type of RCC.&lt;/p&gt; &lt;p&gt;Conclusion: Conducting randomised clinical trials in this rarer sub-group of patients would be challenging and our case report and the evidence reviewed would guide the physicians to make informed decision regarding the management of these patients.&lt;/p&gt

A realistic pattern of fermion masses from a five-dimensional SO(10) model

We provide a unified description of fermion masses and mixing angles in the framework of a supersymmetric grand unified SO(10) model with anarchic Yukawa couplings of order unity. The space-time is five dimensional and the extra flat spatial dimension is compactified on the orbifold $S^1/(Z_2 \times Z_2')$, leading to Pati-Salam gauge symmetry on the boundary where Yukawa interactions are localised. The gauge symmetry breaking is completed by means of a rather economic scalar sector, avoiding the doublet-triplet splitting problem. The matter fields live in the bulk and their massless modes get exponential profiles, which naturally explain the mass hierarchy of the different fermion generations. Quarks and leptons properties are naturally reproduced by a mechanism, first proposed by Kitano and Li, that lifts the SO(10) degeneracy of bulk masses in terms of a single parameter. The model provides a realistic pattern of fermion masses and mixing angles for large values of $\tan\beta$. It favours normally ordered neutrino mass spectrum with the lightest neutrino mass below 0.01 eV and no preference for leptonic CP violating phases. The right handed neutrino mass spectrum is very hierarchical and does not allow for thermal leptogenesis. We analyse several variants of the basic framework and find that the results concerning the fermion spectrum are remarkably stable.Comment: 30 pages, 7 figures, 4 table

A Solvable Regime of Disorder and Interactions in Ballistic Nanostructures, Part I: Consequences for Coulomb Blockade

We provide a framework for analyzing the problem of interacting electrons in a ballistic quantum dot with chaotic boundary conditions within an energy $E_T$ (the Thouless energy) of the Fermi energy. Within this window we show that the interactions can be characterized by Landau Fermi liquid parameters. When $g$, the dimensionless conductance of the dot, is large, we find that the disordered interacting problem can be solved in a saddle-point approximation which becomes exact as $g\to\infty$ (as in a large-N theory). The infinite $g$ theory shows a transition to a strong-coupling phase characterized by the same order parameter as in the Pomeranchuk transition in clean systems (a spontaneous interaction-induced Fermi surface distortion), but smeared and pinned by disorder. At finite $g$, the two phases and critical point evolve into three regimes in the $u_m-1/g$ plane -- weak- and strong-coupling regimes separated by crossover lines from a quantum-critical regime controlled by the quantum critical point. In the strong-coupling and quantum-critical regions, the quasiparticle acquires a width of the same order as the level spacing $\Delta$ within a few $\Delta$'s of the Fermi energy due to coupling to collective excitations. In the strong coupling regime if $m$ is odd, the dot will (if isolated) cross over from the orthogonal to unitary ensemble for an exponentially small external flux, or will (if strongly coupled to leads) break time-reversal symmetry spontaneously.Comment: 33 pages, 14 figures. Very minor changes. We have clarified that we are treating charge-channel instabilities in spinful systems, leaving spin-channel instabilities for future work. No substantive results are change