Benocyclidine (BTCP) as Non‐labelled Reporter Ligand for MS Binding Assays for the PCP Ion Channel Binding Site of the Desensitized Torpedo Nicotinic Acetylcholine Receptor (nAChR)

In this study we present MS Binding Assays for the PCP ion channel binding site of Torpedo californica nicotinic acetylcholine receptor (nAChR) as an alternative to radioligand binding assays. As MS Marker Benocyclidine (BTCP) was employed, found to be more affine (Kd of 84.2 nM) than the radioligands, e. g. [3H]PCP, used so far in respective binding assays. Based on a highly sensitive and fast LC-ESI-MS/MS method for quantification of BTCP samples, BTCP MS Binding Assays for the PCP ion channel binding site of Torpedo nAChR could be established comprising saturation, kinetic and competition experiments. The affinities obtained in competitive BTCP MS Binding Assays for ligands addressing the PCP ion channel binding site of Torpedo nAChR were in excellent accord with those reported from radioligand experiments. Thus, the new BTCP MS Binding Assays represent a potent and reliable alternative to radioligand binding assays used so far for the characterization of ligand binding to the PCP ion channel binding site of the nAChR

Observing and modeling the dynamic atmosphere of the low mass-loss C-star R Sculptoris at high angular resolution

We study the circumstellar environment of the carbon-rich star R Scl using the near- and mid-infrared high spatial resolution observations from the ESO-VLTI instruments VINCI and MIDI. These observations aim at increasing our knowledge of the dynamic processes in play within the very close circumstellar environment where the mass loss of AGB stars is initiated. Data are interpreted using a self-consistent dynamic model. Interferometric observations do not show any significant variability effect at the 16 m baseline between phases 0.17 and 0.23 in the K band, and for both the 15 m baseline between phases 0.66 and 0.97 and the 31 m baseline between phases 0.90 and 0.97 in the N band. We find fairly good agreement between the dynamic model and the spectrophotometric data from 0.4 to 25 $\mu$m. The model agrees well with the time-dependent flux data at 8.5 $\mu$m, whereas it is too faint at 11.3 and 12.5 $\mu$m. The VINCI visibilities are reproduced well, meaning that the extension of the model is suitable in the K-band. In the mid-infrared, the model has the proper extension to reveal molecular structures of C2H2 and HCN located above the stellar photosphere. However, the windless model used is not able to reproduce the more extended and dense dusty environment. Among the different explanations for the discrepancy between the model and the measurements, the strong nonequilibrium process of dust formation is one of the most probable. The complete dynamic coupling of gas and dust and the approximation of grain opacities with the small-particle limit in the dynamic calculation could also contribute to the difference between the model and the data

Synthesis and biological evaluation of novel N-substituted nipecotic acid derivatives with tricyclic cage structures in the lipophilic domain as GABA uptake inhibitors

<jats:title>Abstract</jats:title><jats:p>A new class of GABA reuptake inhibitors with sterically demanding, highly rigid tricyclic cage structures as the lipophilic domain was synthesized and investigated in regard to their biological activity at the murine GABA transporters (mGAT1–mGAT4). The construction of these compounds, consisting of nipecotic acid, a symmetric tricyclic amine, and a plain hydrocarbon linker connecting the two subunits via their amino nitrogens, was accomplished via reductive amination of a nipecotic acid derivative with an <jats:italic>N</jats:italic>-alkyl substituent displaying a terminal aldehyde function with tricyclic secondary amines. The target compounds varied with regard to spacer length, the bridge size of one of the bridges, and the substituents of the tricyclic skeleton to study the impact of these changes on their potency. Among the tested compounds nipecotic acid ethyl ester derivates with phenyl residues attached to the cage subunit showed reasonable inhibitory potency and subtype selectivity in favor of mGAT3 and mGAT4, respectively.</jats:p&gt

4mu spectra of AGB stars I: Observations

We present times series of high resolution spectra of AGB variables at 4mu. Line profiles from the major contributors to the spectra of oxygen rich stars at 4mu, OH, H$_2$O, HCl and SiO, are examined. The velocity as well as shape variations of these profiles with time are discussed. The line profiles investigated frequently have emission and multiple absorption components. The changes with time of the 4mu region lines do not always follow the cyclic variability seen in NIR spectra and in the photometric light curve. We interpret and discuss the results qualitatively considering comparing the spectral variability with that of the well behaved 1.6mu region and of dynamical model atmospheres. Miras and semiregular variables are compared. The origins of non-periodic behavior are discussed, including the role of spatial inhomogeneities in the stellar atmosphere.Comment: 14 pages, 12 figures, accepted for publication in A&

Abundance analysis for long period variables. Velocity effects studied with O-rich dynamic model atmospheres

(abbreviated) Measuring the surface abundances of AGB stars is an important tool for studying the effects of nucleosynthesis and mixing in the interior of low- to intermediate mass stars during their final evolutionary phases. The atmospheres of AGB stars can be strongly affected by stellar pulsation and the development of a stellar wind, though, and the abundance determination of these objects should therefore be based on dynamic model atmospheres. We investigate the effects of stellar pulsation and mass loss on the appearance of selected spectral features (line profiles, line intensities) and on the derived elemental abundances by performing a systematic comparison of hydrostatic and dynamic model atmospheres. High-resolution synthetic spectra in the near infrared range were calculated based on two dynamic model atmospheres (at various phases during the pulsation cycle) as well as a grid of hydrostatic COMARCS models. Equivalent widths of a selection of atomic and molecular lines were derived in both cases and compared with each other. In the case of the dynamic models, the equivalent widths of all investigated features vary over the pulsation cycle. A consistent reproduction of the derived variations with a set of hydrostatic models is not possible, but several individual phases and spectral features can be reproduced well with the help of specific hydrostatic atmospheric models. In addition, we show that the variations in equivalent width that we found on the basis of the adopted dynamic model atmospheres agree qualitatively with observational results for the Mira R Cas over its light cycle. The findings of our modelling form a starting point to deal with the problem of abundance determination in strongly dynamic AGB stars (i.e., long-period variables).Comment: 13 pages, 22 figures, accepted for publication in A&

Synthesis and biological evaluation of α- and β-hydroxy substituted amino acid derivatives as potential mGAT1-4 inhibitors

<jats:title>Abstract</jats:title><jats:p>In this study, we report the synthesis and biological evaluation of a variety of α- and β-hydroxy substituted amino acid derivatives as potential amino acid subunits in inhibitors of GABA uptake transporters (GATs). In order to ensure that the test compounds adopt a binding pose similar to that presumed for related larger GAT inhibitors, lipophilic residues were introduced either at the amino nitrogen atom or at the alcohol function. Several of the synthesized compounds were found to exhibit similar inhibitory activity at the GAT subtypes mGAT2, mGAT3, and mGAT4, respectively, as compared with the reference N-butylnipecotic acid. Hence, these compounds might serve as starting point for future developments of more complex GAT inhibitors.</jats:p&gt

The time variation in infrared water-vapour bands in Mira variables

The time variation in the water-vapour bands in oxygen-rich Mira variables has been investigated using multi-epoch ISO/SWS spectra of four Mira variables in the 2.5-4.0 micron region. All four stars show H2O bands in absorption around minimum in the visual light curve. At maximum, H2O emission features appear in the ~3.5-4.0 micronm region, while the features at shorter wavelengths remain in absorption. These H2O bands in the 2.5-4.0 micron region originate from the extended atmosphere. The analysis has been carried out with a disk shape, slab geometry model. The observed H2O bands are reproduced by two layers; a `hot' layer with an excitation temperature of 2000 K and a `cool' layer with an excitation temperature of 1000-1400 K. The radii of the `hot' layer (R_hot) are ~1 R_* at visual minimum and 2 R_* at maximum, where R_* is a radius of background source of the model. The time variation of R_hot/R_* from 1 to 2 is attributed to the actual variation in the radius of the H2O layer. A high H2O density shell occurs near the surface of the star around minimum, and moves out with the stellar pulsation. This shell gradually fades away after maximum, and a new high H2O density shell is formed in the inner region again at the next minimum. Due to large optical depth of H2O, the near-infrared variability is dominated by the H2O layer, and the L'-band flux correlates with the area of the H2O shell. The infrared molecular bands trace the structure of the extended atmosphere and impose appreciable effects on near-infrared light curve of Mira variables.Comment: 15 pages, 16 figures, accepted by A&

Simultaneous LC-ESI-MS/MS Quantification of Levosimendan and Its Metabolites for Therapeutic Drug Monitoring of Cardiac Surgery Patients

Levosimendan is used in severe chronic cardiac insufficiency, also within the peri-operative setting. Real-life pharmacokinetic data in surgical patients is lacking, making therapeutic drug monitoring (TDM) of levosimendan, its pharmacologically active metabolite OR-1896, and its intermediate OR-1855 important. A simultaneous highly sensitive quantification of levosimendan and its metabolites in small-volume samples has not yet been described. Here, levosimendan (LLOQ 0.450 nM), OR-1896, and OR-1855 (LLOQ both 1.0 nM) were successfully quantified by LC-ESI-MS/MS after liquid-liquid extraction in 300 mu L of blood. A short C8 column under reversed-phase conditions enabled simultaneous and fast quantification of levosimendan in the negative and the metabolites in the positive ionization mode in a single run within 2 min. Interestingly and unexpectedly, constitutional isomers of levosimendan metabolites with identical mass transitions and similar retention times were observed in surgical patients' samples, which we identified as the metamizole metabolites 4-aminoantipyrine and 4-acetamidoantipyrine. A longer C8 column and a modified mobile phase enabled selective quantification of all analytes in a single run within 7 min. We developed, validated, and applied highly sensitive LC-ESI-MS/MS methods for simultaneous quantification of levosimendan and its metabolites, enabling efficient TDM of cardiac surgery patients even with additional metamizole administration

Complex dynamics in a simple model of pulsations for Super-Asymptotic Giant Branch Stars

When intermediate mass stars reach their last stages of evolution they show pronounced oscillations. This phenomenon happens when these stars reach the so-called Asymptotic Giant Branch (AGB), which is a region of the Hertzsprung-Russell diagram located at about the same region of effective temperatures but at larger luminosities than those of regular giant stars. The period of these oscillations depends on the mass of the star. There is growing evidence that these oscillations are highly correlated with mass loss and that, as the mass loss increases, the pulsations become more chaotic. In this paper we study a simple oscillator which accounts for the observed properties of this kind of stars. This oscillator was first proposed and studied by Icke et al. [Astron.Astrophys. 258, 341 (1992)] and we extend their study to the region of more massive and luminous stars - the region of Super-AGB stars. The oscillator consists of a periodic nonlinear perturbation of a linear Hamiltonian system. The formalism of dynamical systems theory has been used to explore the associated Poincare map for the range of parameters typical of those stars. We have studied and characterized the dynamical behaviour of the oscillator as the parameters of the model are varied, leading us to explore a sequence of local and global bifurcations. Among these, a tripling bifurcation is remarkable, which allows us to show that the Poincare map is a nontwist area preserving map. Meandering curves, hierarchical-islands traps and sticky orbits also show up. We discuss the implications of the stickiness phenomenon in the evolution and stability of the Super-AGB stars.Comment: 13 pages, 9 figure