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We present the highest fidelity spectrum to date of a planetary-mass object. VHS 1256 b is a M Jup widely separated (∼8″, a = 150 au), young, planetary-mass companion that shares photometric colors and spectroscopic features with the directly imaged exoplanets HR 8799c, d, and e. As an L-to-T transition object, VHS 1256 b exists along the region of the color–magnitude diagram where substellar atmospheres transition from cloudy to clear. We observed VHS 1256 b with JWST's NIRSpec IFU and MIRI MRS modes for coverage from 1 to 20 μm at resolutions of ∼1000–3700. Water, methane, carbon monoxide, carbon dioxide, sodium, and potassium are observed in several portions of the JWST spectrum based on comparisons from template brown dwarf spectra, molecular opacities, and atmospheric models. The spectral shape of VHS 1256 b is influenced by disequilibrium chemistry and clouds. We directly detect silicate clouds, the first such detection reported for a planetary-mass companion.

Voltage-gated Na+ (NaV) channels are key regulators of myocardial excitability, and Ca2+/calmodulin-dependent protein kinase II (CaMKII)-dependent alterations in NaV1.5 channel inactivation are emerging as a critical determinant of arrhythmias in heart failure. However, the global native phosphorylation pattern of NaV1.5 subunits associated with these arrhythmogenic disorders and the associated channel regulatory defects remain unknown. Here, we undertook phosphoproteomic analyses to identify and quantify in situ the phosphorylation sites in the NaV1.5 proteins purified from adult WT and failing CaMKIIδc-overexpressing (CaMKIIδc-Tg) mouse ventricles. Of 19 native NaV1.5 phosphorylation sites identified, two C-terminal phosphoserines at positions 1938 and 1989 showed increased phosphorylation in the CaMKIIδc-Tg compared with the WT ventricles. We then tested the hypothesis that phosphorylation at these two sites impairs fibroblast growth factor 13 (FGF13)-dependent regulation of NaV1.5 channel inactivation. Whole-cell voltage-clamp analyses in HEK293 cells demonstrated that FGF13 increases NaV1.5 channel availability and decreases late Na+ current, two effects that were abrogated with NaV1.5 mutants mimicking phosphorylation at both sites. Additional co-immunoprecipitation experiments revealed that FGF13 potentiates the binding of calmodulin to NaV1.5 and that phosphomimetic mutations at both sites decrease the interaction of FGF13 and, consequently, of calmodulin with NaV1.5. Together, we have identified two novel native phosphorylation sites in the C terminus of NaV1.5 that impair FGF13-dependent regulation of channel inactivation and may contribute to CaMKIIδc-dependent arrhythmogenic disorders in failing hearts.

We present a statistical comparison of the mass ratio distribution of companions as observed in different multiplicity surveys to the most recent estimate of the single object mass function. The main goal of our analysis is to test whether or not the observed companion mass ratio distribution (CMRD) as a function of primary star mass and star formation environment is consistent with having been drawn from the field star initial mass function (IMF). We consider samples of companions for M dwarfs solar type stars and intermediate mass stars both in the field as well as clusters or associations and compare them with populations of binaries generated by random pairing from the assumed IMF for a fixed primary mass. With regard to the field we can reject the hypothesis that the CMRD was drawn from the IMF for different primary mass ranges: the observed CMRDs show a larger number of equal mass systems than predicted by the IMF. This is in agreement with fragmentation theories of binary formation. For the open clusters a Persei and the Pleiades we also reject the IMF random pairing hypothesis. Concerning young star forming regions currently we can rule out a connection between the CMRD and the field IMF in Taurus but not in Chamaeleon I. Larger and different samples are needed to better constrain the result as a function of the environment. We also consider other companion mass functions and we compare them with observations. Moreover the CMRD both in the field and clusters or associations appears to be independent of separation in the range covered by the observations. Combining therefore the CMRDs of M (1 2400 AU) and G (28 1590 AU) primaries in the field and intermediate mass primary binaries in Sco OB2 (29 1612 AU) for mass ratios q = M 2/M 1 from 0.2 to 1 we find that the best chi square fit follows a power law dN/dqvpropq ß with ß = 0.50 ± 0.29 consistent with previous results. Finally we note that the Kolmogorov Smirnov test gives a 1 probability of the observed CMRD in the Pleiades and Taurus being consistent with that observed for solar type primaries in the field over comparable primary mass range. This highlights the value of using CMRDs to understand which star formation events contribute most to the field.

Obesity has become a serious global health issue affecting both adults and children. Recent devolopments in world demographics and declining health status of the world's population indicate that the prevalence of obesity will continue to increase in the next decades. As a disease obesity has deleterious effects on metabolic homeostasis and affects numerous organ systems including heart kidney and the vascular system. Thus obesity is now regarded as an independent risk factor for atherosclerosis related diseases such as coronary artery disease myocardial infarction and stroke. In the arterial system endothelial cells are both the source and target of factors contributing to atherosclerosis. Endothelial vasoactive factors regulate vascular homeostasis under physiological conditions and maintain basal vascular tone. Obesity results in an imbalance between endothelium derived vasoactive factors favouring vasoconstriction cell growth and inflammatory activation. Abnormal regulation of these factors due to endothelial cell dysfunction is both a consequence and a cause of vascular disease processes. Finally because of the similarities of the vascular pathomechanisms activated obesity can be considered to cause accelerated 'premature' vascular aging. Here we will review some of the pathomechanisms involved in obesity related activation of endothelium dependent vasoconstriction the clinical relevance of obesity associated vascular risk and therapeutic interventions using 'endothelial therapy' aiming at maintaining or restoring vascular endothelial health. LINKED ARTICLES This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue 3.

Many N,N-dialkylated tryptamines show psychoactive properties in humans and the number of derivatives involved in multidisciplinary areas of research has grown over the last few decades. Whereas some derivatives form the basis of a range of medicinal products, others are predominantly encountered as recreational drugs, and in some cases, the areas of therapeutic and recreational use can overlap. In recent years, 5-methoxy-N,N-diallyltryptamine (5-MeO-DALT) has appeared as a new psychoactive substance (NPS) and ‘research chemical’ whereas 4-acetoxy-DALT and the ring-unsubstituted DALT have only been detected very recently. Strategies pursued in the authors’ laboratories included the preparation and biological evaluation of previously unreported N,N-diallyltryptamines (DALTs). This report describes the analytical characterization of seventeen DALTs. Fifteen DALTs were prepared by a microwave-accelerated Speeter and Anthony procedure following established procedures developed previously in the authors’ laboratories. In addition to DALT, the substances included in this study were 2-phenyl-, 4-acetoxy-, 4-hydroxy-, 4,5-ethylenedioxy-, 5-methyl-, 5-methoxy-, 5-methoxy-2-methyl-, 5-ethoxy-, 5-fluoro-, 5-fluoro-2-methyl-, 5-chloro-, 5-bromo-, 5,6-methylenedioxy-, 6-fluoro-, 7-methyl, and 7-ethyl-DALT, respectively. The DALTs were characterized by nuclear magnetic resonance spectroscopy (NMR), gas chromatography (GC) quadrupole and ion trap (EI/CI) mass spectrometry (MS), low and high mass accuracy MS/MS, ultraviolet diode array detection and GC solid-state infrared analysis, respectively. A comprehensive collection of spectral data was obtained that are provided to research communities who face the challenge of encountering newly emerging substances where analytical data are not available. These data are also relevant to researchers who might wish to explore the clinical and non-clinical uses of these substances.

Many N,N-dialkylated tryptamines show psychoactive properties and were encountered as new psychoactive substances. The aims of the presented work were to study the phase I and II metabolism and the detectability in standard urine screening approaches (SUSA) of 5-methoxy-2-methyl-N,N- diallyltryptamine (5-MeO-2-Me-DALT), 5-methoxy-2-methyl-N-allyl-N- cyclohexyltryptamine (5-MeO-2-Me-ALCHT), and 5-methoxy-2-methyl-N,N- diisopropyltryptamine (5-MeO-2-Me-DIPT) using GC-MS, LC-MSn, and LC- HR-MS/MS. For metabolism studies, urine was collected over a 24-h period after administration of the compounds to male Wistar rats at 20 mg/kg body weight (BW). Phase I and II metabolites were identified after urine precipitation with acetonitrile by LC-HR-MS/MS. 5-MeO-2-Me-DALT (24 phase I and 12 phase II metabolites), 5-MeO-2-Me-ALCHT (24 phase I and 14 phase II metabolites), and 5-MeO-2-Me-DIPT (20 phase I and 11 phase II metabolites) were mainly metabolized by O-demethylation, hydroxylation, N-dealkylation, and combinations of them as well as by glucuronidation and sulfation of phase I metabolites. Incubations with mixtures of pooled human liver microsomes and cytosols (pHLM and pHLC) confirmed that the main metabolic reactions in humans and rats might be identical. Furthermore, initial CYP activity screenings revealed that CYP1A2, CYP2C19, CYP2D6, and CYP3A4 were involved in hydroxylation, CYP2C19 and CYP2D6 in O-demethylation, and CYP2C19, CYP2D6, and CYP3A4 in N- dealkylation. For SUSAs, GC-MS, LC-MSn, and LC-HR-MS/MS were applied to rat urine samples after 1 or 0.1 mg/kg BW doses, respectively. In contrast to the GC-MS SUSA, both LC-MS SUSAs were able to detect an intake of 5-MeO-2-Me-ALCHT and 5-MeO-2-Me-DIPT via their metabolites following 1 mg/kg BW administrations and 5-MeO-2-Me-DALT following 0.1 mg/kg BW dosage.