An integrated approach to understand biological stress system dysregulation across depressive and anxiety disorders

Background: Affective disorders involve dysregulation of major biological stress systems (hypothalamic-pituitary adrenal (HPA)-axis, immune system, autonomic nervous system (ANS)). Suchdysregulationshave rarely beensimultaneously examined across different stress systems.Methods: In the Netherlands Study of Depression and Anxiety (n=2789), we investigated whether current or remitted depressive and/or anxiety disorders (based on the CIDI semi-structured interview), including specific symptom profiles, were associated with separate markers and cumulative indexes of the HPA-axis (cortisol awakening response, evening cortisol, dexamethasone suppression test cortisol), immune system (C-reactive protein, interleukin-6, tumor necrosis factor-alpha), and ANS (heart rate, respiratory sinus arrhythmia, pre-ejection period).Results: Depressive andanxiety disorderswere significantlyassociated with changes in three biological stress systemsincluding HPA-axis hyperactivity, increased inflammatory activity, and a higher ANS tone, particularly for integrative and cumulative indexes of these stress systems (pFDR <.05) vs. controls. The strongest associations were seen with current disorders andcumulative indexes of the HPA-axis (13=.124, pFDR=.001), the immune system (13 =.057, pFDR=.032), and total cumulative index across stress systems (13=.102, pFDR=.004). Atypical, energy-related depression severity was linked to immune system markers (pFDR<0.001), melancholic depression severity to HPA-axis markers (pFDR=.032), and anxiety arousal severity to both HPA-axis and immune system markers (pFDR<0.05). Findings were partially explained by poorer lifestyle, more chronic diseases, or (especially for ANS-function) antidepressant use. Limitations: Cross-sectional analyses limit examination of temporal associations.Conclusion: Patients withdepressive and anxiety disorders showed consistent dysregulation across biological stress systems, particularly for current episodes.To understand stress system functionality in affective disorders, an integrated approach capturing cumulative stress indices within and across biological stress systems is important.Stress-related psychiatric disorders across the life spa

A case study of an individual participant data meta-analysis of diagnostic accuracy showed that prediction regions represented heterogeneity well

The diagnostic accuracy of a screening tool is often characterized by its sensitivity and specificity. An analysis of these measures must consider their intrinsic correlation. In the context of an individual participant data meta-analysis, heterogeneity is one of the main components of the analysis. When using a random-effects meta-analytic model, prediction regions provide deeper insight into the effect of heterogeneity on the variability of estimated accuracy measures across the entire studied population, not just the average. This study aimed to investigate heterogeneity via prediction regions in an individual participant data meta-analysis of the sensitivity and specificity of the Patient Health Questionnaire-9 for screening to detect major depression. From the total number of studies in the pool, four dates were selected containing roughly 25%, 50%, 75% and 100% of the total number of participants. A bivariate random-effects model was fitted to studies up to and including each of these dates to jointly estimate sensitivity and specificity. Two-dimensional prediction regions were plotted in ROC-space. Subgroup analyses were carried out on sex and age, regardless of the date of the study. The dataset comprised 17,436 participants from 58 primary studies of which 2322 (13.3%) presented cases of major depression. Point estimates of sensitivity and specificity did not differ importantly as more studies were added to the model. However, correlation of the measures increased. As expected, standard errors of the logit pooled TPR and FPR consistently decreased as more studies were used, while standard deviations of the random-effects did not decrease monotonically. Subgroup analysis by sex did not reveal important contributions for observed heterogeneity; however, the shape of the prediction regions differed. Subgroup analysis by age did not reveal meaningful contributions to the heterogeneity and the prediction regions were similar in shape. Prediction intervals and regions reveal previously unseen trends in a dataset. In the context of a meta-analysis of diagnostic test accuracy, prediction regions can display the range of accuracy measures in different populations and settings

Translocation and de novo synthesis of eicosapentaenoic acid (EPA) during nitrogen starvation in Nannochloropsis gaditana

The microalga Nannochloropsis gaditana is known for accumulating fatty acids, including the commercially interesting eicosapentaenoic acid (EPA) within the polar lipids (PL) and neutral lipids (NL). During microalgal growth EPA is mainly present in the PL. Upon nitrogen starvation N. gaditana accumulates large amounts of TAG in lipid bodies. The neutral lipid fraction will mainly consist of triacylglycerol (TAG). When expressed per total cell dry weight, the NL-localized EPA increased while the PL-localized EPA decreased, suggesting that EPA istranslocated from the PL into the NL lipids during nitrogen starvation. Here, we elucidated the origin of EPA in NL of N. gaditana by firstly growing this microalga under optimal growth conditions with 13CO2 as the sole carbon source followed by nitrogen starvation with 12CO2 as the sole carbon source. By measuring both 12C and 13C fatty acid isotope species in time, the de novo synthesized fatty acids and the already present fatty acids can be distinguished. For the first time, we proved that actual translocation of EPA from the PL into the NL occurs during nitrogen starvation of N. gaditana. Next to being translocated, EPA was synthesized de novo in both PL and NL during nitrogen starvation. EPA was made by carbon reshuffling within the cell as well. EPA was the main fatty acid translocated, suggesting that the enzyme responsible for fatty acid translocation has a high specificity for EPA

High-protein diets prevent steatosis and induce hepatic accumulation of monomethyl branched-chain fatty acids

The hallmark of nonalcoholic fatty liver disease is steatosis of unknown etiology. To test how dietary protein decreases steatosis, we fed female C57BL/6 J mice low-fat (8 en%) or high-fat (42 en%) combined with low-protein (11 en%), high-protein (HP; 35 en%) or extra-high-protein (HPX; 58 en%) diets for 3 weeks. The 35 en% protein diets reduced hepatic triglyceride, free fatty acid, cholesterol and phospholipid contents to ~50% of that in 11 en% protein diets. Every additional 10 en% protein reduced hepatic fat content ~1.5 g%. HP diets had no effect on lipogenic or fatty acid-oxidizing genes except Ppargc1alpha (+30%), increased hepatic PCK1 content 3- to 5-fold, left plasma glucose and hepatic glycogen concentration unchanged, and decreased inflammation and cell stress (decreased Fgf21 and increased Gsta expression). The HP-mediated decrease in steatosis correlated inversely with plasma branched-chain amino-acid (BCAA) concentrations and hepatic content of BCAA-derived monomethyl branched-chain fatty acids (mmBCFAs) 14-methylpentadecanoic (14-MPDA; valine-derived) and, to a lesser extent, 14-methylhexadecanoic acid (isoleucine-derived). Liver lipid content was 1.6- to 1.8-fold higher in females than in males, but the anti-steatotic effect of HP diets was equally strong. The strong up-regulation of PCK1 and literature data showing an increase in phosphoenolpyruvate and a decline in tricarboxylic acid cycle intermediates in liver reveal that an increased efflux of these intermediates from mitochondria represents an important effect of an HP diet. The HP diet-induced increase in 14-MPDA and the dietary response in gene expression were more pronounced in females than males. Our findings are compatible with a facilitating role of valine-derived mmBCFAs in the antisteatotic effect of HP diets

Carotenoid and Fatty Acid Metabolism in Light-Stressed Dunaliella salina

Carotene is overproduced in the alga Dunaliella salina in response to high light intensities. We have studied the effects of a sudden light increase on carotenoid and fatty acid metabolism using a flat panel photobioreactor that was run in turbidostat mode to ensure a constant light regime throughout the experiments. Upon the shift to an increased light intensity, -carotene production commenced immediately. The first 4 h after induction were marked by constant intracellular levels of -carotene (2.2 g LCV-1), which resulted from identical increases in the production rates of cell volume and -carotene. Following this initial phase, -carotene productivity continued to increase while the cell volume productivity dropped. As a result, the intracellular -carotene concentration increased reaching a maximum of 17 g LCV-1 after 2 days of light stress. Approximately 1 day before that, the maximum -carotene productivity of 30 pg cell-1 day-1 (equivalent to 37 mg LRV-1 day-1) was obtained, which was about one order of magnitude larger than the average productivity reported for a commercial -carotene production facility, indicating a vast potential for improvement. Furthermore, by studying the light-induced changes in both -carotene and fatty acid metabolism, it appeared that carotenoid overproduction was associated with oil globule formation and a decrease in the degree of fatty acid unsaturation. Our results indicate that cellular -carotene accumulation in D. salina correlates with accumulation of specific fatty acid species (C16:0 and C18:1) rather than with total fatty acid conten

Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience.

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Seasonal and diel variation in greenhouse gas emissions from an urbanpond and its major drivers

Small water systems are important hotspots of greenhouse gas (GHG) emission, but estimates are poorly constrained as data are scarce. Small ponds are often constructed in urban areas, where they receive large amounts of nutrients and therefore tend to be highly productive. Here, we investigated GHG emissions, seasonal and diel variation, and net ecosystem production (NEP) from an urban pond. In monthly 24‐h field campaigns during 11 months, diffusive water–atmosphere methane (CH4) and carbon dioxide (CO2) fluxes and CH4 ebullition and oxidation were quantified. With oxygen (O2) measurements, NEP was assessed. The pond was a net GHG source the entire year, with an emission of 3.4 kg CO2 eq m−2 yr−1. The dominant GHG emission pathway was CH4 ebullition (bubble flux, 50%), followed by diffusive emissions of CO2 (38%) and CH4 (12%). Sediment CH4 release was primarily driven by temperature and especially ebullition increased exponentially above a temperature threshold of 15°C. The pond's atmospheric CO2 exchange was not related to NEP or temperature but likely to a high allochthonous carbon (C) input via runoff and anaerobic mineralization of C. We expect urban ponds to show a large increase in GHG emission with increasing temperature, which should be considered carefully when constructing ponds in urban areas. Emissions may partly be counteracted by pond management focusing on a reduction of nutrient and organic matter input

Associations of immunometabolic risk factors with symptoms of depression and anxiety:The role of cardiac vagal activity

Objectives: This study examined 1) the cross-sectional relationships between symptoms of depression/anxiety and immunometabolic risk factors, and 2) whether these relationships might be explained in part by cardiac vagal activity. Methods: Data were drawn from the Adult Health and Behavior registries (n = 1785), comprised of community dwelling adults (52.8% women, aged 30–54). Depressive symptoms were measured with the Center for Epidemiological Studies Depression Scale (CES-D) and the Beck Depression Inventory-II (BDI-II), and anxious symptoms with the Trait Anxiety scale of the State-Trait Anxiety Inventory (STAI-T). Immunometabolic risk factors included fasting levels of triglycerides, high-density lipoproteins, glucose, and insulin, as well as blood pressure, waist circumference, body mass index, C-reactive protein, and interleukin-6. Measures of cardiac autonomic activity were high- and low-frequency indicators of heart rate variability (HRV), standard deviation of normal-to-normal R-R intervals, and the mean of absolute and successive differences in R-R intervals. Results: Higher BDI-II scores, in contrast to CES-D and STAI-T scores, were associated with increased immunometabolic risk and decreased HRV, especially HRV likely reflecting cardiac vagal activity. Decreased HRV was also associated with increased immunometabolic risk. Structural equation models indicated that BDI-II scores may relate to immunometabolic risk via cardiac vagal activity (indirect effect: β = .012, p = .046) or to vagal activity via immunometabolic risk (indirect effect: β = −.015, p = .021). Conclusions: Depressive symptoms, as measured by the BDI-II, but not anxious symptoms, were related to elevated levels of immunometabolic risk factors and low cardiac vagal activity. The latter may exhibit bidirectional influences on one another in a meditational framework. Future longitudinal, intervention, an nonhuman animal work is needed to elucidate the precise and mechanistic pathways linking depressive symptoms to immune, metabolic, and autonomic parameters of physiology that predispose to cardiovascular disease risk