Atherogenic Lipid Stress Induces Platelet Hyperactivity Through CD36-Mediated Hyposensitivity To Prostacyclin-; The Role Of Phosphodiesterase 3A

Prostacyclin (PGI2) controls platelet activation and thrombosis through a cyclic adenosine monophosphate (cAMP) signalling cascade. However, in patients with cardiovascular diseases this protective mechanism fails for reasons that are unclear. Using both pharmacological and genetic approaches we describe a mechanism by which oxidised low density lipoproteins (oxLDL) associated with dyslipidaemia promote platelet activation through impaired PGI2 sensitivity and diminished cAMP signalling. In functional assays using human platelets, oxLDL modulated the inhibitory effects of PGI2, but not a PDE-insensitive cAMP analogue, on platelet aggregation, granule secretion and in vitro thrombosis. Examination of the mechanism revealed that oxLDL promoted the hydrolysis of cAMP through the phosphorylation and activation of phosphodiesterase 3A (PDE3A), leading to diminished cAMP signalling. PDE3A activation by oxLDL required Src family kinases, Syk and protein kinase C. The effects of oxLDL on platelet function and cAMP signalling were blocked by pharmacological inhibition of CD36, mimicked by CD36-specific oxidised phospholipids and ablated in CD36-/- murine platelets. The injection of oxLDL into wild type mice strongly promoted FeCl3 induced carotid thrombosis in vivo, which was prevented by pharmacological inhibition of PDE3A. Furthermore, blood from dyslipidaemic mice was associated with increased oxidative lipid stress, reduced platelet sensitivity to PGI2 ex vivo and diminished PKA signalling. In contrast, platelet sensitivity to a PDE-resistant cAMP analogue remained normal. Genetic deletion of CD36, protected dyslipidaemic animals from PGI2 hyposensitivity and restored PKA signalling. These data suggest that CD36 can translate atherogenic lipid stress into platelet hyperactivity through modulation of inhibitory cAMP signalling.  

Controlling passively-quenched single photon detectors by bright light

Single photon detectors based on passively-quenched avalanche photodiodes can be temporarily blinded by relatively bright light, of intensity less than a nanowatt. I describe a bright-light regime suitable for attacking a quantum key distribution system containing such detectors. In this regime, all single photon detectors in the receiver Bob are uniformly blinded by continuous illumination coming from the eavesdropper Eve. When Eve needs a certain detector in Bob to produce a click, she modifies polarization (or other parameter used to encode quantum states) of the light she sends to Bob such that the target detector stops receiving light while the other detector(s) continue to be illuminated. The target detector regains single photon sensitivity and, when Eve modifies the polarization again, produces a single click. Thus, Eve has full control of Bob and can do a successful intercept-resend attack. To check the feasibility of the attack, 3 different models of passively-quenched detectors have been tested. In the experiment, I have simulated the intensity diagrams the detectors would receive in a real quantum key distribution system under attack. Control parameters and side effects are considered. It appears that the attack could be practically possible.Comment: Experimental results from a third detector model added. Minor corrections and edits made. 11 pages, 10 figure

The effects of a Variable IMF on the Chemical Evolution of the Galaxy

In this work we explore the effects of adopting an initial mass function (IMF) variable in time on the chemical evolution of the Galaxy. In order to do that we adopt a chemical evolution model which assumes two main infall episodes for the formation of the Galaxy. We study the effects on such a model of different IMFs. First, we use a theoretical one based on the statistical description of the density field arising from random motions in the gas. This IMF is a function of time as it depends on physical conditions of the site of star formation. We also investigate the behaviour of the model predictions using other variable IMFs, parameterized as a function of metallicity. Our results show that the theoretical IMF when applied to our model depends on time but such time variation is important only in the early phases of the Galactic evolution, when the IMF is biased towards massive stars. We also show that the use of an IMF which is a stronger function of time does not lead to a good agreement with the observational constraints suggesting that if the IMF varied this variation should have been small. Our main conclusion is that the G-dwarf metallicity distribution is best explained by infall with a large timescale and a constant IMF, since it is possible to find variable IMFs of the kind studied here, reproducing the G-dwarf metallicity but this worsens the agreement with other observational constraints.Comment: 7 pages, to appear in "The Chemical Evolution of the Milky Way: Stars vs Clusters", Vulcano, September 1999, F. Giovannelli and F. Matteucci eds. (Kluwer, Dordrecht) in pres

Benefits and Harms of Electrical Neuromodulation for Chronic Pelvic Pain: A Systematic Review

Context: Patients with chronic pelvic pain (CPP) may have pain refractory to conventional pain management strategies. Neuromodulation could provide relief of pain. / Objective: To evaluate the benefits and harms of neuromodulation for CPP. / Evidence acquisition:: A comprehensive search of EMBASE, PUBMED, and SCOPUS was performed for the entire database to January 2018. Studies were selected, data were extracted, and quality was assessed by two independent reviewers. A meta-analysis was used to combine randomized controlled trials (RCTs); otherwise, a narrative analysis was used. / Evidence synthesis: After screening 1311 abstracts, 36 studies including eight RCTs were identified, enrolling 1099 patients. Studies covered a broad range in terms of phenotypes of CPP and methods of neuromodulation. A meta-analysis was possible for percutaneous tibial nerve stimulation and transcutaneous electrical nerve stimulation, which showed improvement in pain. Only narrative synthesis was possible for other modalities (sacral nerve stimulation, spinal cord stimulation, intravaginal electrical stimulation, and pudendal nerve stimulation) which appeared to reduce pain in patients with CPP. Treatments generally improved quality of life but with variable reporting of adverse events. Many studies showed high risks of bias and confounding. / Conclusions: While electrical neuromodulation may improve symptoms in CPP, further work is needed with high-quality studies to confirm it. / Patient summary: Neuromodulation may be useful in reducing pain and improving quality of life in patients with chronic pelvic pain, but more research is needed

Intrinsic biocontainment: Multiplex genome safeguards combine transcriptional and recombinational control of essential yeast genes

Significance The advance of biotechnology opens up greater possibilities of bioterror and bioerror. Here, we propose multiplexed safeguard switches rooted in the development of foundational genomic, regulatory, and metabolic technologies. Safeguard switches can be regulated by submicromolar small molecule(s) and combined in a modular fashion. The resulting safeguard strains show high fitness and low reversion rates. Moreover, two distinct classes of safeguard switches are orthogonal, providing a potential fail-safe mechanism. The safeguard technologies provide a practical and generic approach to containing engineered microbes within defined laboratory and/or industrial environments, and can in principle be used in the field as well.</jats:p

The primordial Helium-4 abundance determination: systematic effects

By extrapolating to O/H = N/H = 0 the empirical correlations Y-O/H and Y-N/H defined by a relatively large sample of ~ 45 Blue Compact Dwarfs (BCDs), we have obtained a primordial 4Helium mass fraction Yp= 0.2443+/-0.0015 with dY/dZ = 2.4+/-1.0. This result is in excellent agreement with the average Yp= 0.2452+/-0.0015 determined in the two most metal-deficient BCDs known, I Zw 18 (Zsun/50) and SBS 0335-052 (Zsun/41), where the correction for He production is smallest. The quoted error (1sigma) of < 1% is statistical and does not include systematic effects. We examine various systematic effects including collisional excitation of Hydrogen lines, ionization structure and temperature fluctuation effects, and underlying stellar HeI absorption, and conclude that combining all systematic effects, our Yp may be underestimated by ~ 2-4%. Taken at face value, our Yp implies a baryon-to-photon number ratio eta = 4.7x10^-10 and a baryon mass fraction Omega_b h^2_{100} = 0.017+/-0.005 (2sigma), consistent with the values obtained from deuterium and Cosmic Microwave Background measurements. Correcting Yp upward by 2-4% would make the agreement even better.Comment: 12 pages, 5 PS figures, to appear in "Matter in the Universe", ed P. Jetzer, K. Pretzl and R. von Steiger, Kluwer, Dordrecht (2002

The Cosmological Baryon Density from the Deuterium Abundance at a redshift z = 3.57

We present a measurement of the deuterium to hydrogen ratio in a quasar absorption system at redshift z = 3.57 towards QSO 1937-1009. We use a two component fit, with redshifts determined from unsaturated metal lines, to fit the hydrogen and deuterium features simultaneously. We find a low value of D/H = 2.3 \pm 0.6 \times 10^{-5}, which does not agree with other measurements of high D/H (Songaila et al. 1994, Carswell et al. 1994). The absorption system is very metal poor, with metallicities less than 1/100 solar. Standard models of chemical evolution show the astration of deuterium is limited to a few percent from primordial for systems this metal-poor, so we believe our value represents the primordial one. Using predictions of standard big-bang nucleosynthesis and measurements of the cosmic microwave background, our measurement gives the density of baryons in units of the critical density, $\Omega_b h^2 = 0.024 \pm 0.006$, where H_0 = 100 h km s^{-1] Mpc^{-1}.Comment: 10 pages, 2 Figures, also available at http://nately.ucsd.edu/ ; submitted to Natur

Very Cold Gas and Dark Matter

We have recently proposed a new candidate for baryonic dark matter: very cold molecular gas, in near-isothermal equilibrium with the cosmic background radiation at 2.73 K. The cold gas, of quasi-primordial abundances, is condensed in a fractal structure, resembling the hierarchical structure of the detected interstellar medium. We present some perspectives of detecting this very cold gas, either directly or indirectly. The H$_2$ molecule has an "ultrafine" structure, due to the interaction between the rotation-induced magnetic moment and the nuclear spins. But the lines fall in the km domain, and are very weak. The best opportunity might be the UV absorption of H$_2$ in front of quasars. The unexpected cold dust component, revealed by the COBE/FIRAS submillimetric results, could also be due to this very cold H$_2$ gas, through collision-induced radiation, or solid H$_2$ grains or snowflakes. The $\gamma$-ray distribution, much more radially extended than the supernovae at the origin of cosmic rays acceleration, also points towards and extended gas distribution.Comment: 16 pages, Latex pages, crckapb macro, 3 postscript figures, uuencoded compressed tar file. To be published in the proceeedings of the "Dust-Morphology" conference, Johannesburg, 22-26 January, 1996, D. Block (ed.), (Kluwer Dordrecht

The Cosmic Infrared Background: Measurements and Implications

The cosmic infrared background records much of the radiant energy released by processes of structure formation that have occurred since the decoupling of matter and radiation following the Big Bang. In the past few years, data from the Cosmic Background Explorer mission provided the first measurements of this background, with additional constraints coming from studies of the attenuation of TeV gamma-rays. At the same time there has been rapid progress in resolving a significant fraction of this background with the deep galaxy counts at infrared wavelengths from the Infrared Space Observatory instruments and at submillimeter wavelengths from the Submillimeter Common User Bolometer Array instrument. This article reviews the measurements of the infrared background and sources contributing to it, and discusses the implications for past and present cosmic processes.Comment: 61 pages, incl. 9 figures, to be published in Annual Reviews of Astronomy and Astrophysics, 2001, Vol. 3

The origin of dust in galaxies revisited: the mechanism determining dust content

The origin of cosmic dust is a fundamental issue in planetary science. This paper revisits the origin of dust in galaxies, in particular, in the Milky Way, by using a chemical evolution model of a galaxy composed of stars, interstellar medium, metals (elements heavier than helium), and dust. We start from a review of time-evolutionary equations of the four components, and then, we present simple recipes for the stellar remnant mass and yields of metal and dust based on models of stellar nucleosynthesis and dust formation. After calibrating some model parameters with the data from the solar neighborhood, we have confirmed a shortage of the stellar dust production rate relative to the dust destruction rate by supernovae if the destruction efficiency suggested by theoretical works is correct. If the dust mass growth by material accretion in molecular clouds is active, the observed dust amount in the solar neighborhood is reproduced. We present a clear analytic explanation of the mechanism for determining dust content in galaxies after the activation of accretion growth: a balance between accretion growth and supernova destruction. Thus, the dust content is independent of the uncertainty of the stellar dust yield after the growth activation. The timing of the activation is determined by a critical metal mass fraction which depends on the growth and destruction efficiencies. The solar system formation seems to have occurred well after the activation and plenty of dust would have existed in the proto-solar nebula.Comment: 12 pages, 11 figure