Monoamine receptor interaction profiles of 4-thio-substituted phenethylamines (2C-T drugs)

4-Thio-substituted phenethylamines (2C-T drugs) are potent psychedelics with poorly defined pharmacological properties. Because of their psychedelic effects, 2C-T drugs are sometimes sold as new psychoactive substances (NPSs). The aim of the present study was to characterize the monoamine receptor and transporter interaction profiles of a series of 2C-T drugs.; We determined the binding affinities of 2C-T drugs at monoamine receptors and transporters in human cells that were transfected with the respective receptors or transporters. We also investigated the functional activation of serotonergic 5-hydroxytryptamine 2A (5-HT2A) and 5-HT2B receptors, activation of human trace amine-associated receptor 1 (TAAR1), and inhibition of monoamine uptake transporters.; 2C-T drugs had high affinity for 5-HT2A and 5-HT2C receptors (1-54 nM and 40-350 nM, respectively). With activation potencies of 1-53 nM and 44-370 nM, the drugs were potent 5-HT2A receptor and 5-HT2B receptor, respectively, partial agonists. An exception to this were the benzylthiophenethylamines, which did not potently activate the 5-HT2B receptor (EC50 > 3000 nM). Furthermore, the compounds bound to serotonergic 5-HT1A and adrenergic receptors. The compounds had high affinity for the rat TAAR1 (5-68 nM) and interacted with the mouse but not human TAAR1. The 2C-T drugs did not potently interact with monoamine transporters (Ki > 4000 nM).; The receptor binding profile of 2C-T drugs predicts psychedelic effects that are mediated by potent 5-HT2 receptor interactions

Scanning reflectance spectroscopy (380-730nm): a novel method for quantitative high-resolution climate reconstructions from minerogenic lake sediments

High-resolution (annual to sub-decadal) quantitative reconstructions of climate variables are needed from a variety of paleoclimate archives across the world to place current climate change in the context of long-term natural climate variability. Rapid, high-resolution, non-destructive scanning techniques are required to produce such high-resolution records from lake sediments. In this study we explored the potential of scanning reflectance spectroscopy (VIS-RS; 380-730nm) to produce quantitative summer temperature reconstructions from minerogenic sediments of proglacial, annually laminated Lake Silvaplana, in the eastern Swiss Alps. The scanning resolution was 2mm, which corresponded to sediment deposition over 1-2years. We found correlations up to r=0.84 (p<0.05) for the calibration period 1864-1950, between six reflectance-dependent variables and summer (JJAS) temperature. These reflectance-dependent variables (e.g. slope of the reflectance 570/630nm, indicative of illite, biotite and chlorite; minimum reflectance at 690nm indicative of chlorite) indicate the mineralogical composition of the clastic sediments, which is, in turn, related to climate in the catchment of this particular proglacial lake. We used multiple linear regression (MLR) to establish a calibration model that explains 84% of the variance of summer (JJAS) temperature during the calibration period 1864-1950. We then applied the calibration model downcore to develop a quantitative summer temperature reconstruction extending back to AD 1177. This temperature reconstruction is in good agreement with two independent temperature reconstructions based on documentary data that extend back to AD 1500 and tree ring data that extend back to AD 1177. This study confirms the great potential of in situ scanning reflectance spectroscopy as a novel non-destructive technique to rapidly acquire high-resolution quantitative paleoclimate information from minerogenic lake sediment

Moderate toxic effects following acute zonisamide overdose

Zonisamide is an antiepileptic drug that acts on voltage-sensitive sodium and calcium channels, with a modulatory effect on GABA-mediated neuronal inhibition and an inhibitory effect on carbonic anhydrase. It is used mainly for the treatment of partial seizures, and is generally well tolerated at therapeutic doses. The most common reported adverse effects are somnolence, anorexia, dizziness, and headache. There are limited data on zonisamide overdose in the literature, and no case of zonisamide mono-intoxication has been published to date. We describe the first case of zonisamide mono-intoxication in a 25-year-old woman who ingested 12.6 g of this substance with suicidal intent. Despite a plasma zonisamide concentration of 182 mg/L on admission, the patient exhibited a benign clinical course with vomiting and central nervous system depression, requiring brief intubation. Somnolence persisted for 50 hours, and normal-anion-gap metabolic acidosis and polyuria for several days. Complete recovery may be expected with supportive care, even after ingestion of large zonisamide overdoses

Early vertical distribution of roots and its association with drought tolerance in tropical maize

Background and aims: Selection for deep roots to improve drought tolerance of maize (Zea mays L.) requires presence of genetic variation and suitable screening methods. Methods: We examined a diverse set of 33 tropical maize inbred lines that were grown in growth columns in the greenhouse up to the 2-, 4-, and 6-leaf stage and in the field in Mexico. To determine length of roots from different depths at high throughput, we tested an approach based on staining roots with methylene blue and measuring the amount of absorbed dye as proxy measure for root length. Results: Staining provided no advantage over root weights that are much easier to measure and therefore preferable. We found significant genotypic variation for all traits at the 6-leaf stage. For development rates between the 2-leaf and the 6-leaf stage, genotypes only differed for rooting depth and the number of crown roots. Positive correlations of leaf area with root length and rooting depth indicated a common effect of plant vigor. However, leaf area in growth columns was negatively related to grain yield under drought (r = −0.50). Conclusion: The selection for deeper roots by an increase in plant vigor likely results in a poorer performance under drought conditions. The proportion of deep roots was independent of other traits but showed a low heritability and was not correlated to field performance. An improved screening protocol is proposed to increase throughput and heritability for this trait

Receptor Interaction Profiles of 4-Alkoxy-3,5-Dimethoxy-Phenethylamines (Mescaline Derivatives) and Related Amphetamines

3,4,5-Trimethoxyphenethylamine (mescaline) is a psychedelic alkaloid found in peyote cactus. Related 4-alkoxy-3,5-dimethoxy-substituted phenethylamines (scalines) and amphetamines (3C-scalines) are reported to induce similarly potent psychedelic effects and are therefore potential novel therapeutics for psychedelic-assisted therapy. Herein, several pharmacologically uninvestigated scalines and 3C-scalines were examined at key monoamine targets; in vitro; . Binding affinity at human serotonergic 5-HT; 1A; , 5-HT; 2A; , and 5-HT; 2C; , adrenergic α; 1A; and α; 2A; , and dopaminergic D; 2; receptors, rat and mouse trace amine-associated receptor 1 (TAAR1), and human monoamine transporters were assessed using target specific transfected cells. Furthermore, activation of human 5-HT; 2A; and 5-HT; 2B; receptors, and TAAR1 was examined. Generally, scalines and 3C-scalines bound with weak to moderately high affinity to the 5-HT; 2A; receptor (; K; i; = 150-12,000 nM). 3C-scalines showed a marginal preference for the 5-HT; 2A; vs the 5-HT; 2C; and 5-HT; 1A; receptors whereas no preference was observed for the scalines. Extending the 4-alkoxy substituent increased 5-HT; 2A; and 5-HT; 2C; receptors binding affinities, and enhanced activation potency and efficacy at the 5-HT; 2A; but not at the 5-HT; 2B; receptor. Introduction of fluorinated 4-alkoxy substituents generally increased 5-HT; 2A; and 5-HT; 2C; receptors binding affinities and increased the activation potency and efficacy at the 5-HT; 2A; and 5-HT; 2B; receptors. Overall, no potent affinity was observed at non-serotonergic targets. As observed for other psychedelics, scalines and 3C-scalines interacted with the 5-HT; 2A; and 5-HT; 2C; receptors and bound with higher affinities (up to 63-fold and 34-fold increase, respectively) when compared to mescaline

Sports-related sudden cardiac deaths in the young population of Switzerland.

In Switzerland, ECG screening was first recommended for national squad athletes in 1998. Since 2001 it has become mandatory in selected high-risk professional sports. Its impact on the rates of sports-related sudden cardiac death (SCD) is unknown. We aimed to study the incidence, causes and time trends of sports-related SCD in comparison to SCD unrelated to exercise in Switzerland. We reviewed all forensic reports of SCDs of the German-speaking region of Switzerland in the age group of 10 to 39 years, occurring between 1999 and 2010. Cases were classified into three categories based on whether or not deaths were associated with sports: no sports (NONE), recreational sports (REC), and competitive sports (COMP). Over the 12-year study period, 349 SCD cases were recorded (mean age 30±7 years, 76.5% male); 297 cases were categorized as NONE, 31 as REC, and 21 as COMP. Incidences of SCD per 100,000 person-years [mean (95% CI)] were the lowest in REC [0.43 (0.35-0.56)], followed by COMP [1.19 (0.89-1.60)] and NONE [2.46 (2.27-2.66)]. In all three categories, coronary artery disease (CAD) with or without acute myocardial infarction (MI) was the most common cause of SCD. Three professional athletes were identified in COMP category which all had SCD due to acute MI. There were no time trends, neither in overall, nor in cause-specific incidences of SCD. The incidence of SCD in young individuals in Switzerland is low, both related and unrelated to sports. In regions, like Switzerland, where CAD is the leading cause of SCD associated with competitions, screening for cardiovascular risk factors in addition to the current PPS recommendations might be indicated to improve detection of silent CAD and further decrease the incidence of SCD

Identification and Characterization of Mediators of Fluconazole Tolerance in Candida albicans.

Candida albicans is an important human pathogen and a major concern in intensive care units around the world. C. albicans infections are associated with a high mortality despite the use of antifungal treatments. One of the causes of therapeutic failures is the acquisition of antifungal resistance by mutations in the C. albicans genome. Fluconazole (FLC) is one of the most widely used antifungal and mechanisms of FLC resistance occurring by mutations have been extensively investigated. However, some clinical isolates are known to be able to survive at high FLC concentrations without acquiring resistance mutations, a phenotype known as tolerance. Mechanisms behind FLC tolerance are not well studied, mainly due to the lack of a proper way to identify and quantify tolerance in clinical isolates. We proposed here culture conditions to investigate FLC tolerance as well as an easy and efficient method to identity and quantify tolerance to FLC. The screening of C. albicans strain collections revealed that FLC tolerance is pH- and strain-dependent, suggesting the involvement of multiple mechanisms. Here, we addressed the identification of FLC tolerance mediators in C. albicans by an overexpression strategy focusing on 572 C. albicans genes. This strategy led to the identification of two transcription factors, CRZ1 and GZF3. CRZ1 is a C2H2-type transcription factor that is part of the calcineurin-dependent pathway in C. albicans, while GZF3 is a GATA-type transcription factor of unknown function in C. albicans. Overexpression of each gene resulted in an increase of FLC tolerance, however, only the deletion of CRZ1 in clinical FLC-tolerant strains consistently decreased their FLC tolerance. Transcription profiling of clinical isolates with variable levels of FLC tolerance confirmed a calcineurin-dependent signature in these isolates when exposed to FLC

Last phase of the Little Ice Age forced by volcanic eruptions

During the first half of the nineteenth century, several large tropical volcanic eruptions occurred within less than three decades. The global climate effects of the 1815 Tambora eruption have been investigated, but those of an eruption in 1808 or 1809 whose source is unknown and the eruptions in the 1820s and 1830s have received less attention. Here we analyse the effect of the sequence of eruptions in observations, global three-dimensional climate field reconstructions and coupled climate model simulations. All the eruptions were followed by substantial drops of summer temperature over the Northern Hemisphere land areas. In addition to the direct radiative effect, which lasts 2–3 years, the simulated ocean–atmosphere heat exchange sustained cooling for several years after these eruptions, which affected the slow components of the climate system. Africa was hit by two decades of drought, global monsoons weakened and the tracks of low-pressure systems over the North Atlantic moved south. The low temperatures and increased precipitation in Europe triggered the last phase of the advance of Alpine glaciers. Only after the 1850s did the transition into the period of anthropogenic warming start. We conclude that the end of the Little Ice Age was marked by the recovery from a sequence of volcanic eruptions, which makes it difficult to define a single pre-industrial baseline

The excited-state structure, vibrations, lifetimes, and nonradiative dynamics of jet-cooled 1-methylcytosine

We have investigated the S0 → S1 UV vibronic spectrum and time-resolved S1 state dynamics of jet-cooled amino-keto 1-methylcytosine (1MCyt) using two-color resonant two-photon ionization, UV/UV holeburning and depletion spectroscopies, as well as nanosecond and picosecond timeresolved pump/delayed ionization measurements. The experimental study is complemented with spin-component-scaled second-order coupled-cluster and multistate complete active space second order perturbation ab initio calculations. Above the weak electronic origin of 1MCyt at 31 852 cm−1 about 20 intense vibronic bands are observed. These are interpreted as methyl group torsional transitions coupled to out-of-plane ring vibrations, in agreement with the methyl group rotation and out-of-plane distortions upon 1ππ∗ excitation predicted by the calculations. The methyl torsion and ν′1 (butterfly) vibrations are strongly coupled, in the S1 state. The S0 → S1 vibronic spectrum breaks off at a vibrational excess energy Eexc ∼ 500 cm−1, indicating that a barrier in front of the ethylene-type S1 S0 conical intersection is exceeded, which is calculated to lie at Eexc = 366 cm−1. The S1 S0 internal conversion rate constant increases from kIC = 2 · 109 s−1 near the S1(v = 0) level to 1 · 1011 s−1 at Eexc = 516 cm−1. The 1ππ∗ state of 1MCyt also relaxes into the lower-lying triplet T1 (3ππ∗) state by intersystem crossing (ISC); the calculated spin-orbit coupling (SOC) value is 2.4 cm−1. The ISC rate constant is 10–100 times lower than kIC; it increases from kISC = 2 · 108 s−1 near S1(v = 0) to kISC = 2 · 109 s−1 at Eexc = 516 cm−1. The T1 state energy is determined from the onset of the time-delayed photoionization efficiency curve as 25 600 ± 500 cm−1. The T2 (3nπ∗) state lies >1500 cm−1 above S1(v = 0), so S1 T2 ISC cannot occur, despite the large SOC parameter of 10.6 cm−1. An upper limit to the adiabatic ionization energy of 1MCyt is determined as 8.41 ± 0.02 eV. Compared to cytosine, methyl substitution at N1 lowers the adiabatic ionization energy by ≥0.32 eV and leads to a much higher density of vibronic bands in the S0 → S1 spectrum. The effect of methylation on the radiationless decay to S0 and ISC to T1 is small, as shown by the similar break-off of the spectrum and the similar computed mechanismsThis research has been supported by the Schweiz. Nationalfonds (Grant Nos. 121993 and 132540), the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) from Catalonia (Spain) (Grant No. 2014SGR1202), the Ministerio de Economía y Competividad (MINECO) from Spain (Grant No. CTQ2015-69363-P), and the National Natural Science Foundation of China (Grant No. 21303007

Diagnostic yield and cost analysis of electrocardiographic screening in Swiss paediatric athletes

OBJECTIVES Athletes performing sports on high level are at increased risk for sudden cardiac death. This includes paediatric athletes, even though data on screening strategies in this age group remain scarce. This study aimed to assess electrocardiogram interpretation criteria in paediatric athletes and to evaluate the cost of screening. METHODS National, multicentre, retrospective, observational study on 891 athletes of paediatric age (<18 years) evaluated by history, physical examination and 12-lead electrocardiogram. The primary outcome measure was abnormal electrocardiogram findings according to the International Recommendations for Electrographic Interpretation in Athletes. The secondary outcome measure was cost of screening. RESULTS 19 athletes (2.1%) presented abnormal electrocardiogram findings requiring further investigations, mainly abnormal T-wave inversion. These 19 athletes were predominantly males, performing endurance sports with a mean volume of 10 weekly hours for a mean duration of 6 years of training. Further investigations did not identify any relevant pathology. All athletes were cleared for competition with regular follow-up. Total costs of the screening were 108,860 USD (122 USD per athlete). CONCLUSIONS Our study using the International Recommendations for Electrographic Interpretation in Athletes identified a low count of abnormal findings in paediatric athletes, yet raising substantially the cost of screening. Hence, the utility of electrocardiogram-inclusive screening of paediatric athletes remains to be elucidated by longitudinal data