Screening an In-House Isoquinoline Alkaloids Library for New Blockers of Voltage-Gated Na+ Channels Using Voltage Sensor Fluorescent Probes: Hits and Biases

Voltage-gated Na⁺ (Na_V) channels are significant therapeutic targets for the treatment of cardiac and neurological disorders, thus promoting the search for novel Na_V channel ligands. With the objective of discovering new blockers of Na_V channel ligands, we screened an In-House vegetal alkaloid library using fluorescence cell-based assays. We screened 62 isoquinoline alkaloids (IA) for their ability to decrease the FRET signal of voltage sensor probes (VSP), which were induced by the activation of Na_V channels with batrachotoxin (BTX) in GH3b6 cells. This led to the selection of five IA: liriodenine, oxostephanine, thalmiculine, protopine, and bebeerine, inhibiting the BTX-induced VSP signal with micromolar IC₅₀. These five alkaloids were then assayed using the Na⁺ fluorescent probe ANG-2 and the patch-clamp technique. Only oxostephanine and liriodenine were able to inhibit the BTX-induced ANG-2 signal in HEK293-hNa_V1.3 cells. Indeed, liriodenine and oxostephanine decreased the effects of BTX on Na⁺ currents elicited by the hNa_V1.3 channel, suggesting that conformation change induced by BTX binding could induce a bias in fluorescent assays. However, among the five IA selected in the VSP assay, only bebeerine exhibited strong inhibitory effects against Na⁺ currents elicited by the hNav1.2 and hNav1.6 channels, with IC₅₀ values below 10 µM. So far, bebeerine is the first BBIQ to have been reported to block Na_V channels, with promising therapeutical applications.     

Strengthening the Connection between Science,Society and Environment to Develop Future French and European Bioeconomies: Cutting-Edge Research of VAALBIO Team at UCCS

The development of the future French and European bioeconomies will involve developing new green chemical processes in which catalytic transformations are key. The VAALBIO team (valorization of alkanes and biomass) of the UCCS laboratory (Unité de Catalyse et Chimie du Solide) are working on various catalytic processes, either developing new catalysts and/or designing the whole catalytic processes. Our research is focused on both the fundamental and applied aspects of the processes. Through this review paper, we demonstrate the main topics developed by our team focusing mostly on oxygen- and hydrogen-related processes as well as on green hydrogen production and hybrid catalysis. The social impacts of the bioeconomy are also discussed applying the concept of the institutional compass.     

Inner multipliers of de Branges's spaces

For a given functionb in the unit ball ofH and an arbitraryH functionm, the question of whenm is a multiplier of the de Branges space (that is, when is invariant under multiplication bym) is examined. Some necessary and sufficient conditions thatm be a multiplier of are found and it is shown that there are no nonconstant inner multipliers of whenb is a nonconstant extreme point of the unit ball ofH . A new proof is given of the known fact that is invariant under multiplication byz whenb is not an extreme point of the unit ball ofH . Finally, we give a new proof of the known fact that an inner functionm is a multiplier of forb(z)=(1+z)/2 if and only ifm belongs to the range of .Some of the work in this paper originally appeared in the author's doctoral disseratation written at the University of California at Berkeley under the supervision of Donald Sarason.     

Bayesian inference for the power law process

The power law process has been used to model reliability growth, software reliability and the failure times of repairable systems. This article reviews and further develops Bayesian inference for such a process. The Bayesian approach provides a unified methodology for dealing with both time and failure truncated data. As well as looking at the posterior densities of the parameters of the power law process, inference for the expected number of failures and the probability of no failures in some given time interval is discussed. Aspects of the prediction problem are examined. The results are illustrated with two data examples.     

Homologies cyclique et de Hochschild de certains espaces homogènes quantiques

Nous quantifions certaines inclusions d'algèbres de Lie semi-simpleshg. Nous calculons les homologies associées aux quantifications, surC((h)), d'une part des algèbres de fonctions formelles surG/H, pourHG une inclusion de groupes de Lie semi-simples associée, et d'autre part des fonctions algébriques sur SL(2,C)/T.We quantize certain inclusions of semisimple Lie algebrashg. We compute the cyclic and Hochschild homologies for theC((h))-quantizations of

Smart Geodesic Tracing in GRworkbench

We have developed a new tool for numerical work in General Relativity: GRworkbench. We discuss how GRworkbench's implementation of a numerically-amenable analogue to Differential Geometry facilitates the development of robust and chart-independent numerical algorithms. We consider, as an example, geodesic tracing on two charts covering the exterior Schwarzschild space-time.     

The 19F and 31P magnetic resonance spectra of phosphorus trifluoride in nematic solution

The phosphorus and fluorine N.M.R. spectra of PF₃ in a nematic solvent (EBBA) are discussed. The molecular geometry is found to agree with structures obtained from microwave and electron diffraction studies. The sign of the ordering parameter is assumed negative, the signs of the phosphorus fluorine coupling constant and of the chemical shift anisotropies follow from this assumption, and are found to be in agreement with theoretical predictions. The effect of temperature on the isotropic chemical shift of fluorine is discussed.     

Regenerative simulation of TES processes

Regenerative simulation has become a familiar and established tool for simulation-based estimation. However, many applications (e.g., traffic in high-speed communications networks) call for autocorrelated stochastic models to which traditional regenerative theory is not directly applicable. Consequently, extensions of regenerative simulation to dependent time series is increasingly gaining in theoretical and practical interest, with Markov chains constituting an important case. Fortunately, a regenerative structure can be identified in Harris-recurrent Markov chains with minor modification, and this structure can be exploited for standard regenerative estimation. In this paper we focus on a versatile class of Harris-recurrent Markov chains, called TES (Transform-Expand-Sample). TES processes can generate a variety of sample paths with arbitrary marginal distributions, and autocorrelation functions with a variety of functional forms (monotone, oscillating and alternating). A practical advantage of TES processes is that they can simultaneously capture the first and second order statistics of empirical sample paths (raw field measurements). Specifically, the TES modeling methodology can simultaneously match the empirical marginal distribution (histogram), as well as approximate the empirical autocorrelation function. We explicitly identify regenerative structures in TES processes and proceed to address efficiency and accuracy issues of prospective simulations. To show the efficacy of our approach, we report on a TES/M/1 case study. In this study, we used the likelihood ratio method to calculate the mean waiting time performance as a function of the regenerative structure and the intrinsic TES parameter controlling burstiness (degree of autocorrelation) in the arrival process. The score function method was used to estimate the corresponding sensitivity (gradient) with respect to the service rate. Finally, we demonstrated the importance of the particular regenerative structure selected in regard to the estimation efficiency and accuracy induced by the regeneration cycle length.     

The effect of viscosity changes in the vocal folds on the range of oscillation

Changes in vocal fold oscillation threshold pressure were induced in excised canine larynges by experimentally causing fluid movement into and out of the vocal folds. The transport was facilitated by exposing the vocal folds to various osmotic solutions, and it was assumed that changes in hydration caused changes in the internal tissue viscosity. A range of oscillation threshold pressures was measured for each condition of hydration by varying length and glottal width. The oscillation threshold pressure shifted as predicted. Decreased hydration (increased viscosity) raised the threshold of oscillation, and increased hydration (decreased viscosity) lowered the threshold of oscillation. This apparently represents the first in vitro model for the study of the effect of viscosity changes of the internal environment of the vocal folds on phonation.