Ca(2+)-activated Cl(-) currents are dispensable for olfaction

Canonical olfactory signal transduction involves the activation of cyclic AMP-activated cation channels that depolarize the cilia of receptor neurons and raise intracellular calcium. Calcium then activates Cl(-) currents that may be up to tenfold larger than cation currents and are believed to powerfully amplify the response. We identified Anoctamin2 (Ano2, also known as TMEM16B) as the ciliary Ca(2+)-activated Cl(-) channel of olfactory receptor neurons. Ano2 is expressed in the main olfactory epithelium (MOE) and in the vomeronasal organ (VNO), which also expresses the related Ano1 channel. Disruption of Ano2 in mice virtually abolished Ca(2+)-activated Cl(-) currents in the MOE and VNO. Ano2 disruption reduced fluid-phase electro-olfactogram responses by only approximately 40%, did not change air-phase electro-olfactograms and did not reduce performance in olfactory behavioral tasks. In contrast with the current view, cyclic nucleotide-gated cation channels do not need a boost by Cl(-) channels to achieve near-physiological levels of olfaction

Differential atom interferometry beyond the standard quantum limit

We analyze methods to go beyond the standard quantum limit for a class of atomic interferometers, where the quantity of interest is the difference of phase shifts obtained by two independent atomic ensembles. An example is given by an atomic Sagnac interferometer, where for two ensembles propagating in opposite directions in the interferometer this phase difference encodes the angular velocity of the experimental setup. We discuss methods of squeezing separately or jointly observables of the two atomic ensembles, and compare in detail advantages and drawbacks of such schemes. In particular we show that the method of joint squeezing may improve the variance by up to a factor of 2. We take into account fluctuations of the number of atoms in both the preparation and the measurement stage, and obtain bounds on the difference of the numbers of atoms in the two ensembles, as well as on the detection efficiency, which have to be fulfilled in order to surpass the standard quantum limit. Under realistic conditions, the performance of both schemes can be improved significantly by reading out the phase difference via a quantum non-demolition (QND) measurement. Finally, we discuss a scheme using macroscopically entangled ensembles.Comment: 10 pages, 5 figures; eq. (3) corrected and other minor change

Gauss sum factorization with cold atoms

We report the first implementation of a Gauss sum factorization algorithm by an internal state Ramsey interferometer using cold atoms. A sequence of appropriately designed light pulses interacts with an ensemble of cold rubidium atoms. The final population in the involved atomic levels determines a Gauss sum. With this technique we factor the number N=263193.Comment: 4 pages, 5 figure

LRRC8 amino-termini influence pore properties and gating of volume-regulated VRAC anion channels

Volume-regulated anion channels (VRACs) are crucial for cell volume regulation and have various roles in physiology and pathology. VRACs were recently discovered to be formed by heteromers of LRRC8 (leucine-rich repeat-containing 8) proteins. However, the structural determinants of VRAC permeation and gating remain largely unknown. We show here that the short stretch preceding the first LRRC8 transmembrane domain determines VRAC conductance, ion permeability and inactivation gating. Substituted cysteine accessibility studies revealed that several of the first 15 LRRC8 residues are functionally important and exposed to a hydrophilic environment. Substituting glutamate 6 with cysteine decreased the amplitudes of swelling-activated ICl,vol currents, strongly increased iodide-over-chloride permeability, and markedly shifted the voltage-dependence of channel inactivation. Importantly, these effects were reversed by 2-sulfonatoethyl-methanethiosulfonate which restores the negative charge at this amino-acid position. Cd2+-mediated blocking of ICl,vol in cysteine variants suggested that the LRRC8 N-termini come close together in the multimeric channel complex and might form part of the pore. We propose a model in which the N termini of the LRRC8 subunits line the cytoplasmic portion of the VRAC pore, possibly by folding back into the ion permeation pathway

Cell-specific responses to the cytokine TGFβ are determined by variability in protein levels

The cytokine TGFβ provides important information during embryonic development, adult tissue homeostasis, and regeneration. Alterations in the cellular response to TGFβ are involved in severe human diseases. To understand how cells encode the extracellular input and transmit its information to elicit appropriate responses, we acquired quantitative time-resolved measurements of pathway activation at the single-cell level. We established dynamic time warping to quantitatively compare signaling dynamics of thousands of individual cells and described heterogeneous single-cell responses by mathematical modeling. Our combined experimental and theoretical study revealed that the response to a given dose of TGFβ is determined cell specifically by the levels of defined signaling proteins. This heterogeneity in signaling protein expression leads to decomposition of cells into classes with qualitatively distinct signaling dynamics and phenotypic outcome. Negative feedback regulators promote heterogeneous signaling, as a SMAD7 knock-out specifically affected the signal duration in a subpopulation of cells. Taken together, we propose a quantitative framework that allows predicting and testing sources of cellular signaling heterogeneity

Experimental identification of the dominant fabric in widely graded soils

To estimate the vulnerability of widely graded soils to internal erosion, the soil structure has to be analysed. Based on the theory of the bimodal fabric, each particle size distribution (PSD) has a unique diameter that divides the PSD into particles of the soil skeleton and finer mobile particles. The particle diameter, which divides the PSD into these two fractions, is defined as the separation point (dT) and part of the soil skeleton. In this study the Sequential Fill Test (SFT) is used to identify the mobility of particle fractions and the soil matrix. This study is an extension of a series of descriptions of this particular test method. The paper is focused on a widely graded PSD, which is prone to internal erosion. This study demonstrates the change of the soil matrix by variation of the amount of the fine particles. The soil matrix of the investigated PSD does not change until the pore volume is completely filled with mobile particles. If the mobile particles filled completely the pore volume of the coarse soil skeleton, they become also part of the soil skeleton. This matrix is called dual matrix. With further increase of the amount of fine particles, the coarse skeleton is replaced by a new skeleton, where all particles belong to the soil skeleton. For the assessment of a selected PSD, which is prone to internal erosion, it is important to identify the amount of fine fractions, which can stabilize an internally instable dominant fine matrix (i.e. building a dual matrix)

Numerical investigation of the particle skeleton of widely graded soils prone to suffusion

The soil structure affects directly the capability of distributing and transmitting forces between its particles. Thus, the particle arrangement dictates the performance of soil under hydraulic and dynamic loads. This paper describes an analysis method in which the skeletal force chains of the particle assembly (packing) can be identified based on Discrete-Element-Method (DEM) modelling. For the simulations the software LIGGGHTS is used. A widely graded particle size distribution (PSD) is investigated to find correlations between PSD and the micromechanical properties of the particle assemblies. These PSD is based on common internal stability criteria prone to suffusion. The different roles of fractions of the PSD in packings and the force chains under specified load are analysed. Therefor a packing is generated with the Modified-Force-Biased-Algorithm (MFBA). A method based on the bimodality of widely graded PSDs is proposed to differentiate the soil skeleton and the fill of packings of such a PSD. Particle contact number and contact forces are evaluated to identify the amount of loose particles, which are potentially mobile particles. The influence of the packing homogeneity on its skeleton is also addressed. The described method provides a better understanding of the soil structure as well as of internally stability of widely graded soil

Pulmonary vasoconstrictor action of KCNQ potassium channel blockers

KCNQ channels have been widely studied in the nervous system, heart and inner ear, where they have important physiological functions. Recent reports indicate that KCNQ channels may also be expressed in portal vein where they are suggested to influence spontaneous contractile activity. The biophysical properties of K+ currents mediated by KCNQ channels resemble a current underlying the resting K+ conductance and resting potential of pulmonary artery smooth muscle cells. We therefore investigated a possible role of KCNQ channels in regulating the function of pulmonary arteries by determining the ability of the selective KCNQ channel blockers, linopirdine and XE991, to promote pulmonary vasoconstriction. Linopirdine and XE991 both contracted rat and mouse pulmonary arteries but had little effect on mesenteric arteries. In each case the maximum contraction was almost as large as the response to 50 mM K+. Linopirdine had an EC50 of around 1 μM and XE991 was almost 10-fold more potent. Neither removal of the endothelium nor exposure to phentolamine or α,β-methylene ATP, to block α1-adrenoceptors or P2X receptors, respectively, affected the contraction. Contraction was abolished in Ca2+-free solution and in the presence of 1 μM nifedipine or 10 μM levcromakalim