Investigation of the μ- and κ-opioid receptor activation by eight new synthetic opioids using the [35^{35}S]-GTPγS assay: U-47700, isopropyl U-47700, U-49900, U-47931E, N-methyl U-47931E, U-51754, U-48520, and U-48800

In 2009, new synthetic opioids appeared on the new psychoactive substances market. This class of new psychoactive substances generally poses a health risk due to the high affinity and potency of most of these compounds for the opioid receptors. It is known that overdoses can lead to respiratory depression and result in death. However, for many new synthetic opioids, data on toxicological and toxicokinetic properties are scarce. In the present study, eight U-opioids were investigated for their structure activity relationships at the μ- and κ-opioid receptors using a [$^{35}$S]-GTPγS assay. The potencies of the investigated U-opioids were lower than those of the reference compounds (μ-opioid receptor: hydromorphone, fentanyl; κ-opioid receptor: U-69593, U-50488). At the μ-opioid receptor, U-47700 showed the highest potency with an EC$_{50}$ value of 111 nM, and at the κ-opioid receptor, U-51754 was found to be the most potent compound with an EC$_{50}$ value of 120 nM. The following structural features were advantageous for activating the μ-opioid receptor: two chlorine substituents in 3,4-position at the aromatic ring, the absence of the methylene group between the amide group and the aromatic ring, a methyl group at the amide nitrogen, and/or a dimethylamine residue at the amine nitrogen of the cyclohexane ring. Further, the following structural features were beneficial for κ-opioid receptor activation: a methylene group between the amide group and the aromatic ring, a pyrrolidine residue at the amine nitrogen of the cyclohexane ring, a methyl group at the amide nitrogen, and/or a chlorine substitution at the 3,4-position of the aromatic ring

Attentional bias in individuals with depression and adverse childhood experiences: influence of the noradrenergic system?

Rationale: Major depressive disorder (MDD) is a severe mental disorder with affective, cognitive, and somatic symptoms. Mood congruent cognitive biases, including a negative attentional bias, are important for development, maintenance, and recurrence of depressive symptoms. MDD is associated with maladaptive changes in the biological stress systems such as dysregulations of central noradrenergic alpha2-receptors in the locus coeruleus-noradrenergic system, which can affect cognitive processes including attention. Patients with adverse childhood experiences (ACE), representing severe stress experiences in early life, might be particularly affected. Objectives: With an experimental design, we aimed to gain further knowledge about the role of noradrenergic activity for attentional bias in MDD patients with and without ACE. Methods: We tested the effect of increased noradrenergic activity induced by the alpha2-receptor blocker yohimbine on attentional bias in a placebo-controlled repeated measures design. Four groups were included as follows: MDD patients with and without ACE, and healthy participants with and without ACE (total N = 128, all without antidepressant medication). Results: A significant effect of MDD on attentional bias scores of sad face pictures (p = .037) indicated a facilitated attentional processing of sad face pictures in MDD patients (compared to non-MDD individuals). However, we found no such effect of ACE. For attentional bias of happy face pictures, we found no significant effects of MDD and ACE. Even though a higher increase of blood pressure and salivary alpha-amylase following yohimbine compared to placebo indicated successful noradrenergic stimulation, we found no significant effects of yohimbine on attentional bias of happy or sad face pictures. Conclusions: Our results are consistent with the hypothesis of a negative attentional bias in MDD patients. However, as we found no effect of ACE or yohimbine, further research is needed to understand the mechanisms by which ACE increases the risk of MDD and to understand the biological basis of the MDD-related negative attentional bias

Critical Crossover Between Yosida-Kondo Dominant Regime and Magnetic Frustration Dominant Regime in the System of a Magnetic Trimer on a Metal Surface

Quantum Monte Carlo simulations were carried out for the system of a magnetic trimer on a metal surface. The magnetic trimer is arranged in two geometric configurations, viz., isosceles and equilateral triangles. The calculated spectral density and magnetic susceptibility show the existence of two phases: Yosida-Kondo dominant phase and magnetic frustration dominant phase. Furthermore, a critical transition between these two phases can be induced by changing the configuration of the magnetic trimers from isosceles to equilateral triangle.Comment: 8 pages, 4 figures; accepted for publication in J. Phys. Soc. Jp

Inflammatory measures in depressed patients with and without a history of adverse childhood experiences

Background: Major depressive disorder (MDD) is a complex psychiatric condition with different subtypes and etiologies. Exposure to adverse childhood experiences (ACE) is an important risk factor for the development of MDD later in life. Evidence suggests that pro-inflammatory processes may convey this risk as both MDD and ACE have been related to increased levels of inflammation. In the present study, we aimed to disentangle the effects of MDD and ACE on inflammation levels. Methods: Markers of inflammation (plasma interleukin(IL)-6 and high sensitive C-reactive protein (hsCRP) concentrations, white blood cell (WBC) count and a composite inflammation score (CIS) combining all three) were assessed in 23 MDD patients with ACE, 23 MDD patients without ACE, 21 healthy participants with ACE, and 21 healthy participants without ACE (mean age: 35 +/- 11 (SD) years). None of the patients and participants was taking psychotropic medication. ACE was assessed with the Early Trauma Inventory (ETI) and was defined as moderate to severe exposure to sexual or physical abuse. Results: Group differences in the different inflammatory measures were observed. MDD patients with ACE showed significantly higher IL-6 concentrations (p = 0.018), higher WBC counts (p = 0.003) and increased general inflammation levels as indicated by the CIS (p = 0.003) compared to healthy controls. In contrast, MDD patients without ACE displayed similar inflammation levels to the control group (p = 0.93). Conclusion: We observed elevated inflammation in MDD patients with a history of ACE, which could indicate a subtype of "inflammatory depression". Accordingly, MDD patients with ACE might potentially benefit from anti-inflammatory therapies

Parallel electron-hole bilayer conductivity from electronic interface reconstruction

The perovskite SrTiO$_3$-LaAlO$_3$ structure has advanced to a model system to investigate the rich electronic phenomena arising at polar interfaces. Using first principles calculations and transport measurements we demonstrate that an additional SrTiO$_3$ capping layer prevents structural and chemical reconstruction at the LaAlO$_3$ surface and triggers the electronic reconstruction at a significantly lower LaAlO$_3$ film thickness than for the uncapped systems. Combined theoretical and experimental evidence (from magnetotransport and ultraviolet photoelectron spectroscopy) suggests two spatially separated sheets with electron and hole carriers, that are as close as 1 nm.Comment: Phys. Rev. Lett., in pres

Diffuse Ionized Gas in the Dwarf Irregular Galaxy DDO 53

The spectral characteristics throughout the dwarf irregular galaxy DDO 53 are studied. The results are very similar to those for other irregular galaxies: high excitation and low values of the [SII]/Halpha ratio. The most likely ionization source is photon leakage from the classical HII regions, without any other source, although the interstellar medium of the galaxy is quite perturbed. Moreover, the physical conditions throughout the galaxy do not change very much because both the photon leakage percentage and the ionization temperature are very similar. In addition, the determined metal content for two HII regions indicates that DDO 53 is a low-metallicity galaxy.Comment: 32 pages, 9 figures, 7 tables. AJ, in pres

General Practitioners' Attitudes towards Essential Competencies in End-of-Life Care: A Cross-Sectional Survey.

Identifying essential competencies in end-of-life care, as well as general practitioners' (GPs) confidence in these competencies, is essential to guide training and quality improvement efforts in this domain. To determine which competencies in end-of-life care are considered important by GPs, to assess GPs' confidence in these competencies in a European context and their reasons to refer terminally ill patients to a specialist. Cross-sectional postal survey involving a stratified random sample of 2000 GPs in Switzerland in 2014. Survey development was informed by a previous qualitative exploration of relevant end-of-life GP competencies. Main outcome measures were GPs' assessment of the importance of and confidence in 18 attributes of end-of-life care competencies, and reasons for transferring care of terminally-ill patients to a specialist. GP characteristics associated with main outcome measures were tested using multivariate regression models. The response rate was 31%. Ninety-nine percent of GPs considered the recognition and treatment of pain as important, 86% felt confident about it. Few GPs felt confident in cultural (16%), spiritual (38%) and legal end-of-life competencies such as responding to patients seeking assisted suicide (35%) although more than half of the respondents regarded these competencies as important. Most frequent reasons to refer terminally ill patients to a specialist were lack of time (30%), better training of specialists (23%) and end-of-life care being incompatible with other duties (19%). In multiple regression analyses, confidence in end-of-life care was positively associated with GPs' age, practice size, home visits and palliative training. GPs considered non-somatic competencies (such as spiritual, cultural, ethical and legal aspects) nearly as important as pain and symptom control. Yet, few GPs felt confident in these non-somatic competencies. These findings should inform training and quality improvement efforts in this domain, in particular for younger, less experienced GPs

Using Biographical Texts as Linked Data for Prosopographical Research and Applications

This paper argues that representing texts as semantic Linked Data provides a useful basis for analyzing their contents in Digital Humanities research and for Cultural Heritage application development. The idea is to transform Cultural Heritage texts into a knowledge graph and a Linked Data service that can be used flexibly in different applications via a SPARQL endpoint. The argument is discussed and evaluated in the context of biographical and prosopographical research and a case study where over 13 000 life stories form biographical collections of Biographical Centre of the Finnish Literature Society were transformed into RDF, enriched by data linking, and published in a SPARQL endpoint. Tools for biography and prosopography, data clustering, network analysis, and linguistic analysis were created with promising first results.Peer reviewe

OVI Emission in the Halos of Edge-on Spiral Galaxies

We have used the Far Ultraviolet Spectroscopic Explorer to search for OVI 1031.926, 1037.617 A emission in the halos of the edge-on spiral galaxies NGC4631 and NGC891. In NGC4631, we detected OVI in emission toward a soft X-ray bubble above a region containing numerous Halpha arcs and filaments. The line-of-sight component of the motion of the OVI gas appears to match the underlying disk rotation. The observed OVI luminosities can account for 0.2-2% of the total energy input from supernovae (assuming a full OVI emitting halo) and yield mass flux cooling rates between 0.48 and 2.8 M_sun/yr depending on the model used in the derivations. Based on these findings, we believe it is likely that we are seeing cooling, galactic fountain gas. No emission was detected from the halo of NGC891, a galaxy in a direction with considerably high foreground Galactic extinction.Comment: accepted for publication in ApJ, 16 pages including 4 figure