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Background: Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than 1 year. Methods: We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants. Results: We identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume. Conclusions: Our work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies.

This study investigated whether vitamin D is associated with the presence or severity of chronic tic disorders and their psychiatric comorbidities. This cross-sectional study compared serum 25-hydroxyvitamin D [25(OH)D] (ng/ml) levels among three groups: children and adolescents (3–16 years) with CTD (n = 327); first-degree relatives (3–10 years) of individuals with CTD who were assessed for a period of up to 7 years for possible onset of tics and developed tics within this period (n = 31); and first-degree relatives who did not develop tics and were ≥ 10 years old at their last assessment (n = 93). The relationship between 25(OH)D and the presence and severity of tics, as well as comorbid obsessive–compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD), were analysed controlling for age, sex, season, centre, latitude, family relatedness, and comorbidities. When comparing the CTD cohort to the unaffected cohort, the observed result was contrary to the one expected: a 10 ng/ml increase in 25(OH)D was associated with higher odds of having CTD (OR 2.08, 95% CI 1.27–3.42, p p = 0.01) and was inversely associated with ADHD symptom severity (β = − 2.52, 95% CI − 4.16–0.88, p

Background Adjunctive immune-modulation can be safe and effective for treatment-resistant bipolar depression (TRBDD), but molecular work is needed to further characterize the safety and efficacy involved in treatment response and the reversal of treatment resistance. Here we profiled the kynurenine pathway (KP) for biomarkers associated with TRBDD and treatment response to celecoxib (CBX)-augmentation. Methods 47 TRBDD patients with moderately severe HAMD-17 scores were randomized to receive either escitalopram (ESC) (10 mg twice daily) + CBX (200 mg twice daily), or ESC (10 mg twice daily) + placebo (PBO) (twice daily). Plasma kynurenine pathway (KP) metabolite levels were measured at baseline, week 4, and week 8, and in a healthy control (HC) group of subjects (N = 35) once. Results Patients receiving ESC + CBX had 4.278 greater odds of responding (p = 0.021) with NNT=3, and 15.300 greater odds of remitting (p Conclusion Clinical response to CBX augmentation is not associated with altered neurotoxic or neuroprotective indices within the time frame of this study. TRBDD revealed alterations in neuroprotective and neurotoxic indices, in the context of low kynurenine/tryptophan and high tryptophan. Treatment responders revealed a depletion in tryptophan by week 8, without concomitant kynurenine pathway (KP) activation.

Objectives Treatment-resistance is high in bipolar disorder and is associated with a pro-inflammatory state and diversion of tryptophan toward the kynurenine pathway. This study as part of a large clinical trial, sought to determine, if modulation of the inflammatory response by inhibiting cyclooxygenase-2 (COX-2) with celecoxib combined with escitalopram, would convert treatment-resistant bipolar depression to response or remission and whether blood levels of quinolinic acid (QA) differ from healthy controls and change with treatment response. Methods This was a randomized, double-blind, two-arm, placebo-controlled study. Subjects who met study criteria were randomized to receive escitalopram + celecoxib, or escitalopram + placebo. Inflammation biomarkers and kynurenine pathway intermediates were determined at baseline and weeks 4 and 8. Results Patients receiving the celecoxib combination showed improved response and higher remission rate. All patients had significantly lower QA levels at baseline compared to healthy controls. QA values did not change significantly over time, but a downtrend was noted through treatment. Responders had marginally lower QA values than non-responders. Factors that might have led to low QA levels may include prior exposure to a variety of psychoactive agents. Conclusions Although QA did not significantly change, symptom reduction and remission occurred more frequently in the celecoxib group, demonstrating the beneficial effect of inflammation modulation.

Given the ongoing and planned hydropower development projects in the Amazon River basin, appalling losses in biodiversity, river ecology and river connectivity are inevitable. These hydropower projects are proposed to be built in exceptionally endemic sites, setting records in environmental losses by impeding fish movement, altering flood pulse, causing large-scale deforestation, and increasing greenhouse gas emissions. With the burgeoning energy demand combined with the aforementioned negative impacts of conventional hydropower technology, there is an imminent need to re-think the design of hydropower to avoid the potentially catastrophic consequences of large dams. It is certain that the Amazon will undergo some major hydrological changes in the near future because of the compounded effects of climate change and proposed dams, if built with the conventional hydropower technology. In this study, we present a transformative hydropower outlook that integrates low-head hydropower technology (e.g., in-stream turbines) and multiple environmental aspects, such as river ecology and protected areas. We employ a high resolution (~2km) continental scale hydrological model called LEAF-Hydro-Flood (LHF) to assess the in-stream hydropower potential in the Amazon River basin. We particularly focus on quantifying the potential and feasibility of employing instream turbines in the Amazon instead of building large dams. We show that a significant portion of the total energy planned to be generated from conventional hydropower in the Brazilian Amazon could be harnessed using in-stream turbines that utilize kinetic energy of water without requiring storage. Further, we also find that implementing in-stream turbines as an alternative to large storage-based dams could prove economically feasible, since most of the environmental and social costs associated with dams are eliminated. Our results open multiple pathways to achieve sustainable hydropower development in the Amazon to meet the ever-increasing energy demands while minimizing hydrological, social, and ecological impacts. It also provides important insight for sustainable hydropower development in other global regions. The results presented are based on a manuscript under revision for Nature Sustainability.

Summary The tumor-like growth of larval Echinococcus multilocularis tissue (causing alveolar echinococcosis, AE) is directly linked to the nature/orientation of the periparasitic host immune-mediated processes. Parasite-mediated immune suppression is a hallmark triggering infection outcome in both chronic human and murine AE. So far, little is known about secondary systemic immune effects of this pathogen on other concomitant diseases, e.g. endogenous gut inflammation. We examined the influence of E. multilocularis infection on murine Dextran sodium sulfate (DSS)-induced colitis. At 3 months post-E. multilocularis infection (chronic stage), the mice were challenged with 3% DSS in the drinking water for 5 days plus subsequently with tap water (alone) for another 4 days. After necropsy, fixed tissues/organs were sectioned and stained with Hematoxylin and Eosin (H&E) for assessing inflammatory reaction. Cytokine levels were measured by flow cytometry and quantitative RT-PCR. Colitis severity was assessed (by board-certified veterinary pathologists) regarding (i) colon length, (ii) weight loss and (iii) a semiquantitative score of morphologic changes. The histopathological analysis of the colon showed a significant reduction of DSS-induced gut inflammation by concomitant E. multilocularis infection, which correlated with down-regulation of Th1/Th17 T cell responses in the colon tissue. E. multilocularis infection markedly reduced the severity of DSS-induced gut inflammation upon down-regulation of Th1/Th17 cytokine expression, and attenuation of CD11b+ Dendritic Cell maturation cell activation. In conclusion, E. multilocularis infection remarkably reduces DSS-induced colitis in mice by attenuating Th1/Th17 mediated immune reactions. This article is protected by copyright. All rights reserved.

BackgroundHypovitaminosis-D has been linked to neuropsychiatric conditions, but little is known about vitamin D status in individuals with chronic tic disorders (CTD). This study sought to determine whether vitamin D levels are associated with the severity of tics and presence and severity of comorbid obsessive-compulsive disorder (OCD) and/ or attention-deficit/hyperactivity disorder (ADHD).MethodsThis is a cross-sectional sub-study of the European Multicentre Tics in Children Studies (EMTICS). Vitamin D [25(OH)D] levels (ng/ml) were obtained for 327 participants with CTD at study entry and tic severity was measured using the Yale Global Tic Severity Scale (YGTSS). An association between tic severity and presence and severity of comorbid OCD and/or ADHD symptoms was analysed using multilevel models controlling for season, site, sex, age and presence of comorbid OCD and/or ADHD.ResultsThe participants comprised 247 boys and 80 girls (4-16 years, mean [SD], 10.9 [2.72]). Hypovitaminosis-D ([25(OH)D] < 20ng/ml) was present in 33% of participants with CTD and/ or comorbid OCD and/ or ADHD. The authors found no association between 25(OH)D levels and tic severity or OCD symptom severity. However, lower 25(OH)D levels were significantly associated with increased severity of ADHD symptoms in participants with CTD (β = -0.25, s.e. = 0.08, 95% CI, -0.42 to -0.09; p < 0.01).ConclusionAdditional research is needed to confirm these findings and assess whether hypovitaminosis-D may represent an underlying biological vulnerability for comorbid ADHD symptoms in CTD as it may signpost novel strategies for prevention and treatment.

The objective of this study is to perform an experimental and numerical investigation of a stoichiometric methane/air premixed flame propagating in a curved constant volume channel. The mixture, initially at rest, had temperature 296 K and pressure 102.65 kPa. In the experimental study, a high speed camera and a pressure sensor captured the evolving flame shape and recorded the temporal pressure history during burning. In the numerical study, the commercial computational fluid dynamics package ANSYS Fluent was used to solve the two dimensional, compressible reacting flow and transport equations for 50 species using the San-Diego combustion mechanism under the same conditions as the experiments. It was found that the premixed flame propagating in the curved and converging channel exhibits different features than previously reported in straight or 90° bend channels. There was a definitive curvature effect on tulip flame development. The conversion of the convex tulip flame back into a concave flame revealed the influence of channel geometry on flame evolution: this conversion does not occur in straight channels. The experiments showed that the rate of pressure change eventually becomes negative mainly due to heat losses which engender correspondingly slower flame propagation during the final stage of the tests. The analysis of the numerical results revealed the effect of the interaction between flame front, pressure field and flame-induced flow on flame evolution during all five stages of flame evolution.

The invention and application of antilock braking systems (ABS) has resulted in a significant improvement of traffic safety and a reduction of stopping distance, especially on wet roads [1]. The reason for this success is rather clear: ABS is designed to steer the braking process in the most efficient way by keeping an optimal level of tire slip. At the same time, it must be clear that ABS uses braking forces generated in the tire footprint, and really good braking is possible only with high-performance tires. The best way to probe tire performance is to build tires and test them. This is, however, a long and an expensive procedure, so prediction of ABS performance based on results of some simple experiments is a very attractive supplement to the development process. Tire-braking performance is related to the friction of rubber on a surface. Relevant friction mechanisms can include adhesion, rubber hysteresis, and various kinds of viscous friction. All of these phenomena depend on the local sliding velocity, load, and temperature of tread rubber. Tire blocks pass the footprint area of a braking tire very rapidly, but their dynamics are indeed influenced by ABS. All of these aspects make the problem of ABS-braking prediction very intricate. In this publication, we present an approach for prediction of the ABS-braking performance. The approach links friction measurements conducted in laboratory to tire tests results. The friction of six specially designed compounds was measured on dry and wet surfaces using a high-speed linear friction test rig. Obtained experimental results are analyzed with the aid of rubber friction theory [2,3] involving both surface and rubber as input parameters. It is demonstrated that lab friction test procedures can be used for prediction of ABS wet braking performance.

This article examines the detailed combustion process in a theoretical model with applicability to combustion in a wave rotor or wave disc engine. The model comprises a single channel into which an initial loading of methane and air is admitted and ignited after all inlet and exit ports have been closed. Combustion takes place at constant volume. However, the initial gaseous mixture in the channel is not at rest. The initial opening and closing of the ports generates significant vorticity which influences the evolution of the combustion process. Numerical evaluations are provided for the detailed flame shape for simplified (one-step) chemistry and a simulation using the detailed 235-step San Diego scheme. Quantities examined are the evolution of vorticity, pressure fluctuations, mass consumption rate, flame surface area and the influences on combustion of adiabatic and non-adiabatic channel walls. Combustion regimes are identified and compared with simpler model studies (no initial flow). Pointwise quanti...

Aim An imbalance between T-helper type 1 (Th1) and type 2 (Th2) cytokines has been implicated in schizophrenia, although empirical evidence is rare. The aim of this study was to examine if a Th1/Th2 imbalance occurs in schizophrenia and schizophrenia-related disorder. Methods Twenty-six subjects with schizophrenia, 26 subjects with schizophrenia-related disorders, and 26 healthy controls were recruited. The Human Th1/Th2 Cytokine Cytometric Bead Array Kit-II was utilized to assess serum Th1/Th2 cytokines and ratios simultaneously. MANOVA was used to detect differences among the three diagnostic groups in distinct Th1/Th2 cytokines/ratios. Pearson/Spearman correlations were used to examine the relationships between distinct Th1/Th2 cytokines/ratios and clinical/psychopathological data in schizophrenia. Results Interferon (IFN)-γ/interleukin (IL)-4, IFN-γ/IL-10, IL-2/IL-4, and tumor necrosis factor (TNF)-α/IL-4 ratios were significantly decreased in schizophrenia, but not in schizophrenia-related disorders compared to healthy controls. IFN-γ/IL-4 and IFN-γ/IL-10 in schizophrenia subjects positively correlated with age, but not in schizophrenia-related disorder subjects or in healthy controls. Conclusion A clear Th2 shift was observed in schizophrenia, but not in schizophrenia-related disorders. The Th2 shift in schizophrenia appeared to be an aberrant developmental phenomenon.

Neospora caninum is an apicomplexan parasite that is capable of infecting, a wide range of tissues. The fact that Neospora represents an important abortion-causing parasite in cattle has transformed neosporosis research from an earlier, rather esoteric field, to a significant research topic, and considerable investments have been made in the last years to develop an efficacious vaccine or other means of intervention that would prevent infection and abortion due to N. caninum infection in cattle. Antigenic molecules associated with proteins involved in adhesion/invasion or other parasite-host-cell interaction processes can confer protection against Neospora caninum infection, and such proteins represent valuable targets for the development of a vaccine to limit economical losses due to neosporosis. Although not ideal, small laboratory animal models that mimic cerebral infection, acute disease and fetal loss upon infection during pregnancy have been used for the assessment of vaccine candidates, in parallel with studies on experimental infections in cattle. Herein, we review and critically assess these vaccination approaches and discuss potential options for improvements.

A consistent finding in major depressive disorder (MDD) research is dysfunction of the immune system. One of the relevant metabolic pathways in this regard is the kynurenine pathway. In patients with major depression, an imbalance between neuroprotective and neurotoxic arms of the pathway with lower plasma kynurenic acid concentration was demonstrated. Therefore, we investigated Single Nucleotide Polymorphism (SNP) and haplotype association of three candidate genes of the three enzymes involved in this metabolism. The three genes, namely, tryptophan hydroxylase 2 (TPH2), kynurenine 3 monooxygenase (KMO) and kynurenine amino transferase 3 (KAT III) SNPs and haplotype association analysis was performed in 338 (266 major depression and 72 bipolar depression) unrelated Caucasian patients with major depressive episodes and 310 age, gender and ethnicity matched controls. In sliding window analyses using PLINK of the haplotypes of KAT III, all windows which include the first SNP (rs12729558), the overall haplotype distribution (OMNIBUS) was significantly different between patients with a major depressive episode and control for all windows, with p-values ranging between 1.75 × 10 = 5 and 0.006. This is due to the haplotype CGCTCT (referring to 6 SNP window analysis), which is found in about 5.7% of patients and 1.9% of healthy controls. It was due to CGCTCT haplotype and the frequencies of this haplotype in both bipolar patients and patients with major depression showed significantly higher than the control population (p < 0.001). This haplotype of KAT III gene CGCTCT may have effect on the function of this enzyme in formation of kynurenic acid in some patients with major depressive episodes.

Centrifugal forces are generated by a spinning impeller, of magnitudes that create large stresses. Aerodynamic forces are also imparted on an impeller blade, which varies with time and position. These two forces play different roles during compressor events. Damage accumulated from these events results in the fatigue failure of impeller material and structure. Therefore, it is important to design an impeller against dynamic and fatigue failure. The finite element method has been used in the study of impeller fracture mechanics and is regarded as an important tool in the design and analysis of material and structures. Novel axial composite impellers, manufactured through filament winding technology, were invented and studied at Michigan State University. These impellers will be used to compress water vapor so as to use it as a refrigerant. In this study dynamic and fatigue behavior of two types of composite impellers 8B and 8C, were analyzed using commercial code ANSYS. Firstly, load cases were identified calculated and evaluated. Static analysis was then performed with a full 3-D finite element model. The critical zone where fatigue failure begins was extracted and used to determine life assessment positions. Secondly, aerodynamic forces imparted on the blade were obtained from FLUENT, so that damage from dynamic stresses could be calculated. Finally, based on the FEM and FLUENT simulation results, a linear damage accumulation model was employed as a damage estimation rule to predict life of the two composite impellers. A conservative life of 6498 h for 8B was calculated by this method, as was a life of 5435 h of 8C. Based on the method, safe fatigue life reduces for about 32% in case of 8B and 40% in case of 8C compared with conventional approaches where aerodynamic forces are omitted.

the inclination angle dur-ing circular rotation at up to 20000 r.p.m. The presented trepanning systems are able to laser ma-chine through-holes diameters of 100 µm with a negative taper of up to 5°. Starting from an early stage of implementation, the novel trepanning system has been customized for different applications and industrial partners. The conference paper outlines the development steps and advanced per-formance, accenting laser micro machining results utilizing the novel LMTB trepanning system in operation at different laser parameters.

A versatile laser trepanning system has been designed and implemented to enable the adjustment of circular beam displacement and inclination during the rotation of the optics. The presented systems drill differently tapered through-holes with a diameter in the range of 50 to over 1000μm. The novel trepanning systems have been customized for different industrial applications. This paper outlines the development steps and advanced performance, accenting laser micro machining of up to 1mm thick metal and ceramic samples and laser parameters. The results presented in this contribution emphasize differently tapered through holes with an entrance diameter of 90 to 150μm.

Interferon-alpha (IFN-alpha) treatment is frequently complicated by symptoms of depression. The mechanism by which peripherally administered IFN-alpha enters and modulates the central nervous system remains unclear. The cell adhesion molecule ICAM-1 is involved in the regulation of blood-brain barrier (BBB) permeability. ICAM-1 expression was shown to increase during IFN-alpha treatment and recently the expression of ICAM-1 on vascular endothelial cells in the brain was found to be correlated with the development of depression. We therefore hypothesized that soluble ICAM-1 may be involved in the development of IFN-alpha associated depression. In a prospective study, serum levels of soluble ICAM-1 (double sandwich ELISA test) and symptoms of depression (SDS) were measured in 48 patients with malignant melanoma before and during adjuvant IFN-alpha treatment. Both, depression scores and the serum levels of sICAM-1 significantly increased after three months of IFN-alpha treatment compared to baseline levels (p.001). Patients who developed depression (SDS-index scoresor = 50) after three months of treatment had higher sICAM-1 levels compared to non-depressed patients. Furthermore, sICAM-1 levels were positively correlated with SDS values (r = .367, p = .018). Our data provides evidence for an association between the induction of sICAM-1 and the development of symptoms of depression during IFN-alpha treatment, possibly by enhancing BBB-permeability.

Background & Aims: In patients with functional dyspepsia, altered α-adrenoreceptor function and depression are prevalent, features that are linked to a G-protein β3 (GNB3) subunit gene polymorphism (C825T). We aimed to assess the association of specific G-protein β3 subunit genotypes with functional dyspepsia.Methods: In study A, abdominal symptoms were assessed in 67 patients with unexplained, upper abdominal symptoms and 259 consecutive blood donors with and without abdominal symptoms. In study B, a further 56 patients with functional dyspepsia and 112 age- and sex-matched healthy controls from a blood donor population study were evaluated. Genomic DNA was isolated from buccal swabs and genotyping of the C825T polymorphisms was performed by polymerase chain reaction and restriction analysis.Results: In the blood donors with no abdominal symptoms in study A (controls, n=161), genotype distribution was 17 TT, 77 TC, and 67 CC. In blood donors and patients with unexplained abdominal symptoms, genotype distribution was 22 TT, 54 TC, and 89 CC ( P = 0.007 vs. controls). In study B, the genotype distribution in functional dyspepsia patients was 4 TT, 18 CT, and 34 CC compared with 4 TT, 62 CT, and 46 CC in the controls ( P GNB3 825C carrier status is associated with unexplained predominantly upper abdominal symptoms.

Positive ions and radicals in C2F6 and CHF3 high density discharges were measured using a direct-line-of-sight mass spectrometer. The ion energy distributions of the dominant ions were measured as a function of process conditions. Appearance potential mass spectrometry was performed to measure trends of the radical densities. For C2F6 plasmas CF3 and CF3+are the most abundant neutral and ionic species, respectively. CF3 is the most abundant neutral species for a CHF3 plasma, whereas CHF2+ and CF+ are the most abundant ionic species at 600–1000 and 1400 W, respectively. Erosion of the quartz coupling window is an important contaminant source for our inductively coupled plasma system. For comparison, downstream mass spectrometry was also applied using a closed ion source system since this approach is of interest for real-time monitoring and control. Endpoint detection for Si and SiO2 film etching in a CHF3 plasma was investigated using the downstream mass spectrometer system and compared with data obtained ...