Molecular insights into vascular aging.

Aging of the vasculature is the leading risk factor for cardiovascular and cerebrovascular disease [1]. As such, strategies that delay vascular aging could minimize the risk of developing life-threatening vascular complications, enhance healthspan and prolong lifespan. However, such preventative and therapeutic approaches require identification of the pathophysiological changes underlying vascular aging, and the associated molecular mechanisms responsible.This work was supported by Briitsh Heart Foundation grants BHF) grants PG/13/25/30014, PG/14/69/31032, PG/16/63/32307 and RG/13/14/30314, the National Institute for Health Research Cambridge Biomedical Research Centre, the BHF Centre for Research Excellence

Tissue Inhibitor of Metalloproteinase–3 (TIMP-3) induces FAS dependent apoptosis in human vascular smooth muscle cells

Over expression of Tissue Inhibitor of Metalloproteinases-3 (TIMP-3) in vascular smooth muscle cells (VSMCs) induces apoptosis and reduces neointima formation occurring after saphenous vein interposition grafting or coronary stenting. In studies to address the mechanism of TIMP-3-driven apoptosis in human VSMCs we find that TIMP-3 increased activation of caspase-8 and apoptosis was inhibited by expression of Cytokine response modifier A (CrmA) and dominant negative FAS-Associated protein with Death Domain (FADD). TIMP-3 induced apoptosis did not cause mitochondrial depolarisation, increase activation of caspase-9 and was not inhibited by over-expression of B-cell Lymphoma 2 (Bcl2), indicating a mitochondrial independent/type-I death receptor pathway. TIMP-3 increased levels of the First Apoptosis Signal receptor (FAS) and depletion of FAS with shRNA showed TIMP-3-induced apoptosis was FAS dependent. TIMP-3 induced formation of the Death-Inducing Signalling Complex (DISC), as detected by immunoprecipitation and by immunofluorescence. Cellular-FADD-like IL-1 converting enzyme-Like Inhibitory Protein (c-FLIP) localised with FAS at the cell periphery in the absence of TIMP-3 and this localisation was lost on TIMP-3 expression with c-FLIP adopting a perinuclear localisation. Although TIMP-3 inhibited FAS shedding, this did not increase total surface levels of FAS but instead increased FAS levels within localised regions at the cell surface. A Disintegrin And Metalloproteinase 17 (ADAM17) is inhibited by TIMP-3 and depletion of ADAM17 with shRNA significantly decreased FAS shedding. However ADAM17 depletion did not induce apoptosis or replicate the effects of TIMP-3 by increasing localised clustering of cell surface FAS. ADAM17-depleted cells could activate caspase-3 when expressing levels of TIMP-3 that were otherwise sub-apoptotic, suggesting a partial role for ADAM17 mediated ectodomain shedding in TIMP-3 mediated apoptosis. We conclude that TIMP-3 induced apoptosis in VSMCs is highly dependent on FAS and is associated with changes in FAS and c-FLIP localisation, but is not solely dependent on shedding of the FAS ectodomain

Mitochondrial DNA damage and atherosclerosis.

Mitochondria are often regarded as the cellular powerhouses through their ability to generate ATP, the universal fuel for metabolic processes. However, in recent years mitochondria have been recognised as critical regulators of cell death, inflammation, metabolism, and the generation of reactive oxygen species (ROS). Thus, mitochondrial dysfunction directly promotes cell death, inflammation, and oxidative stress and alters metabolism. These are key processes in atherosclerosis and there is now evidence that mitochondrial DNA (mtDNA) damage leads to mitochondrial dysfunction and promotes atherosclerosis directly. In this review we discuss the recent evidence for and mechanisms linking mtDNA defects and atherosclerosis and suggest areas of mitochondrial biology that are potential therapeutic targets.NoneThis is the Author Accepted Manuscript of the article "Mitochondrial DNA damage and atherosclerosis" published in Trends in Endocrinology and Metabolism on September 2104. This version is embargoed until September 2015 in line with publisher requirements. The published version of record is available on the journal website at http://dx.doi.org/10.1016/j.tem.2014.06.00

Mitochondrial DNA damage and atherosclerosis

This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Elsevier.Mitochondria are the cellular powerhouses, fuelling metabolic processes through their generation of ATP. However we now recognise that these organelles also have pivotal roles in the generation of reactive oxygen species (ROS) and the regulation of cell death, inflammation and metabolism. Mitochondrial dysfunction therefore leads to oxidative stress, cell death, inflammation and altered metabolism, which are all key processes in atherosclerosis. Recent evidence indicates that mitochondrial DNA (mtDNA) damage is present and promotes atherosclerosis through mitochondrial dysfunction. In this review we discuss the role and mechanisms linking mtDNA damage and atherosclerosis, and identify areas of mitochondrial biology that may yield potential therapeutic targets.This work was supported by British Heart Foundation grants PG/14/69/31032 and RG/13/14/30314, the National Institute for Health Research Cambridge Biomedical Research Centre, and the Academy of Medical Sciences

Confronting hybrid inflation in supergravity with CMB data

$F$-term GUT inflation coupled to N=1 Supergravity is confronted with CMB data. Corrections to the string mass-per-unit-length away from the Bogomolny limit are taken into account. We find that a superpotential coupling 10^{-7}/\mcN \lesssim \kappa \lesssim 10^{-2}/\mcN, with \mcN the dimension of the Higgs-representation, is still compatible with the data. The parameter space is enlarged in warm inflation, as well as in the curvaton and inhomogeneous reheat scenario. $F$-strings formed at the end of $P$-term inflation are also considered. Because these strings satisfy the Bogomolny bound the bounds are stronger: the gauge coupling is constrained to the range $10^{-7} < g <10^{-4}$.Comment: 36 pages, 15 figure

Interleukin-1α Activity in Necrotic Endothelial Cells Is Controlled by Caspase-1 Cleavage of Interleukin-1 Receptor-2: IMPLICATIONS FOR ALLOGRAFT REJECTION.

Inflammation is a key instigator of the immune responses that drive atherosclerosis and allograft rejection. IL-1α, a powerful cytokine that activates both innate and adaptive immunity, induces vessel inflammation after release from necrotic vascular smooth muscle cells (VSMCs). Similarly, IL-1α released from endothelial cells (ECs) damaged during transplant drives allograft rejection. However, IL-1α requires cleavage for full cytokine activity, and what controls cleavage in necrotic ECs is currently unknown. We find that ECs have very low levels of IL-1α activity upon necrosis. However, TNFα or IL-1 induces significant levels of active IL-1α in EC necrotic lysates without alteration in protein levels. Increased activity requires cleavage of IL-1α by calpain to the more active mature form. Immunofluorescence and proximity ligation assays show that IL-1α associates with interleukin-1 receptor-2, and this association is decreased by TNFα or IL-1 and requires caspase activity. Thus, TNFα or IL-1 treatment of ECs leads to caspase proteolytic activity that cleaves interleukin-1 receptor-2, allowing IL-1α dissociation and subsequent processing by calpain. Importantly, ECs could be primed by IL-1α from adjacent damaged VSMCs, and necrotic ECs could activate neighboring normal ECs and VSMCs, causing them to release inflammatory cytokines and up-regulate adhesion molecules, thus amplifying inflammation. These data unravel the molecular mechanisms and interplay between damaged ECs and VSMCs that lead to activation of IL-1α and, thus, initiation of adaptive responses that cause graft rejection.This study was supported by British Heart Foundation Grants FS/09/005/26845, FS/13/3/30038 and FS/11/77/29327 (MCHC) & RG/13/14/30314 (MRB); the BHF Cambridge CRE; and the NIHR Cambridge BRC.This is the final version of the article. It first appeared from ASBMB via http://dx.doi.org/10.1074/jbc.M115.66791

Quantum Games and Quantum Strategies

We investigate the quantization of non-zero sum games. For the particular case of the Prisoners' Dilemma we show that this game ceases to pose a dilemma if quantum strategies are allowed for. We also construct a particular quantum strategy which always gives reward if played against any classical strategy.Comment: 4 pages, 4 figures, typographic sign error in the definition of the operator J correcte

The vanishing atrial mass.

HEFCEThis is the final version of the article. It first appeared from Oxford University Press via https://doi.org10.1093/ehjci/jew12

What have we already learned from the CMB?

The COBE satellite, and the DMR experiment in particular, was extraordinarily successful. However, the DMR results were announced about 7 years ago, during which time a great deal more has been learned about anisotropies in the Cosmic Microwave Background (CMB). The CMB experiments currently being designed and built, including long-duration balloons, interferometers, and two space missions, promise to address several fundamental cosmological issues. We present our evaluation of what we already know, what we are beginning to learn now, and what the future may bring.Comment: 20 pages, 3 figures. Changes to match version accepted by PAS

Entangled graphs: Bipartite entanglement in multi-qubit systems

Quantum entanglement in multipartite systems cannot be shared freely. In order to illuminate basic rules of entanglement sharing between qubits we introduce a concept of an entangled structure (graph) such that each qubit of a multipartite system is associated with a point (vertex) while a bi-partite entanglement between two specific qubits is represented by a connection (edge) between these points. We prove that any such entangled structure can be associated with a pure state of a multi-qubit system. Moreover, we show that a pure state corresponding to a given entangled structure is a superposition of vectors from a subspace of the $2^N$-dimensional Hilbert space, whose dimension grows linearly with the number of entangled pairs.Comment: 6 revtex pages, 2 figures, to appear in Phys. Rev.