Caveolin-3 differentially orchestrates cholinergic and serotonergic constriction of murine airways

The mechanisms of controlling airway smooth muscle (ASM) tone are of utmost clinical importance as inappropriate constriction is a hallmark in asthma and chronic obstructive pulmonary disease. Receptors for acetylcholine and serotonin, two relevant mediators in this context, appear to be incorporated in specialized, cholesterol-rich domains of the plasma membrane, termed caveolae due to their invaginated shape. The structural protein caveolin-1 partly accounts for anchoring of these receptors. We here determined the role of the other major caveolar protein, caveolin-3 (cav-3), in orchestrating cholinergic and serotonergic ASM responses, utilizing newly generated cav-3 deficient mice. Cav-3 deficiency fully abrogated serotonin-induced constriction of extrapulmonary airways in organ baths while leaving intrapulmonary airways unaffected, as assessed in precision cut lung slices. The selective expression of cav-3 in tracheal, but not intrapulmonary bronchial epithelial cells, revealed by immunohistochemistry, might explain the differential effects of cav-3 deficiency on serotonergic ASM constriction. The cholinergic response of extrapulmonary airways was not altered, whereas a considerable increase was observed in cav-3â -/- intrapulmonary bronchi. Thus, cav-3 differentially organizes serotonergic and cholinergic signaling in ASM through mechanisms that are specific for airways of certain caliber and anatomical position. This may allow for selective and site-specific intervention in hyperreactive states

On the use of electron-multiplying CCDs for astronomical spectroscopy

Conventional CCD detectors have two major disadvantages: they are slow to read out and they suffer from read noise. These problems combine to make high-speed spectroscopy of faint targets the most demanding of astronomical observations. It is possible to overcome these weaknesses by using electron-multiplying CCDs (EMCCDs). EMCCDs are conventional frame-transfer CCDs, but with an extended serial register containing high-voltage electrodes. An avalanche of secondary electrons is produced as the photon-generated electrons are clocked through this register, resulting in signal amplification that renders the read noise negligible. Using a combination of laboratory measurements with the QUCAM2 EMCCD camera and Monte Carlo modelling, we show that it is possible to significantly increase the signal-to-noise ratio of an observation by using an EMCCD, but only if it is optimised and utilised correctly. We also show that even greater gains are possible through the use of photon counting. We present a recipe for astronomers to follow when setting up a typical EMCCD observation which ensures that maximum signal-to-noise ratio is obtained. We also discuss the benefits that EMCCDs would bring if used with the next generation of extremely large telescopes. Although we mainly consider the spectroscopic use of EMCCDs, our conclusions are equally applicable to imaging.Comment: 18 figures, 3 tables, 18 page

Quantum-limited force measurement with an optomechanical device

We study the detection of weak coherent forces by means of an optomechanical device formed by a highly reflecting isolated mirror shined by an intense and highly monochromatic laser field. Radiation pressure excites a vibrational mode of the mirror, inducing sidebands of the incident field, which are then measured by heterodyne detection. We determine the sensitivity of such a scheme and show that the use of an entangled input state of the two sideband modes improves the detection, even in the presence of damping and noise acting on the mechanical mode.Comment: 8 pages, 4 figure

ELK1 Uses Different DNA Binding Modes to Regulate Functionally Distinct Classes of Target Genes

Eukaryotic transcription factors are grouped into families and, due to their similar DNA binding domains, often have the potential to bind to the same genomic regions. This can lead to redundancy at the level of DNA binding, and mechanisms are required to generate specific functional outcomes that enable distinct gene expression programmes to be controlled by a particular transcription factor. Here we used ChIP–seq to uncover two distinct binding modes for the ETS transcription factor ELK1. In one mode, other ETS transcription factors can bind regulatory regions in a redundant fashion; in the second, ELK1 binds in a unique fashion to another set of genomic targets. Each binding mode is associated with different binding site features and also distinct regulatory outcomes. Furthermore, the type of binding mode also determines the control of functionally distinct subclasses of genes and hence the phenotypic response elicited. This is demonstrated for the unique binding mode where a novel role for ELK1 in controlling cell migration is revealed. We have therefore uncovered an unexpected link between the type of binding mode employed by a transcription factor, the subsequent gene regulatory mechanisms used, and the functional categories of target genes controlled

Squeezing of a coupled state of two spinors

The notion of spin squeezing involves reduction in the uncertainty of a component of the spin vector below a certain limit. This aspect has been studied earlier for pure and mixed states of definite spin. In this paper, this study has been extended to coupled spin states which do not possess sharp spin value. A general squeezing criterion has been obtained by requiring that a direct product state for two spinors is not squeezed. The squeezing aspect of entangled states is studied in relation to their spin- spin correlations.Comment: Typeset in LaTeX 2e using the style iopart, packages iopams,times,amssymb,graphicx; 17 pages, 5 eps figure file

Novel approach to the study of quantum effects in the early universe

We develop a theoretical frame for the study of classical and quantum gravitational waves based on the properties of a nonlinear ordinary differential equation for a function $\sigma(\eta)$ of the conformal time $\eta$, called the auxiliary field equation. At the classical level, $\sigma(\eta)$ can be expressed by means of two independent solutions of the ''master equation'' to which the perturbed Einstein equations for the gravitational waves can be reduced. At the quantum level, all the significant physical quantities can be formulated using Bogolubov transformations and the operator quadratic Hamiltonian corresponding to the classical version of a damped parametrically excited oscillator where the varying mass is replaced by the square cosmological scale factor $a^{2}(\eta)$. A quantum approach to the generation of gravitational waves is proposed on the grounds of the previous $\eta-$dependent Hamiltonian. An estimate in terms of $\sigma(\eta)$ and $a(\eta)$ of the destruction of quantum coherence due to the gravitational evolution and an exact expression for the phase of a gravitational wave corresponding to any value of $\eta$ are also obtained. We conclude by discussing a few applications to quasi-de Sitter and standard de Sitter scenarios.Comment: 20 pages, to appear on PRD. Already published background material has been either settled up in a more compact form or eliminate

GRAIL An E3 Ubiquitin Ligase that Inhibits Cytokine Gene Transcription Is Expressed in Anergic CD4+ T Cells

AbstractT cell anergy may serve to limit autoreactive T cell responses. We examined early changes in gene expression after antigen-TCR signaling in the presence (activation) or absence (anergy) of B7 costimulation. Induced expression of GRAIL (gene related to anergy in lymphocytes) was observed in anergic CD4+ T cells. GRAIL is a type I transmembrane protein that localizes to the endocytic pathway and bears homology to RING zinc-finger proteins. Ubiquitination studies in vitro support GRAIL function as an E3 ubiquitin ligase. Expression of GRAIL in retrovirally transduced T cell hybridomas dramatically limits activation-induced IL-2 and IL-4 production. Additional studies suggest that GRAIL E3 ubiquitin ligase activity and intact endocytic trafficking are critical for cytokine transcriptional regulation. Expression of GRAIL after an anergizing stimulus may result in ubiquitin-mediated regulation of proteins essential for mitogenic cytokine expression, thus positioning GRAIL as a key player in the induction of the anergic phenotype

Entangling macroscopic oscillators exploiting radiation pressure

It is shown that radiation pressure can be profitably used to entangle {\it macroscopic} oscillators like movable mirrors, using present technology. We prove a new sufficient criterion for entanglement and show that the achievable entanglement is robust against thermal noise. Its signature can be revealed using common optomechanical readout apparatus.Comment: 4 pages, 2 eps figures, new separability criterion added, new figure 2, authors list change

Retrodictively Optimal Localisations in Phase Space

In a previous paper it was shown that the distribution of measured values for a retrodictively optimal simultaneous measurement of position and momentum is always given by the initial state Husimi function. This result is now generalised to retrodictively optimal simultaneous measurements of an arbitrary pair of rotated quadratures x_theta1 and x_theta2. It is shown, that given any such measurement, it is possible to find another such measurement, informationally equivalent to the first, for which the axes defined by the two quadratures are perpendicular. It is further shown that the distribution of measured values for such a meaurement belongs to the class of generalised Husimi functions most recently discussed by Wuensche and Buzek. The class consists of the subset of Wodkiewicz's operational probability distributions for which the filter reference state is a squeezed vaccuum state.Comment: 11 pages, 2 figures. AMS Latex. Replaced with published versio