Large Eddy Simulation and Acoustic Analysis of Combustion Instability in an Annular Combustor with Low-Swirl Flames.

Self-excited combustion instability in an annular combustor with low-swirl flames is studied with a combination of large eddy simulation (LES) and acoustic solvers. Acoustic analysis with a Helmholtz solver provides an estimate of frequencies and modal structures in the annular combustor. LES gives detailed modal dynamics for specific instability modes. Combustion instabilities in the annular combustor including longitudinal, spinning, and standing modes are successfully captured in a single LES. Numerical results show that the instability modes are not constant; they switch among these modes randomly and rapidly. The flow oscillates back and forth in phase with the largest pressure amplitude located near the outlet of the injectors for the longitudinal mode. The azimuthal instability oscillates in the 1A2L mode of the annular system. In the spinning mode, the pressure antinodes move forward while the modal structure keeps constant. For the standing mode, the locations of pressure antinodes are fixed in the annular combustor and the fluctuations at the pressure antinodes keep out of phase. The near-zero value of the mean spin ratio indicates that the dominant azimuthal mode is the standing mode. The azimuthal modes captured by LES are in good agreement with that predicted by Helmholtz solver in terms of frequency and modal structure. The maximum deviation of the predicted frequency is less than 5%. This adds values before the low-swirl injector is placed into the actual annular combustor.

Causal effects of fatty acids on depression: Mendelian randomization study.

Objectives: Fatty acids (FA) are widely believed to play a role in the pathophysiology of depression. However, the causal relationships between FA and depression remain elusive and warrant further research. We aimed to investigate the potential causal relationship between FA [saturated fatty acids (SFA), mono-unsaturated fatty acids (MUFA), and polyunsaturated fatty acids (PUFA)] and the risk of depression using Mendelian randomization (MR) analysis. Methods: We conducted a two-sample MR analysis using large-scale European-based genome-wide association studies (GWASs) summary data related to depression (n = 500,199 individuals) and FA [saturated fatty acids (SFA), mono-unsaturated fatty acids (MUFA), and polyunsaturated fatty acids (PUFA)] levels. MR analysis was performed using the Wald ratio and inverse variance-weighted (IVW) methods, and sensitivity analysis was conducted by the simple mode, weighted mode, weighted median method, and MR-Egger method. Results: We found the causal effects for the levels of oleic acid (OA; OR = 1.07, p = 5.72 × 10-4), adrenic acid (OR = 0.74, p = 1.01 × 10-3), α-linolenic acid (ALA; OR = 2.52, p = 1.01 × 10-3), eicosapentaenoic acid (EPA; OR = 0.84, p = 3.11 × 10-3) on depression risk, after Bonferroni correction. The sensitivity analyses indicated similar trends. No causal effect between the levels of SFA and depression risk was observed. Conclusion: Our study suggests that adrenic acid and EPA are protective against the risk of depression, while OA and ALA are potential risk factors for depression. Nonetheless, the underlying mechanisms that mediate the association between these FAs and depression risk should be investigated in further experiments.

Identification of genetic loci that overlap between schizophrenia and metabolic syndrome.

Patients with schizophrenia (SCZ) frequently exhibit an elevated risk of metabolic syndrome (MetS), which may lead to a worse clinical outcome. Even though these two phenotypes are genetically linked, little is known about their shared genetic determinants. Here, we investigated whether SCZ and MetS share genetic risk factors. To examine the genetic overlap between the two disorders, we applied a comprehensive genetic overlap analysis by integrating GWAS data for SCZ (n = 320,404) and MetS (n = 291,107) at the genome, genetic variants, and gene levels. At the genome level, we observed polygenic overlap between SCZ and MetS by utilizing LDSC (rg=-0.09, P = 1 × 10-4) and GNOVA (rho=-0.04, P = 1.39 × 10-8) analysis. At the SNP level, we performed conjunctional FDR (conjFDR) analysis to identify genetic variants simultaneously associated with two phenotypes. Based on conjFDR < 0.05, we identified 22 loci shared between SCZ and MetS. At the gene level, we further demonstrated that SCZ- and MetS-inferred gene expression overlapped across 49 GTEx tissues and highlighted the PCCB and KCTD13 genes as putative mediators of the genetic association. Overall, these findings shed novel light on the association between SCZ and MetS, and potentially enhance our knowledge of the high comorbidity and genetic processes that overlap between the two disorders.

Cigarette smoking, coffee consumption, alcohol intake, and clozapine metabolism: A Mendelian randomization study.

Background: Clozapine is an effective antipsychotic medication for patients with treatment-resistant schizophrenia. Previous studies revealed that smoking, alcohol intake, and coffee consumption altered the metabolism of clozapine. However, causal associations between substance use and clozapine levels were not sufficiently established. Methods: Several genome-wide association studies provided genetic tools for six measures of substance use, including age of smoking, cigarettes per day, smoking cessation, smoking initiation, coffee consumption, and alcohol consumption (GWASs). Utilizing the CLOZUK consortium's dataset, their associations with clozapine and its metabolite concentrations were evaluated. All GWAS data were collected from the European population. Mendelian randomization (MR) estimations from each genetic test were combined using inverse variance weighted (IVW) meta-analysis in combination with complementing techniques (such as weighted median and MR Egger). We also analyze horizontal pleiotropy and heterogeneity using various sensitivity analyses. Results: Genetically predicted higher level of smoking initiation was significantly associated with reduced clozapine (ß = -0.14, P = 4.53E-04) concentrations and norclozapine concentrations (ß = -0.14, P = 3.33E-04), and increased coffee consumption was significantly associated with lower level of clozapine concentrations (ß = -0.42, P = 1.70E-14), norclozapine concentrations (ß = -0.27, P = 1.51E-07), and the metabolic ratio of clozapine to norclozapine (ß = -0.15, P = 5.35E-07), survived after the Bonferroni correction (P = 0.05/6 = 0.008). In sensitivity analyses, the weighted median and MR Egger methods demonstrated directionally consistent effects. In addition, our sensitive test indicated no significant horizontal pleiotropy and heterogeneity (P > 0.05). However, other measures of substance use (age of initiation smoking, cigarettes per day, smoking cessation, and drinks per week) were not associated with clozapine metabolism. Conclusion: Our investigation revealed a correlation between greater smoking initiation and coffee consumption and reduced blood levels of clozapine and norclozapine. Providing clinicians with guidance on how to adjust clozapine levels for clozapine-treated patients.

The Effects of Plasma Homocysteine Level on the Risk of Three Major Psychiatric Disorders: A Mendelian Randomization Study.

Background: Higher homocysteine (Hcy) level has been suggested to be associated with major psychiatric disorders (MPDs), such as schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD). We investigated the causal relationships between plasma Hcy level and MPDs risks using the Mendelian randomization (MR) method. Methods: We selected 18 loci associated with plasma Hcy level from a large-scale genome-wide association study (GWAS) as genetic instruments. Genetic associations with SCZ, MDD, BD and BD subtypes (BD-I and BD-II) were extracted from several GWAS datasets from the Psychiatric Genomics Consortium. We used the Generalized Summary-data-based Mendelian Randomization (GSMR) method to estimate the associations of genetically predicted plasma Hcy levels with MPDs risks. We also performed inverse variance-weighted (IVW) analysis to verify the GSMR results and used MR-Egger regression and leave-one-out analysis to test the assumptions for a valid MR analysis. Results: Genetically predicted plasma Hcy levels were associated with risks of SCZ (odds ratio [OR] = 1.12, P GSMR = 1.73 × 10-3) and BD-I (OR = 1.14, P IVW = 5.23 × 10-3) after Bonferroni correction. These associations were statistically significant when using IVW analysis (SCZ: OR = 1.11, P IVW = 2.74 × 10-3; BD-I: OR = 1.13, P IVW = 9.44 × 10-3). Furthermore, no significant horizontal pleiotropy was found by sensitivity analysis, and leave-one-out analyses showed no specific SNP affected the overall estimate. However, genetically determined plasma Hcy levels were not causally associated with MDD, BD, or BD-II risks. Conclusion: Our results suggest that elevated plasma Hcy levels may increase the risk of SCZ or BD-I. Further randomized clinical trials are warranted to validate the MR findings in our study.

Assessment of the relationships between genetic determinants of thyroid functions and bipolar disorder: A mendelian randomization study.

BACKGROUND: Thyroid functions (TFs) have been implicated in the initiation and propagation of psychiatric disorders. Observational studies have shown associations of TFs with psychiatric disorders. However, the relationship between TFs and psychiatric diseases were still unclear. METHODS: Genetic instruments for 6 TF-realted indexes, including free thyroxine (FT4), triiodothyronine (FT3):FT4 ratio, thyrotropin (TSH), thyroid peroxidase antibodies (TPOAb) concentration, hypothyroidism, and hyperthyroidism, were obtained from several genome-wide association studies (GWASs). Their associations with BD were evaluated using Psychiatric Genomics Consortium (PGC) datasets (41,917 cases and 371,549 controls). All GWAS summary statitics were from European ancestry. Mendelian randomization (MR) estimates from each genetic instrument were combined using inverse variance weighted (IVW) meta-analysis, with complementary methods (eg, weighted median and MR Egger). We also multiple sensitivity analyses to examine horizontal pleiotropy and heterogeneity. RESULTS: Genetically predicted level of FT4 was significantly associated with BD (odds ratio (OR)=0.89, 95% confidence interval (CI): 0.83-0.95; P=4.65 × 10-3), survived after the Bonferroni correction (P<0.05/6=0.008). Consistent directional effects for all sensitivity analyses were observed in the weighted median and MR Egger methods. Furthermore, our sensitive test suggested no significant horizontal pleiotropy (intercept=-0.01, P=0.12) and no notable heterogeneity (Q = 29.9; P=0.09). However, other TF indexes (FT3:FT4 ratio [OR=1.24, P=0.10], TSH [OR=1.01, P=0.61], TPOAb concentration [OR=1.20, P=0.54], hypothyroidism [OR=1.00, P=0.91], and hyperthyroidism [OR=0.99, P=0.57]) were not associated with BD. CONCLUSIONS: Our results provide further evidence that higher FT4 level is associated with a reduced risk of BD, and suggest the importance of FT4 level in BD risk assessment and potential therapeutic targets development.

Examining the Causal Inference of Leptin and Soluble Plasma Leptin Receptor Levels on Schizophrenia: A Mendelian Randomization Study.

Background: Observational studies that have supported the role of the leptin level in schizophrenia (SCZ) risk are conflicting. Therefore, we performed a two-sample Mendelian randomization (MR) analysis to investigate whether the circulating leptin and soluble plasma leptin receptor (sOB-R) levels play a causal role in SCZ risk. Methods: We first selected five independent single-nucleotide polymorphisms (SNPs) associated with the circulating leptin level and three independent SNPs associated with the sOB-R level from two genome-wide association studies (GWASs) of European individuals. Then, we extracted their associations with SCZ using a large-scale GWAS that consisted of 40,675 patients with SCZ and 64,643 controls of European ancestry. We performed an MR analysis using the inverse variance-weighted (IVW) method to examine the causal effect of leptin on SCZ risk. Moreover, we performed sensitivity analyses to verify our MR results using the weighted median and MR-Egger methods. Results: According to the IVW method, genetically predicted circulating leptin levels were not associated with SCZ risk (OR = 1.98, for per 1-SD unit increase in leptin level; 95% CI, 0.87-4.53; p = 0.10). In addition, the sOB-R level showed no causal effect on the SCZ risk using IVW (OR = 0.98 for per 1-SD unit increase in sOB-R level; 95% CI, 0.97-1.00; p = 0.06). Our sensitivity analysis results confirmed our MR findings. Conclusions: By estimating the causal effect of leptin on SCZ risk using the MR methods, we identified no effect of genetically predicted circulating leptin or the sOB-R level on SCZ. As such, our study suggests that leptin might not be a risk factor for SCZ.

Corticotropin-releasing hormone 1 receptor antagonism attenuates chronic unpredictable mild stress-induced depressive-like behaviors in rats.

Hyperactivity of the hypothalamic-pituitary-adrenal axis and impairment of the central corticotropin-releasing factor system are factors in the pathogenesis of depression. Though several antagonists of the corticotropin-releasing factor 1 receptor were effective in the recognized behavioral tests for antidepressant activity, there is still little information on the potential interactions between corticotropin-releasing factor 1 receptor inhibitors and conventional antidepressant therapy. The aim of our study was to assess the influence of CP154526, a corticotropin-releasing factor 1 receptor blocker, which presented some signs of depression. Our results revealed that CP154526 (5 and 10 mg/kg) or fluoxetine (10 mg/kg) treatment notably improved the sucrose consumption, produced anti-depressive-like behavior in open-field test, as well as immobility time in forced swimming test. The levels of interleukin-6, interleukin-1ß, tumor necrosis factor-α, and corticotropin-releasing hormone concentration in the serum were inhibited effectively by CP154526 or fluoxetine administration. Real-time quantitative PCR and western blot analysis showed the upregulated levels of brain-derived neurotrophic factor and growth associated protein 43 (GAP43) in the hypothalamus of the rats exposed to chronic unpredictable mild stress (CUMS), while different degrees of downregulation in their expression were detected after CP154526 (5 and 10 mg/kg) or fluoxetine (10 mg/kg) treatment, respectively. Thus, our data demonstrated that CP154526 exhibited antidepressant effect in CUMS rats, which might be mediated by decreasing the brain-derived neurotrophic factor and GAP43 expression in the hypothalamus.

Ginsenoside Rg1 attenuates chronic unpredictable mild stress-induced depressive-like effect via regulating NF-κB/NLRP3 pathway in rats.

Ginsenoside (GS Rg1), which has neuroprotection and anti-inflammation activities, is the main active ingredient of Radix Ginseng. However, its antidepressant-like effect in rats remains unclear. Our study was conducted to investigate whether GS Rg1 confers an antidepressant effect in rats exposed to a chronic unpredictable mild stress model of depression and to explore its possible mechanisms. Our results revealed that GS Rg1 treatments for 3 weeks alleviated the depression-related behaviors of chronic unpredictable mild stress-exposed rats, as indicated by increasing sucrose preference, improving locomotor activity and shortening immobile time in both the forced swimming tests and tail suspension tests. And these ameliorative effects of GS Rg1 treatment were involved with regulating chronic unpredictable mild stress-induced pro-inflammatory cytokine interleukin beta (IL-1ß) related neuro-inflammation. In addition, we further found that GS Rg1 reversed chronic unpredictable mild stress-induced IL-1ß elevation, possibly by inhibiting nuclear factor kappa B pathway activation and regulating nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 inflammasome expression. In short, our results suggested that GS Rg1 exerted a potential antidepressant-like effect in chronic unpredictable mild stress rat model of depression, which may provide an insight into the potential of GS Rg1 in therapeutic implications for depression.

Effect of Cognitive Behavioral Therapy on Improving the Cognitive Function in Major and Minor Depression.

The aim of this study was to investigate the effectiveness of cognitive behavioral therapy (CBT) on improving the cognitive function in minor depression (MiD) and major depression (MaD). The study will constitute a placebo-controlled single-blind parallel-group randomized controlled trial. The selected participants will be randomly allocated into one of two parallel groups with a 1:1 ratio: the CBT-based group and the general health education group. CBT significantly alleviated depressive symptoms of MiD and MaD at 12 weeks (p < 0.001), and the treatment effect was maintained for at least 12 months (p < 0.001). Interestingly, CBT significantly promotes more cognitive function of MiD and partial cognitive function of MaD at 12 weeks in the intervention group than in the control group (p < 0.01). CBT can alleviate depressive symptoms of both minor and MaDs. The effectiveness of CBT is different on improving the cognitive function in MiD and MaD.