Improving Electro-Weak Fits with TeV-scale Sterile Neutrinos

We study the impact of TeV-scale sterile neutrinos on electro-weak precision observables and lepton number and flavour violating decays in the framework of a type-I see-saw extension of the Standard Model. At tree level sterile neutrinos manifest themselves via non-unitarity of the PMNS matrix and at one-loop level they modify the oblique radiative corrections. We derive explicit formulae for the S,T,U parameters in terms of the neutrino masses and mixings and perform a numerical fit to the electro-weak observables. We find regions of parameter space with a sizable active-sterile mixing which provide a better over-all fit compared to the case where the mixing is negligible. Specifically we find improvements of the invisible Z-decay width, the charged-to-neutral-current ratio for neutrino scattering experiments and of the deviation of the W boson mass from the theoretical expectation.Comment: 16 pages, 17 figures, Journal accepted versio

Molecular mechanism of endothelial and vascular aging: implications for cardiovascular disease

Western societies are aging due to an increasing life span, decreased birth rates, and improving social and health conditions. On the other hand, the prevalence of cardiovascular (CV) and cerebrovascular (CBV) diseases rises with age. Thus, in view of the ongoing aging pandemic, it is appropriate to better understand the molecular pathways of aging as well as age-associated CV and CBV diseases. Oxidative stress contributes to aging of organs and the whole body by an accumulation of reactive oxygen species promoting oxidative damage. Indeed, increased oxidative stress produced in the mitochondria and cytosol of heart and brain is a common denominator to almost all CV and CBV diseases. The mitochondrial adaptor protein p66Shc and the family of deacetylase enzymes, the sirtuins, regulate the aging process, determine lifespan of many species and are involved in CV diseases. GDF11, a member of TGFβ superfamily with homology to myostatin also retards the aging process via yet unknown mechanisms. Recent evidence points towards a promising role of this novel ‘rejuvenation' factor in reducing age-related heart disease. Finally, telomere length is also involved in aging and the development of age-related CV dysfunction. This review focuses on the latest scientific advances in understanding age-related changes of the CV and CBV system, as well as delineating potential novel therapeutic targets derived from aging research for CV and CBV disease

Guggulsterone, an anti-inflammatory phytosterol, inhibits tissue factor and arterial thrombosis

Background: The phytosterol guggulsterone is a potent anti-inflammatory mediator with less side effects than classic steroids. This study assesses the impact of guggulsterone on tissue factor (TF) expression and thrombus formation. Methods and results: Guggulsterone inhibited TNF-α-induced endothelial TF protein expression and surface activity in a concentration-dependent manner; in contrast, dexamethasone did not affect TNF-α-induced TF expression. Guggulsterone enhanced endothelial tissue factor pathway inhibitor and impaired plasminogen activator inhibitor-1 as well as vascular cell adhesion molecule-1 protein. Real-time polymerase chain reaction revealed that guggulsterone inhibited TNF-α-induced TF mRNA expression; moreover, it impaired activation of the MAP kinases JNK and p38, while that of ERK remained unaffected. In vivo, guggulsterone inhibited TF activity and photochemical injury induced thrombotic occlusion of mouse carotid artery. Guggulsterone also inhibited TF expression, proliferation, and migration of vascular smooth muscle cells in a concentration-dependent manner. Conclusions: Guggulsterone inhibits TF expression in vascular cells as well as thrombus formation in vivo; moreover, it impairs vascular smooth muscle cell activation. Hence, this phytosterol offers novel therapeutic options, in particular in inflammatory diseases associated with an increased risk of thrombosi

Amphetamines induce tissue factor and impair tissue factor pathway inhibitor: role of dopamine receptor type 4

Aims Amphetamine intake is associated with acute vascular syndromes. Since these events are caused by arterial thrombosis and this in turn is triggered by tissue factor (TF), this study examines whether amphetamines regulate TF in human endothelial cells. Methods and results Amphetamine (10−7-10−4 mol/L) enhanced thrombin- and tumour necrosis factor (TNF)-α-induced as well as basal TF expression (P = 0.029, 0.0003, and 0.003 at maximal concentration), and TNF-α-induced plasminogen activator inhibitor (PAI)-1 expression (P = 0.003), whereas tissue factor pathway inhibitor expression was impaired (P = 0.008). Similarly, 3,4-methylenedioxymethamphetamine (10−7-10−4 mol/L) enhanced TF expression (P = 0.046). These effects were paralleled by an increased TF activity (P = 0.002); moreover, clotting time of human plasma was accelerated by supernatant from amphetamine-treated cells (P = 0.03). Amphetamine enhanced TF mRNA expression via phosphorylation of the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase (ERK) and p38 (P = 0.03 and 0.033), but not c-Jun NH2-terminal kinase (JNK; P = 0.81). The effect of amphetamine on TF expression was abrogated by the dopamine D4 receptor antagonists L-745,870 and L-750,667, but not D2 or D3 receptor antagonists; furthermore, L-745,870 blunted the amphetamine-induced activation of ERK and p38, but not JNK. Conclusion Amphetamines induce endothelial TF expression via stimulation of dopamine D4 receptor and activation of the MAPKs p38 and ERK. These effects occur at clinically relevant amphetamine concentrations and may account for the increased incidence of acute vascular syndromes after amphetamine consumptio

Infrared Sensitivity of Unstable Vacua

We discover that some unstable vacua have long memory. By that we mean that even in the theories containing only massive particles, there are correllators and expectation values which grow with time. We examine the cases of instabilities caused by the constant electric fields, expanding and contracting universes and, most importantly, the global de Sitter space. In the last case the interaction leads to a remarkable UV/IR mixing and to a large back reaction. This gives reasons to believe that the cosmological constant problem could be resolved by the infrared physics.Comment: 23 pages, references adde

PDGF-CC induces tissue factor expression: role of PDGF receptor α/β

Tissue factor (TF) is the principal trigger of the coagulation cascade and involved in arterial thrombus formation. Platelet-derived growth factor CC (PDGF-CC) is a recently discovered member of the PDGF family released upon platelet activation. This study assesses the impact of PDGF-CC on TF expression in human cells. PDGF-CC concentration-dependently induced TF expression by 2.5-fold in THP-1 cells, by 2.0-fold in human peripheral blood monocytes, by 1.4-fold in vascular smooth muscle cells, and by 2.6-fold in microvascular endothelial cells, but did not affect TF expression in aortic endothelial cells. A similar pattern was observed with PDGF-BB. In contrast, PDGF-AA did not alter TF expression in THP-1 cells. TF whole cell activity was induced following stimulation with PDGF-BB and PDGF-CC in THP-1 cells. Real-time polymerase chain reaction revealed that PDGF-CC induced TF mRNA. PDGF-CC transiently activated p42/44 MAP kinase [extracellular signal-regulated kinase (ERK)], while phosphorylation of the MAP kinases c-Jun NH2-terminal kinase (JNK) and p38 remained unaffected. PD98059, a specific inhibitor of ERK phosphorylation, but not the p38 inhibitor SB203580 or the JNK inhibitor SP600125 prevented PDGF-CC induced TF expression in a concentration-dependent manner. The effect of PDGF-CC was antagonized by both PDGF receptor α and PDGF receptor β neutralizing antibodies; in contrast, PDGF-BB was only inhibited by PDGF receptor β blocking antibody. PDGF receptor α and PDGF receptor β inhibition prevented PDGF-CC-induced ERK phosphorylation. PDGF-CC induces TF expression via activation of α/β receptor heterodimers and an ERK-dependent signal transduction pathwa

Dronedarone reduces arterial thrombus formation

Dronedarone has been associated with a reduced number of first hospitalisation due to acute coronary syndromes. Whether this is only due to the reduction in ventricular heart rate and blood pressure or whether other effects of dronedarone may be involved is currently elusive. This study was designed to investigate the role of dronedarone in arterial thrombus formation. C57Bl/6 mice were treated with dronedarone and arterial thrombosis was investigated using a mouse photochemical injury model. Dronedarone inhibited carotid artery thrombus formation in vivo (P<0.05). Thrombin- and collagen-induced platelet aggregation was impaired in dronedarone-treated mice (P<0.05), and expression of plasminogen activator inhibitor-1 (PAI1), an inhibitor of the fibrinolytic system, was reduced in the arterial wall (P<0.05). In contrast, the level of tissue factor (TF), the main trigger of the coagulation cascade, and that of its physiological inhibitor, TF pathway inhibitor, did not differ. Similarly, coagulation times as measured by prothrombin time and activated partial thromboplastin time were comparable between the two groups. Dronedarone inhibits thrombus formation in vivo through inhibition of platelet aggregation and PAI1 expression. This effect occurs within the range of dronedarone concentrations measured in patients, and may represent a beneficial pleiotropic effect of this dru

A new solution to the solar neutrino deficit

We reexamine the transition magnetic moment solution to the solar neutrino problem. We argue that the absence of large time variations in the Super-Kamiokande rate provides strong evidence against spin-flavor flip in the solar convective zone. Spin-flavor flip could, however, occur in the primordial magnetic field in the radiative zone. We compute the longest lived toroidal mode for this field and show that spin-flavor flip in the radiative zone can account for all available solar data.Comment: 6 pages, 5 figures, version accepted for publication in Astroparticle Physic

Sirt1 inhibition promotes in vivo arterial thrombosis and tissue factor expression in stimulated cells

Aims The mammalian silent information regulator-two 1 (Sirt1) blunts the noxious effects of cardiovascular risk factors such as type 2 diabetes mellitus and obesity. Nevertheless, the role of Sirt1 in regulating the expression of tissue factor (TF), the key trigger of coagulation, and arterial thrombus formation remains unknown. Methods and results Human as well as mouse cell lines were used for in vitro experiments, and C57Bl/6 mice for in vivo procedures. Sirt1 inhibition by splitomicin or sirtinol enhanced cytokine-induced endothelial TF protein expression as well as surface activity, while TF pathway inhibitor protein expression did not change. Sirt1 inhibition further enhanced TF mRNA expression, TF promoter activity, and nuclear translocation as well as DNA binding of the p65 subunit of nuclear factor-kappa B (NFκB/p65). Sirt1 siRNA enhanced TF protein and mRNA expression, and this effect was reduced in NFκB/p65−/− mouse embryonic fibroblasts reconstituted with non-acetylatable Lys310-mutant NFκB/p65. Activation of the mitogen-activated protein kinases p38, c-Jun NH2-terminal kinase, and p44/42 (ERK) remained unaffected. In vivo, mice treated with the Sirt1 inhibitor splitomicin exhibited enhanced TF activity in the arterial vessel wall and accelerated carotid artery thrombus formation in a photochemical injury model. Conclusion We provide pharmacological and genetic evidence that Sirt1 inhibition enhances TF expression and activity by increasing NFκB/p65 activation in human endothelial cells. Furthermore, Sirt1 inhibition induces arterial thrombus formation in vivo. Hence, modulation of Sirt1 may offer novel therapeutic options for targeting thrombosi

The Solar Neutrino Problem - An Update

The $^8$B solar neutrino flux as measured by Super-Kamiokande is consistent with the $^{37}$Ar production rate in $^{37}$Cl at Homestake. GALLEX and SAGE, continue to observe $^{71}$Ge production rates in $^{71}$Ga that are consistent with the minimal signal expected from the solar luminosity. The observed $^8$B solar neutrino flux is in good agreement with that predicted by the standard solar model of Dar and Shaviv with nuclear reaction rates that are supported by recent measurements of nuclear fusion cross sections at low energies. The measurements of Super-Kamiokande, SAGE and GALLEX suggest that the expected the pep, $^7$Be and NO solar neutrino fluxes are strongly suppressed. This can be explained by neutrino oscillations and the Mikheyev-Smirnov-Wolfenstein effect. Since neither a flavor change, nor a terrestrial variation, nor a spectral distortion of the $^8$B solar neutrino flux has been observed yet, the solar neutrino problem does not provide conclusive evidence for neutrino properties beyond the standard electroweak model. The deviations of the experimental results from those predicted by the standard solar models may reflect the approximate nature of of solar models and of our knowledge of nuclear reaction rates, radiation transport and particle diffusion in dense stellar plasmas. Only future observations of spectral distortions, or terrestrial modulation or flavor change of solar neutrinos in solar neutrino experiments, such as Super-Kamiokande, SNO, Borexino and HELLAZ will be able to establish that neutrino properties beyond the minimal standard electroweak model are responsible for the solar neutrino problem.Comment: To be published in Physics Reports, Proceedings of ``From Atomic Nuclei to Stars and Galaxies'' Haifa, January 12-16, 1998. No enclosed figure