Ryanodine receptors

Excitation-contraction coupling involves the faithful conversion of electrical stimuli to mechanical shortening in striated muscle cells, enabled by the ubiquitous second messenger, calcium. Crucial to this process are ryanodine receptors (RyRs), the sentinels of massive intracellular calcium stores contained within the sarcoplasmic reticulum. In response to sarcolemmal depolarization, RyRs release calcium into the cytosol, facilitating mobilization of the myofilaments and enabling cell contraction. In order for the cells to relax, calcium must be rapidly resequestered or extruded from the cytosol. The sustainability of this cycle is crucially dependent upon precise regulation of RyRs by numerous cytosolic metabolites and by proteins within the lumen of the sarcoplasmic reticulum and those directly associated with the receptors in a macromolecular complex. In addition to providing the majority of the calcium necessary for contraction of cardiac and skeletal muscle, RyRs act as molecular switchboards that integrate a multitude of cytosolic signals such as dynamic and steady calcium fluctuations, β-adrenergic stimulation (phosphorylation), nitrosylation and metabolic states, and transduce these signals to the channel pore to release appropriate amounts of calcium. Indeed, dysregulation of calcium release via RyRs is associated with life-threatening diseases in both skeletal and cardiac muscle. In this paper, we briefly review some of the most outstanding structural and functional attributes of RyRs and their mechanism of regulation. Further, we address pathogenic RyR dysfunction implicated in cardiovascular disease and skeletal myopathies

De Sitter Vacua from Matter Superpotentials

Consistent uplifting of AdS vacua in string theory often requires extra light degrees of freedom in addition to those of a (Kaehler) modulus. Here we consider the possibility that de Sitter and Minkowski vacua arise due to hidden sector matter interactions. We find that, in this scheme, the hierarchically small supersymmetry breaking scale can be explained by the scale of gaugino condensation and that interesting patterns of the soft terms arise. In particular, a matter-dominated supersymmetry breaking scenario and a version of the mirage mediation scheme appear in the framework of spontaneously broken supergravity.Comment: 12 pages, 2 figure

Crosschecks for Unification at the LHC

Experiments at the Large Hadron Collider (LHC) might test the picture of supersymmetric Grand Unification in particle physics. We argue that the identification of gaugino masses is the most promising step in this direction. Mass predictions for gauginos are pretty robust and often related to the values of the gauge couplings constants. They might allow a meaningful crosscheck for grand unification, at least in simple schemes like gravity, anomaly or mirage mediation.Comment: 23 pages, 8 figure

Role of extracellular histones in the cardiomyopathy of sepsis

The purpose of this study was to define the relationship in polymicrobial sepsis (in adult male C57BL/6 mice) between heart dysfunction and the appearance in plasma of extracellular histones. Procedures included induction of sepsis by cecal ligation and puncture and measurement of heart function using echocardiogram/Doppler parameters. We assessed the ability of histones to cause disequilibrium in the redox status and intracellular [Ca2+]i levels in cardiomyocytes (CMs) (from mice and rats). We also studied the ability of histones to disturb both functional and electrical responses of hearts perfused with histones. Main findings revealed that extracellular histones appearing in septic plasma required C5a receptors, polymorphonuclear leukocytes (PMNs), and the Nachtâ , LRRâ , and PYDâ domainsâ containing protein 3 (NLRP3) inflammasome. In vitro exposure of CMs to histones caused loss of homeostasis of the redox system and in [Ca2+]i, as wellas defects in mitochondrial function. Perfusion of hearts with histones caused electrical and functional dysfunction. Finally, in vivo neutralization of histones in septic mice markedly reduced the parameters of heart dysfunction. Histones caused dysfunction in hearts during polymicrobial sepsis. These events could be attenuated by histone neutralization, suggesting that histones may be targets in the setting of sepsis to reduce cardiac dysfunction.â Kalbitz, M., Grailer, J. J., Fattahi, F., Jajou, L., Herron, T. J., Campbell, K. F., Zetoune, F. S., Bosmann, M., Sarma, J. V., Huberâ Lang, M., Gebhard, F., Loaiza, R., Valdivia, H. H., Jalife, J., Russell, M. W., Ward, P. A. Role of extracellular histones in the cardiomyopathy of sepsis. FASEB J. 29, 2185â 2193 (2015). www.fasebj.orgPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154273/1/fsb2fj14268730.pd

Supersymmetric Higgs and Radiative Electroweak breaking

We review the mechanism of radiative electroweak symmetry breaking taking place in SUSY versions of the standard model. We further discuss different proposals for the origin of SUSY-breaking and the corresponding induced SUSY-breaking soft terms. Several proposals for the understanding of the little hierarchy problem are critically discussed.Comment: To be published in Comptes Rendus de l'Academie des Science

Sparticle Spectrum of Large Volume Compactification

We examine the large volume compactification of Type IIB string theory or its F theory limit and the associated supersymmetry breakdown and soft terms. It is crucial to incorporate the loop-induced moduli mixing, originating from radiative corrections to the Kahler potential. We show that in the presence of moduli mixing, soft scalar masses generically receive a D-term contribution of the order of the gravitino mass m_{3/2} when the visible sector cycle is stabilized by the D-term potential of an anomalous U(1) gauge symmetry, while the moduli-mediated gaugino masses and A-parameters tend to be of the order of m_{3/2}/8pi^2. It is noticed also that a too large moduli mixing can destabilize the large volume solution by making it a saddle point.Comment: 29 page

The heterotic string yields natural supersymmetry

The most promising MSSM candidates of the heterotic string reveal some distinctive properties. These include gauge-top unification, a specific solution to the mu-problem and mirage pattern for the gaugino masses. The location of the top- and the Higgs-multiplets in extra dimensions differs significantly from that of the other quarks and leptons leading to a characteristic signature of suppressed soft breaking terms, reminiscent of a scheme known as natural supersymmetry.Comment: 11 pages, 3 figure

Moduli Stabilisation and Applications in IIB String Theory

This article represents the author's PhD thesis. It describes moduli stabilisation in IIB string theory and applications to phenomenological topics. The first half of the thesis starts with an introductory review. It continues with an account of the statistics of complex structure moduli stabilisation before moving to Kahler moduli stabilisation. It describes in detail the large-volumes models and justifies the assumptions used in their construction. The second half of the thesis is concerned with applications to phenomenological topics. These include supersymmetry breaking and soft terms, inflationary model building and axions.Comment: 219 pages, 16 figures. Author's PhD thesi

Anomalous U(1) Mediation in Large Volume Compactification

We study the general effects of anomalous U(1)_A gauge symmetry on soft supersymmetry (SUSY) breaking terms in large volume scenario, where the MSSM sector is localized on a small cycle whose volume is stabilized by the D-term potential of the U(1)_A. Since it obtains SUSY breaking mass regardless of the detailed form of K\"ahler potential, the U(1)_A vector superfield acts as a messenger mediating the SUSY breaking in the moduli sector to the MSSM sector. Then, through the loops of U(1)_A vector superfield, there arise soft masses of the order of m_{3/2}^2/8\pi^2 for scalar mass squares, m_{3/2}/(8\pi^2)^2 for gaugino masses, and m_{3/2}/8\pi^2 for A-paramteres. In addition, the massive U(1)_A vector superfield can have non-zero F and D-components through the moduli mixing in the K\"ahler potential, and this can result in larger soft masses depending upon the details of the moduli mixing. For instance, in the presence of one-loop induced moduli mixing between the visible sector modulus and the large volume modulus, the U(1)_A D-term provides soft scalar mass squares of the order of m_{3/2}^2. However, if the visible sector modulus is mixed only with small cycle moduli, its effect on soft terms depends on how to stabilize the small cycle moduli.Comment: 28pages, no fi