Pro-Secretory Activity and Pharmacology in Rabbits of an Aminophenyl-1,3,5-Triazine CFTR Activator for Dry Eye Disorders.

PurposePharmacological activation of ocular surface cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels is a potential pro-secretory approach to treat dry eye disorders. We previously reported the discovery of aminophenyl-1,3,5-triazines, one of which, N-methyl-N-phenyl-6-(2,2,3,3-tetrafluoropropoxy)-1,3,5-triazine-2,4-diamine (herein called CFTRact-K267), fully activated human wildtype CFTR with EC50 ∼ 30 nM and increased tear volume for 8 hours in mice. Here, functional and pharmacological studies of CFTRact-K267 were done in adult New Zealand white rabbits.MethodsCFTR chloride conductance was measured in vivo by ocular surface potential differences and in ex vivo conjunctiva by short-circuit current. Tear volume was measured by the Schirmer tear test II and CFTRact-K267 pharmacokinetics and tissue distribution by liquid chromatography/mass spectrometry. Toxicity profile was studied for 28 days with twice-daily topical administration.ResultsElectrophysiological measurements in vivo and in ex vivo conjunctiva demonstrated CFTR activation by CFTRact-K267. A single topical dose of 3 nmol CFTRact-K267 increased tear production by >5 mm for 9 hours by the Schirmer tear test, with predicted therapeutic concentrations maintained in tear fluid. No tachyphylaxis was seen following 28-day twice-daily administration, and changes were not observed in corneal surface integrity or thickness, intraocular pressure, or ocular histology. At day 28, CFTRact-K267 was concentrated in the cornea and conjunctiva and was not detectable in blood or peripheral organs.ConclusionsThese studies support the development of CFTRact-K267 as a pro-secretory therapy for dry eye disorders

Collective synchronization in populations of globally coupled phase oscillators with drifting frequencies

We generalize the Kuramoto model for coupled phase oscillators by allowing the frequencies to drift in time according to Ornstein-Uhlenbeck dynamics. Such drifting frequencies were recently measured in cellular populations of circadian oscillator and inspired our work. Linear stability analysis of the Fokker-Planck equation for an infinite population is amenable to exact solution and we show that the incoherent state is unstable passed a critical coupling strength K_c(\ga, \sigf), where \ga is the inverse characteristic drifting time and \sigf the asymptotic frequency dispersion. Expectedly $K_c$ agrees with the noisy Kuramoto model in the large \ga (Schmolukowski) limit but increases slower as \ga decreases. Asymptotic expansion of the solution for \ga\to 0 shows that the noiseless Kuramoto model with Gaussian frequency distribution is recovered in that limit. Thus varying a single parameter allows to interpolate smoothly between two regimes: one dominated by the frequency dispersion and the other by phase diffusion.Comment: 5 pages, 5 figures, accepted in Phys. Rev.

www.common-metrics.org: a web application to estimate scores from different patient-reported outcome measures on a common scale

BACKGROUND: Recently, a growing number of Item-Response Theory (IRT) models has been published, which allow estimation of a common latent variable from data derived by different Patient Reported Outcomes (PROs). When using data from different PROs, direct estimation of the latent variable has some advantages over the use of sum score conversion tables. It requires substantial proficiency in the field of psychometrics to fit such models using contemporary IRT software. We developed a web application ( http://www.common-metrics.org ), which allows estimation of latent variable scores more easily using IRT models calibrating different measures on instrument independent scales. RESULTS: Currently, the application allows estimation using six different IRT models for Depression, Anxiety, and Physical Function. Based on published item parameters, users of the application can directly estimate latent trait estimates using expected a posteriori (EAP) for sum scores as well as for specific response patterns, Bayes modal (MAP), Weighted likelihood estimation (WLE) and Maximum likelihood (ML) methods and under three different prior distributions. The obtained estimates can be downloaded and analyzed using standard statistical software. CONCLUSIONS: This application enhances the usability of IRT modeling for researchers by allowing comparison of the latent trait estimates over different PROs, such as the Patient Health Questionnaire Depression (PHQ-9) and Anxiety (GAD-7) scales, the Center of Epidemiologic Studies Depression Scale (CES-D), the Beck Depression Inventory (BDI), PROMIS Anxiety and Depression Short Forms and others. Advantages of this approach include comparability of data derived with different measures and tolerance against missing values. The validity of the underlying models needs to be investigated in the future

Electron Pair Resonance in the Coulomb Blockade

We study many-body corrections to the cotunneling current via a localized state with energy $\epsilon_d$ at large bias voltages $V$. We show that the transfer of {\em electron pairs}, enabled by the Coulomb repulsion in the localized level, results in ionization resonance peaks in the third derivative of the current with respect to $V$, centered at $eV=\pm 2\epsilon_d/3$. Our results predict the existence of previously unnoticed structure within Coulomb-blockade diamonds.Comment: 5 pages, 4 figure

Visual exploration and retrieval of XML document collections with the generic system X2

This article reports on the XML retrieval system X2 which has been developed at the University of Munich over the last five years. In a typical session with X2, the user first browses a structural summary of the XML database in order to select interesting elements and keywords occurring in documents. Using this intermediate result, queries combining structure and textual references are composed semiautomatically. After query evaluation, the full set of answers is presented in a visual and structured way. X2 largely exploits the structure found in documents, queries and answers to enable new interactive visualization and exploration techniques that support mixed IR and database-oriented querying, thus bridging the gap between these three views on the data to be retrieved. Another salient characteristic of X2 which distinguishes it from other visual query systems for XML is that it supports various degrees of detailedness in the presentation of answers, as well as techniques for dynamically reordering and grouping retrieved elements once the complete answer set has been computed

Estimation de la qualité des données d'expertise des barrages

National audienceLa maîtrise des risques de rupture des barrages est d'une importance majeure dans notre société de par les enjeux associés. De plus, la pertinence des actions de maintenance ou de réparation d'un barrage dépend de la connaissance de sa performance vis-à-vis de ses principaux modes de rupture et de la fiabilité de cette connaissance. Nous nous intéressons ici à l'estimation de la fiabilité du résultat du modèle d'évaluation possibiliste de la performance des barrages, développé par le Cemagref, à partir de l'estimation de la qualité de ses données d'entrée. Ce modèle est en effet basé sur l'utilisation de données multisources hétérogènes et imparfaites (imprécises, incertaines et incomplètes). Cette communication détaille plus particulièrement les phases d'analyse et de validation des grilles d'analyse de la qualité des données et d'agrégation des critères de ces grilles de qualité. / The control of failure risks of dams is of major importance in our society as regards the associated consequences. Moreover, the relevance of maintenance or repair actions depends on the dam performance knowledge as regards their main failure modes and the reliability of this knowledge. Here, the estimation of the result reliability of the dam performance assessment model, based on evidence theory and developed by the Cemagref, will be considered. The result reliability estimation is done by the quality estimation of the input data. This performance assessment model is based on the use of multisource, heterogeneous and imperfect data (imprecise, uncertain and incomplete data). This communication is more detailing the analysis validation phases of the grids of data quality analysis and the aggregation phase of the criteria of these quality grids

Shedding Light on the Oxidizing Properties of Spin-Flip Excited States in a CrIII Polypyridine Complex and Their Use in Photoredox Catalysis

The photoredox activity of well-known RuII complexes stems from metal-to-ligand charge transfer (MLCT) excited states, in which a ligand-based electron can initiate chemical reductions and a metal-centered hole can trigger oxidations. CrIII polypyridines show similar photoredox properties, although they have fundamentally different electronic structures. Their photoactive excited state is of spin-flip nature, differing from the electronic ground state merely by a change of one electron spin, but with otherwise identical d-orbital occupancy. We find that the driving-force dependence for photoinduced electron transfer from 10 different donors to a spin-flip excited state of a CrIII complex is very similar to that for a RuII polypyridine, and thereby validate the concept of estimating the redox potential of d3 spin-flip excited states in analogous manner as for the MLCT states of d6 compounds. Building on this insight, we use our CrIII complex for photocatalytic reactions not previously explored with this compound class, including the aerobic bromination of methoxyaryls, oxygenation of 1,1,2,2-tetraphenylethylene, aerobic hydroxylation of arylboronic acids, and the vinylation of N-phenyl pyrrolidine. This work contributes to understanding the fundamental photochemical properties of first-row transition-metal complexes in comparison to well-explored precious-metal-based photocatalysts

Probing the Galactic cosmic ray flux with submillimeter and gamma ray data

The study of Galactic diffuse $\gamma$ radiation combined with the knowledge of the distribution of the molecular hydrogen in the Galaxy offers a unique tool to probe the cosmic ray flux in the Galaxy. A methodology to study the level of the cosmic ray "sea" and to unveil target-accelerator systems in the Galaxy, which makes use of the data from the high resolution survey of the Galactic molecular clouds performed with the NANTEN telescope and of the data from gamma-ray instruments, has been developed. Some predictions concerning the level of the cosmic ray "sea" and the $\gamma$-ray emission close to cosmic ray sources for instruments such as Fermi and Cherenkov Telescope Array are presented.Comment: Proceedings of the 4th Heidelberg International Symposium on High Energy Gamma-Ray Astronom