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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.

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.

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.

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.

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.