Reassessment of candidate gene studies for idiopathic restless legs syndrome in a large genome-wide association study dataset of European ancestry

Study Objectives Several candidate gene studies have been published for idiopathic restless legs syndrome (RLS) in populations of European ancestry, but the reported associations have not been confirmed in independent samples. Our aim was to reassess these findings in a large case-control dataset in order to evaluate their validity. Methods We screened PubMed for RLS candidate gene studies. We used the genome-wide association study (GWAS) dataset of the International EU-RLS-GENE Consortium as our replication sample, which provided genome-wide single-variant association data based on at most 17 220 individuals of European ancestry. We performed additional gene-based tests using the software MAGMA and assessed the power of our study using the genpwr R package. Results We identified 14 studies conducted in European samples which assessed 45 variants in 27 genes of which 5 variants had been reported as significantly associated. None of these individual variants were replicated in our GWAS-based reassessment (nominal p > 0.05) and gene-based tests for the respective five genes ADH1B, GABRR3, HMOX1, MAOA, and VDR, were also nonsignificant (nominal p > 0.05). Our replication dataset was well powered to detect the reported effects, even when adjusting for effect size overestimation due to winner's curse. Power estimates were close to 100% for all variants. Conclusion In summary, none of the significant single-variant associations from candidate gene studies were confirmed in our GWAS dataset. Therefore, these associations were likely false positive. Our observations emphasize the need for large sample sizes and stringent significance thresholds in future association studies for RLS

Aquatic occurrence of phytotoxins in small streams triggered by biogeography, vegetation growth stage, and precipitation

Toxic plant secondary metabolites (PSMs), so-called phytotoxins, occur widely in plant species. Many of these phytotoxins have similar mobility, persistence, and toxicity properties in the environment as anthropogenic micropollutants, which increasingly contaminate surface waters. Although recent case studies have shown the aquatic relevance of phytotoxins, the overall exposure remains unknown. Therefore, we performed a detailed occurrence analysis covering 134 phytotoxins from 27 PSM classes. Water samples from seven small Swiss streams with catchment areas from 1.7 to 23 km(2) and varying land uses were gathered over several months to investigate seasonal impacts. They were complemented with samples from different biogeographical regions to cover variations in vegetation. A broad SPE-LC-HRMS/MS method was applied with limits of detection below 5 ng/L for over 80% of the 134 included phytotoxins. In total, we confirmed 39 phytotoxins belonging to 13 PSM classes, which corresponds to almost 30% of all included phytotoxins. Several alkaloids were regularly detected in the low ng/L-range, with average detection frequencies of 21%. This is consistent with the previously estimated persistence and mobility properties that indicated a high contamination potential. Coumarins were previously predicted to be unstable, however, detection frequencies were around 89%, and maximal concentrations up to 90 ng/L were measured for fraxetin produced by various trees. Overall, rainy weather conditions at full vegetation led to the highest total phytotoxin concentrations, which might potentially be most critical for aquatic organisms

Intronic elements associated with insomnia and restless legs syndrome exhibit cell-type-specific epigenetic features contributing to MEIS1 regulation

A highly evolutionarily conserved myeloid ecotropic viral integration site 1 (MEIS1) intronic region is strongly associated with restless legs syndrome (RLS) and insomnia. To understand its regulatory function, we dissected the region by analyzing chromatin accessibility, enhancer-promoter contacts, DNA methylation and expression quantitative trait locus (eQTLs) in different human neural cell types and tissues. We observed specific activity with respect to cell type and developmental maturation, indicating a prominent role for distinct highly conserved intronic elements in forebrain inhibitory neuron differentiation. Two elements were hypomethylated in neural cells with higher MEIS1 expression, suggesting a role of enhancer demethylation in gene regulation. MEIS1 eQTLs showed a striking modular chromosomal distribution, with forebrain eQTLs clustering in intron 8/9. Clustered regularly interspersed short palindromic repeats interference targeting of individual elements in this region attenuated MEIS1 expression, revealing a complex regulatory interplay of distinct elements. In summary, we found that MEIS1 regulation is organized in a modular pattern. Disease-associated intronic regulatory elements control MEIS1 expression with cell type and maturation stage specificity, particularly in the inhibitory neuron lineage. The precise spatiotemporal activity of these elements likely contributes to the pathogenesis of insomnia and RLS

Eye movements track prioritized auditory features in selective attention to natural speech

Over the last decades, cognitive neuroscience has identified a distributed set of brain regions that are critical for attention. Strong anatomical overlap with brain regions critical for oculomotor processes suggests a joint network for attention and eye movements. However, the role of this shared network in complex, naturalistic environments remains understudied. Here, we investigated eye movements in relation to (un)attended sentences of natural speech. Combining simultaneously recorded eye tracking and magnetoencephalographic data with temporal response functions, we show that gaze tracks attended speech, a phenomenon we termed ocular speech tracking. Ocular speech tracking even differentiates a target from a distractor in a multi-speaker context and is further related to intelligibility. Moreover, we provide evidence for its contribution to neural differences in speech processing, emphasizing the necessity to consider oculomotor activity in future research and in the interpretation of neural differences in auditory cognition

Микрофлора природных вод источников нецентрализованного питьевого водоснабжения

Изучен микробиологический состав источников нецентрализованного водоснабжения г. Томска. Выявлено большое разнообразие и численность различных групп микроорганизмов, отрицательно влияющих на качество воды. Показана опасность использования природных вод источников нецентрализованного водоснабжения в питьевых целях без процедуры водоподготовки. The microbiological composition of the decentralized water supply sources of Tomsk city is investigated. There is revealed the large diversity and significant count of different microorganism groups that adversely affect a water quality. It is demonstrated the hazard of using of decentralized water supply sources for drinking without treatment

Reasons for Living and Dying in Suicide Attempters: A Two-year Prospective Study

Background: The aim of this study was to explore Reasons for Living (RFL) and Reasons for Dying (RFD) of suicide attempters and their association with current and future suicidal ideation and behavior. Method: The sample consisted of 60 patients who were admitted at a psychiatric emergency unit in Switzerland following an attempted suicide. They received treatment as usual, participated in an assessment interview and completed self-report questionnaires including written RFL and RFD responses, depressive symptoms, and suicide ideation at baseline and 6, 12 and 24 months follow-ups. Outcome measures were suicide ideation and repeated suicide attempts. Multiple imputations were used in order to address missing data. Results: The number of RFD responses was the strongest predictor for increased suicide ideation at baseline. The number of RFL responses was not associated with suicide ideation and reattempts. RFD, depressive symptoms, and baseline suicide ideation predicted subsequent suicide reattempt up to 12 months later in simple regression analyses. Mediation analyses suggested that RFD mediated the effect of depressive symptoms at baseline on suicide ideation at 12-months follow-up. Conclusion: RFL were unrelated to the mental health of study participants and did not function as protective factor against suicide risk. RFD may be an important motivational driver in the suicidal process. Clinical interventions should focus more on the reduction of RFD than on RFL in suicidal individuals

Vitamin B12 Attenuates Changes in Phospholipid Levels Related to Oxidative Stress in SH-SY5Y Cells

Oxidative stress is closely linked to Alzheimer’s disease (AD), and is detected peripherally as well as in AD-vulnerable brain regions. Oxidative stress results from an imbalance between the generation and degradation of reactive oxidative species (ROS), leading to the oxidation of proteins, nucleic acids, and lipids. Extensive lipid changes have been found in post mortem AD brain tissue; these changes include the levels of total phospholipids, sphingomyelin, and ceramide, as well as plasmalogens, which are highly susceptible to oxidation because of their vinyl ether bond at the sn-1 position of the glycerol-backbone. Several lines of evidence indicate that a deficiency in the neurotropic vitamin B12 is linked with AD. In the present study, treatment of the neuroblastoma cell line SH-SY5Y with vitamin B12 resulted in elevated levels of phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, and plasmalogens. Vitamin B12 also protected plasmalogens from hydrogen peroxide (H2O2 )-induced oxidative stress due to an elevated expression of the ROS-degrading enzymes superoxide-dismutase (SOD) and catalase (CAT). Furthermore, vitamin B12 elevates plasmalogen synthesis by increasing the expression of alkylglycerone phosphate synthase (AGPS) and choline phosphotransferase 1 (CHPT1) in SH-SY5Y cells exposed to H2O2 -induced oxidative stress

Aspartame and Its Metabolites Cause Oxidative Stress and Mitochondrial and Lipid Alterations in SH-SY5Y Cells

Due to a worldwide increase in obesity and metabolic disorders such as type 2 diabetes, synthetic sweeteners such as aspartame are frequently used to substitute sugar in the diet. Possible uncertainties regarding aspartame’s ability to induce oxidative stress, amongst others, has led to the recommendation of a daily maximum dose of 40 to 50 mg per kg. To date, little is known about the effects of this non-nutritive sweetener on cellular lipid homeostasis, which, besides elevated oxidative stress, plays an important role in the pathogenesis of various diseases, including neurodegenerative diseases such as Alzheimer’s disease. In the present study, treatment of the human neuroblastoma cell line SH-SY5Y with aspartame (271.7 µM) or its three metabolites (aspartic acid, phenylalanine, and methanol (271.7 µM)), generated after digestion of aspartame in the human intestinal tract, resulted in significantly elevated oxidative stress associated with mitochondrial damage, which was illustrated with reduced cardiolipin levels, increased gene expression of SOD1/2, PINK1, and FIS1, and an increase in APF fluorescence. In addition, treatment of SH-SY5Y cells with aspartame or aspartame metabolites led to a significant increase in triacylglycerides and phospholipids, especially phosphatidylcholines and phosphatidylethanolamines, accompanied by an accumulation of lipid droplets inside neuronal cells. Due to these lipid-mediating properties, the use of aspartame as a sugar substitute should be reconsidered and the effects of aspartame on the brain metabolism should be addressed in vivo