Voltage-dependent Block of the Cystic Fibrosis Transmembrane Conductance Regulator Cl- Channel by Two Closely Related Arylaminobenzoates

The gene defective in cystic fibrosis encodes a Cl- channel, the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is blocked by diphenylamine-2-carboxylate (DPC) when applied extracellularly at millimolar concentrations. We studied the block of CFTR expressed in Xenopus oocytes by DPC or by a closely related molecule, flufenamic acid (FFA). Block of whole-cell CFTR currents by bath-applied DPC or by FFA, both at 200 µM, requires several minutes to reach full effect. Blockade is voltage dependent, suggesting open-channel block: currents at positive potentials are not affected but currents at negative potentials are reduced. The binding site for both drugs senses ~40% of the electric field across the membrane, measured from the inside. In single-channel recordings from excised patches without blockers, the conductance was 8.0 ± 0.4 pS in symmetric 150 mM Cl^-. A subconductance state, measuring ~60% of the main conductance, was often observed. Bursts to the full open state lasting up to tens of seconds were uninterrupted at depolarizing membrane voltages. At hyperpolarizing voltages, bursts were interrupted by brief closures. Either DPC or FFA (50 µM) applied to the cytoplasmic or extracellular face of the channel led to an increase in flicker at V_m =-100 mV and not at V_m = +100 mV, in agreement with whole-cell experiments. DPC induced a higher frequency of flickers from the cytoplasmic side than the extracellular side. FFA produced longer closures than DPC; the FFA closed time was roughly equal (~ 1.2 ms) at -100 mV with application from either side. In cell-attached patch recordings with DPC or FFA applied to the bath, there was flickery block at V_m = -100 mV, confirming that the drugs permeate through the membrane to reach the binding site. The data are consistent with the presence of a single binding site for both drugs, reached from either end of the channel. Open-channel block by DPC or FFA may offer tools for use with site-directed mutagenesis to describe the permeation pathway

The Role of Voltage-Gated Calcium Channels in Neurotransmitter Phenotype Specification: Coexpression and Functional Analysis in Xenopus laevis

Calcium activity has been implicated in many neurodevelopmental events, including the specification of neurotransmitter phenotypes. Higher levels of calcium activity lead to an increased number of inhibitory neural phenotypes, whereas lower levels of calcium activity lead to excitatory neural phenotypes. Voltage-gated calcium channels (VGCCs) allow for rapid calcium entry and are expressed during early neural stages, making them likely regulators of activity-dependent neurotransmitter phenotype specification. To test this hypothesis, multiplex fluorescent in situ hybridization was used to characterize the coexpression of eight VGCC alpha 1 subunits with the excitatory and inhibitory neural markers xVGlut1 and xVIAAT in Xenopus laevis embryos. VGCC coexpression was higher with xVGlut1 than xVIAAT, especially in the hindbrain, spinal cord, and cranial nerves. Calcium activity was also analyzed on a single-cell level, and spike frequency was correlated with the expression of VGCC alpha 1 subunits in cell culture. Cells expressing Ca(V)2.1 and Ca(V)2.2 displayed increased calcium spiking compared with cells not expressing this marker. The VGCC antagonist diltiazem and agonist (-)BayK 8644 were used to manipulate calcium activity. Diltiazem exposure increased the number of glutamatergic cells and decreased the number of gamma-aminobutyric acid (GABA)ergic cells, whereas (2) BayK 8644 exposure decreased the number of glutamatergic cells without having an effect on the number of GABAergic cells. Given that the expression and functional manipulation of VGCCs are correlated with neurotransmitter phenotype in some, but not all, experiments, VGCCs likely act in combination with a variety of other signaling factors to determine neuronal phenotype specification. (C) 2014 Wiley Periodicals, Inc

Teleology and Realism in Leibniz's Philosophy of Science

This paper argues for an interpretation of Leibniz’s claim that physics requires both mechanical and teleological principles as a view regarding the interpretation of physical theories. Granting that Leibniz’s fundamental ontology remains non-physical, or mentalistic, it argues that teleological principles nevertheless ground a realist commitment about mechanical descriptions of phenomena. The empirical results of the new sciences, according to Leibniz, have genuine truth conditions: there is a fact of the matter about the regularities observed in experience. Taking this stance, however, requires bringing non-empirical reasons to bear upon mechanical causal claims. This paper first evaluates extant interpretations of Leibniz’s thesis that there are two realms in physics as describing parallel, self-sufficient sets of laws. It then examines Leibniz’s use of teleological principles to interpret scientific results in the context of his interventions in debates in seventeenth-century kinematic theory, and in the teaching of Copernicanism. Leibniz’s use of the principle of continuity and the principle of simplicity, for instance, reveal an underlying commitment to the truth-aptness, or approximate truth-aptness, of the new natural sciences. The paper concludes with a brief remark on the relation between metaphysics, theology, and physics in Leibniz

Factorial validity of an abbreviated Neighborhood Environment Walkability Scale for seniors in the Nurses’ Health Study

Background: Using validated measures of individuals’ perceptions of their neighborhood built environment is important for accurately estimating effects on physical activity. However, no studies to date have examined the factorial validity of a measure of perceived neighborhood environment among older adults in the United States. The purpose of this measurement study was to test the factorial validity of a version of the Abbreviated Neighborhood Environment Walkability Scale (NEWS-A) modified for seniors in the Nurses’ Health Study (NHS). Findings: A random sample of 2,920 female nurses (mean age = 73 ± 7 years) in the NHS cohort from California, Massachusetts, and Pennsylvania completed a 36-item modified NEWS-A for seniors. Confirmatory factor analyses were conducted to test measurement models for both the modified NEWS-A for seniors and the original NEWS-A. Internal consistency within factors was examined using Cronbach’s alpha. The hypothesized 7-factor measurement model was a poor fit for the modified NEWS-A for seniors. Overall, the best-fitting measurement model was the original 6-factor solution to the NEWS-A. Factors were correlated and internally consistent. Conclusions: This study provided support for the construct validity of the original NEWS-A for assessing perceptions of neighborhood environments in older women in the United States

Non-Fermi Liquid Behavior in Dilute Quadrupolar System Prx_{x}La1−x_{1-x}Pb3_3 with xx≤\le0.05

We have studied the low-temperature properties of Pr$_{x}$La$_{1-x}$Pb$_{3}$ with non-Kramers $\Gamma_{3}$ quadrupolar moments of the crystal-electric-field ground state, for a wide concentration range of Pr ions. For $x$$\le$0.05, the specific heat $C/T$ increases monotonically below $T$=1.5 K, which can be scaled with a characteristic temperature $T^{*}$ defined at each concentration $x$. The electrical resistivity $\rho$$(T)$ in the corresponding temperature region shows a marked decrease deviating from a Fermi-liquid behavior $\rho$$(T)$$\propto$$T^{2}$. The Kondo effect arising from the correlation between the dilute $\Gamma_{3}$ moments and the conduction electrons may give rise to such anomalous behavior

The perception of nasalized vowels in American English: An investigation of on-line use of vowel nasalization in lexical access

The goal of the presented study was to investigate the use of coarticulatory vowel nasalization in lexical access by native speakers of American English. In particular, we compare the use of coart culatory place of articulation cues to that of coarticulatory vowel nasalization. Previous research on lexical access has shown that listeners use cues to the place of articulation of a postvocalic stop in the preceding vowel. However, vowel nasalization as cue to an upcoming nasal consonant has been argued to be a more complex phenomenon. In order to establish whether coarticulatory vowel nasalization aides in the process of lexical access in the same way as place of articulation cues do, we conducted two perception experiments: an off-line 2AFC discrimination task and an on-line eyetracking study using the visual world paradigm. The results of our study suggest that listeners are indeed able to use vowel nasalization in similar ways to place of articulation information, and that both types of cues aide in lexical access

Studies of MCP-PMTs in the miniTimeCube neutrino detector

This report highlights two different types of cross-talk in the photodetectors of the miniTimeCube neutrino experiment. The miniTimeCube detector has 24 $8 \times 8$-anode Photonis MCP-PMTs Planacon XP85012, totalling 1536 individual pixels viewing the 2-liter cube of plastic scintillator

Imaging the Earth's Interior: the Angular Distribution of Terrestrial Neutrinos

Decays of radionuclides throughout the Earth's interior produce geothermal heat, but also are a source of antineutrinos. The (angle-integrated) geoneutrino flux places an integral constraint on the terrestrial radionuclide distribution. In this paper, we calculate the angular distribution of geoneutrinos, which opens a window on the differential radionuclide distribution. We develop the general formalism for the neutrino angular distribution, and we present the inverse transformation which recovers the terrestrial radioisotope distribution given a measurement of the neutrino angular distribution. Thus, geoneutrinos not only allow a means to image the Earth's interior, but offering a direct measure of the radioactive Earth, both (1) revealing the Earth's inner structure as probed by radionuclides, and (2) allowing for a complete determination of the radioactive heat generation as a function of radius. We present the geoneutrino angular distribution for the favored Earth model which has been used to calculate geoneutrino flux. In this model the neutrino generation is dominated by decays in the Earth's mantle and crust; this leads to a very ``peripheral'' angular distribution, in which 2/3 of the neutrinos come from angles > 60 degrees away from the downward vertical. We note the possibility of that the Earth's core contains potassium; different geophysical predictions lead to strongly varying, and hence distinguishable, central intensities (< 30 degrees from the downward vertical). Other uncertainties in the models, and prospects for observation of the geoneutrino angular distribution, are briefly discussed. We conclude by urging the development and construction of antineutrino experiments with angular sensitivity. (Abstract abridged.)Comment: 25 pages, RevTeX, 7 figures. Comments welcom