Ethylenedioxy homologs of N-methyl-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) and its corresponding cathinone analog methylenedioxymethcathinone: Interactions with transporters for serotonin, dopamine, and norepinephrine

N-Methyl-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA; 'Ecstasy'; 1) and its β-keto analog methylone (MDMC; 2) are popular drugs of abuse. Little is known about their ring-expanded ethylenedioxy homologs. Here, we prepared N-methyl-(3,4-ethylenedioxyphenyl)-2-aminopropane (EDMA; 3), both of its optical isomers, and β-keto EDMA (i.e., EDMC; 4) to examine their effects at transporters for serotonin (SERT), dopamine (DAT), and norepinephrine (NET). In general, ring-expansion of the methylenedioxy group led to a several-fold reduction in potency at all three transporters. With respect to EDMA (3), S(+)3 was 6-fold, 50-fold, and 8-fold more potent than its R(-) enantiomer at SERT, DAT, and NET, respectively. Overall, in the absence of a β-carbonyl group, the ethylenedioxy (i.e., 1,4-dioxane) substituent seems better accommodated at SERT than at DAT and NET

Surface waves in solar granulation observed with {\sc Sunrise}

Solar oscillations are expected to be excited by turbulent flows in the intergranular lanes near the solar surface. Time series recorded by the IMaX instrument aboard the {\sc Sunrise} observatory reveal solar oscillations at high resolution, which allow studying the properties of oscillations with short wavelengths. We analyze two times series with synchronous recordings of Doppler velocity and continuum intensity images with durations of 32\thinspace min and 23\thinspace min, resp., recorded close to the disk center of the Sun to study the propagation and excitation of solar acoustic oscillations. In the Doppler velocity data, both the standing acoustic waves and the short-lived, high-degree running waves are visible. The standing waves are visible as temporary enhancements of the amplitudes of the large-scale velocity field due to the stochastic superposition of the acoustic waves. We focus on the high-degree small-scale waves by suitable filtering in the Fourier domain. Investigating the propagation and excitation of $f$- and $p_1$-modes with wave numbers $k > 1.4$\thinspace 1/Mm we find that also exploding granules contribute to the excitation of solar $p$-modes in addition to the contribution of intergranular lanes.Comment: 12 pages, 4 figures, to appear in a special volume on Sunrise in Astrophysical Journal Letter

Detection of vortex tubes in solar granulation from observations with Sunrise

We have investigated a time series of continuum intensity maps and corresponding Dopplergrams of granulation in a very quiet solar region at the disk center, recorded with the Imaging Magnetograph eXperiment (IMaX) on board the balloon-borne solar observatory Sunrise. We find that granules frequently show substructure in the form of lanes composed of a leading bright rim and a trailing dark edge, which move together from the boundary of a granule into the granule itself. We find strikingly similar events in synthesized intensity maps from an ab initio numerical simulation of solar surface convection. From cross sections through the computational domain of the simulation, we conclude that these `granular lanes' are the visible signature of (horizontally oriented) vortex tubes. The characteristic optical appearance of vortex tubes at the solar surface is explained. We propose that the observed vortex tubes may represent only the large-scale end of a hierarchy of vortex tubes existing near the solar surface.Comment: Astrophysical Journal Letters: Sunrise Special Issue, reveived 2010 June 16; accepted 2010 August

Sunrise: instrument, mission, data and first results

The Sunrise balloon-borne solar observatory consists of a 1m aperture Gregory telescope, a UV filter imager, an imaging vector polarimeter, an image stabilization system and further infrastructure. The first science flight of Sunrise yielded high-quality data that reveal the structure, dynamics and evolution of solar convection, oscillations and magnetic fields at a resolution of around 100 km in the quiet Sun. After a brief description of instruments and data, first qualitative results are presented. In contrast to earlier observations, we clearly see granulation at 214 nm. Images in Ca II H display narrow, short-lived dark intergranular lanes between the bright edges of granules. The very small-scale, mixed-polarity internetwork fields are found to be highly dynamic. A significant increase in detectable magnetic flux is found after phase-diversity-related reconstruction of polarization maps, indicating that the polarities are mixed right down to the spatial resolution limit, and probably beyond.Comment: accepted by ApJ

Interaction of glutathione transferase from horse erythrocytes with 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole

7-Chloro-4-nitrobenzo-2-oxa-1,3-diazole reacts with two thiol groups of the dimeric horse erythrocyte glutathione transferase at pH 5.0, with strong inactivation reversible on dithiothreitol treatment. The inactivation kinetic follows a biphasic pattern, similar to that caused by other thiol reagents as recently reported. Both S-methylglutathione and 1-chloro-2,4-dinitrobenzene protect the enzyme from inactivation. Analysis of the reactive SH group-containing peptide gives the sequence Ala-Ser-Cys-Leu-Tyr, identical with that of the peptide that contains the reactive cysteine 47 of the human placental transferase. In the presence of glutathione, the enzyme is not inactivated by this reagent, but it catalyzes its conjugation to glutathione. At higher pH values, 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole reacts with 2 tyrosines/dimer and lysines, as well as with cysteines. Reaction with lysine seems essentially without effect on activity; whether the reactive tyrosines are important for activity could not be determined using this reagent only. However, 2 tyrosines among the 4 that are nitrated by tetranitro-methane are important for activity

Novel Potent Muscarinic Receptor Antagonists: Investigation on the Nature of Lipophilic Substituents in the 5- and/or 6-Positions of the 1,4-Dioxane Nucleus

A series of novel 1,4-dioxane analogues of the muscarinic acetylcholine receptor (mAChR) antagonist 2 was synthesized and studied for their affinity at M1-M5 mAChRs. The 6-cyclohexyl-6-phenyl derivative 3b, with a cis configuration between the CH2N+(CH3)3 chain in the 2-position and the cyclohexyl moiety in the 6-position, showed pKi values for mAChRs higher than those of 2 and a selectivity profile analogous to that of the clinically approved drug oxybutynin. The study of the enantiomers of 3b and the corresponding tertiary amine 33b revealed that the eutomers are (2S,6S)-(-)-3b and (2S,6S)-(-)-33b, respectively. Docking simulations on the M3 mAChR-resolved structure rationalized the experimental observations. The quaternary ammonium function, which should prevent the crossing of the blood-brain barrier, and the high M3/M2 selectivity, which might limit cardiovascular side effects, make 3b a valuable starting point for the design of novel antagonists potentially useful in peripheral diseases in which M3 receptors are involved

Two-dimensional solar spectropolarimetry with the KIS/IAA Visible Imaging Polarimeter

Spectropolarimetry at high spatial and spectral resolution is a basic tool to characterize the magnetic properties of the solar atmosphere. We introduce the KIS/IAA Visible Imaging Polarimeter (VIP), a new post-focus instrument that upgrades the TESOS spectrometer at the German VTT into a full vector polarimeter. VIP is a collaboration between the KIS and the IAA. We describe the optical setup of VIP, the data acquisition procedure, and the calibration of the spectropolarimetric measurements. We show examples of data taken between 2005 and 2008 to illustrate the potential of the instrument. VIP is capable of measuring the four Stokes profiles of spectral lines in the range from 420 to 700 nm with a spatial resolution better than 0.5". Lines can be sampled at 40 wavelength positions in 60 s, achieving a noise level of about 2 x 10E-3 with exposure times of 300 ms and pixel sizes of 0.17" x 0.17" (2 x 2 binning). The polarization modulation is stable over periods of a few days, ensuring high polarimetric accuracy. The excellent spectral resolution of TESOS allows the use of sophisticated data analysis techniques such as Stokes inversions. One of the first scientific results of VIP presented here is that the ribbon-like magnetic structures of the network are associated with a distinct pattern of net circular polarization away from disk center. VIP performs spectropolarimetric measurements of solar magnetic fields at a spatial resolution that is only slightly worse than that of the Hinode spectropolarimeter, while providing a 2D field field of view and the possibility to observe up to four spectral regions sequentially with high cadence. VIP can be used as a stand-alone instrument or in combination with other spectropolarimeters and imaging systems of the VTT for extended wavelength coverage.Comment: 10 pages, 8 figures, accepted by Astronomy and Astrophysics v2: figures updated with improved qualit

Phylogeography of SARS-CoV-2 pandemic in Spain: a story of multiple introductions, micro-geographic stratification, founder effects, and super-spreaders

Spain has been one of the main global pandemic epicenters for coronavirus disease 2019 (COVID-19). Here, we analyzed >41 000 genomes (including >26 000 high-quality (HQ) genomes) downloaded from the GISAID repository, including 1 245 (922 HQ) sampled in Spain. The aim of this study was to investigate genome variation of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and reconstruct phylogeographic and transmission patterns in Spain. Phylogeographic analysis suggested at least 34 independent introductions of SARS-CoV-2 to Spain at the beginning of the outbreak. Six lineages spread very successfully in the country, probably favored by super-spreaders, namely, A2a4 (7.8%), A2a5 (38.4%), A2a10 (2.8%), B3a (30.1%), and B9 (8.7%), which accounted for 87.9% of all genomes in the Spanish database. One distinct feature of the Spanish SARS-CoV-2 genomes was the higher frequency of B lineages (39.3%, mainly B3a+B9) than found in any other European country. While B3a, B9, (and an important sub-lineage of A2a5, namely, A2a5c) most likely originated in Spain, the other three haplogroups were imported from other European locations. The B3a strain may have originated in the Basque Country from a B3 ancestor of uncertain geographic origin, whereas B9 likely emerged in Madrid. The time of the most recent common ancestor (TMRCA) of SARS-CoV-2 suggested that the first coronavirus entered the country around 11 February 2020, as estimated from the TMRCA of B3a, the first lineage detected in the country. Moreover, earlier claims that the D614G mutation is associated to higher transmissibility is not consistent with the very high prevalence of COVID-19 in Spain when compared to other countries with lower disease incidence but much higher frequency of this mutation (56.4% in Spain vs. 82.4% in rest of Europe). Instead, the data support a major role of genetic drift in modeling the micro-geographic stratification of virus strains across the country as well as the role of SARS-CoV-2 super-spreaders