Major depression is a debilitating psychiatric illness that is typically associated with low mood and anhedonia. Depression has a heritable component that has remained difficult to elucidate with ...current sample sizes due to the polygenic nature of the disorder. To maximize sample size, we meta-analyzed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 genesets associated with depression, including both genes and gene pathways associated with synaptic structure and neurotransmission. An enrichment analysis provided further evidence of the importance of prefrontal brain regions. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant after multiple testing correction. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding etiology and developing new treatment approaches.
Isoprene-derived secondary organic aerosol (iSOA) is a significant
contributor to organic carbon (OC) in some forested regions, such as
tropical rainforests and the Southeastern US. However, its ...contribution to
organic aerosol in urban areas that have high levels of anthropogenic
pollutants is poorly understood. In this study, we examined the formation of
anthropogenically influenced iSOA during summer in Beijing, China. Local
isoprene emissions and high levels of anthropogenic pollutants, in
particular NOx and particulate SO42-, led to the formation of
iSOA under both high- and low-NO oxidation conditions, with significant
heterogeneous transformations of isoprene-derived oxidation products to
particulate organosulfates (OSs) and nitrooxy-organosulfates (NOSs).
Ultra-high-performance liquid chromatography coupled to high-resolution mass
spectrometry was combined with a rapid automated data processing technique
to quantify 31 proposed iSOA tracers in offline PM2.5 filter
extracts. The co-elution of the inorganic ions in the extracts caused matrix
effects that impacted two authentic standards differently. The average
concentration of iSOA OSs and NOSs was 82.5 ng m−3, which was around 3 times
higher than the observed concentrations of their oxygenated precursors
(2-methyltetrols and 2-methylglyceric acid). OS formation was dependant on
both photochemistry and the sulfate available for reactive uptake, as shown by a
strong correlation with the product of ozone (O3) and particulate
sulfate (SO42-). A greater proportion of high-NO OS products were
observed in Beijing compared with previous studies in less polluted
environments. The iSOA-derived OSs and NOSs represented 0.62 %
of the oxidized organic aerosol measured by aerosol mass spectrometry on average, but
this increased to ∼3 % on certain days. These results
indicate for the first time that iSOA formation in urban Beijing is strongly
controlled by anthropogenic emissions and results in extensive conversion to
OS products from heterogenous reactions.
Near-continuous measurements of hydroxyl radical (OH) reactivity in the urban background atmosphere of central London during the summer of 2012 are presented. OH reactivity behaviour is seen to be ...broadly dependent on air mass origin, with the highest reactivity and the most pronounced diurnal profile observed when air had passed over central London to the east, prior to measurement. Averaged over the entire observation period of 26 days, OH reactivity peaked at ∼ 27 s−1 in the morning, with a minimum of ∼ 15 s−1 during the afternoon. A maximum OH reactivity of 116 s−1 was recorded on one day during morning rush hour. A detailed box model using the Master Chemical Mechanism was used to calculate OH reactivity, and was constrained with an extended measurement data set of volatile organic compounds (VOCs) derived from a gas chromatography flame ionisation detector (GC-FID) and a two-dimensional GC instrument which included heavier molecular weight (up to C12) aliphatic VOCs, oxygenated VOCs and the biogenic VOCs α-pinene and limonene. Comparison was made between observed OH reactivity and modelled OH reactivity using (i) a standard suite of VOC measurements (C2–C8 hydrocarbons and a small selection of oxygenated VOCs) and (ii) a more comprehensive inventory including species up to C12. Modelled reactivities were lower than those measured (by 33 %) when only the reactivity of the standard VOC suite was considered. The difference between measured and modelled reactivity was improved, to within 15 %, if the reactivity of the higher VOCs (⩾ C9) was also considered, with the reactivity of the biogenic compounds of α-pinene and limonene and their oxidation products almost entirely responsible for this improvement. Further improvements in the model's ability to reproduce OH reactivity (to within 6 %) could be achieved if the reactivity and degradation mechanism of unassigned two-dimensional GC peaks were estimated. Neglecting the contribution of the higher VOCs (⩾ C9) (particularly α-pinene and limonene) and model-generated intermediates increases the modelled OH concentrations by 41 %, and the magnitude of in situ ozone production calculated from the production of RO2 was significantly lower (60 %). This work highlights that any future ozone abatement strategies should consider the role that biogenic emissions play alongside anthropogenic emissions in influencing London's air quality.
The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited ...statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen's d=-0.14, % difference=-1.24). This effect was driven by patients with recurrent MDD (Cohen's d=-0.17, % difference=-1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen's d=-0.20, % difference=-1.85) and a trend toward smaller amygdala (Cohen's d=-0.11, % difference=-1.23) and larger lateral ventricles (Cohen's d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.
Our understanding of the complex relationship between schizophrenia symptomatology and etiological factors can be improved by studying brain-based correlates of schizophrenia. Research showed that ...impairments in value processing and executive functioning, which have been associated with prefrontal brain areas particularly the medial orbitofrontal cortex (MOFC), are linked to negative symptoms. Here we tested the hypothesis that MOFC thickness is associated with negative symptom severity.
This study included 1985 individuals with schizophrenia from 17 research groups around the world contributing to the ENIGMA Schizophrenia Working Group. Cortical thickness values were obtained from T1-weighted structural brain scans using FreeSurfer. A meta-analysis across sites was conducted over effect sizes from a model predicting cortical thickness by negative symptom score (harmonized Scale for the Assessment of Negative Symptoms or Positive and Negative Syndrome Scale scores).
Meta-analytical results showed that left, but not right, MOFC thickness was significantly associated with negative symptom severity (β std = -0.075; p = 0.019) after accounting for age, gender, and site. This effect remained significant (p = 0.036) in a model including overall illness severity. Covarying for duration of illness, age of onset, antipsychotic medication or handedness weakened the association of negative symptoms with left MOFC thickness. As part of a secondary analysis including 10 other prefrontal regions further associations in the left lateral orbitofrontal gyrus and pars opercularis emerged.
Using an unusually large cohort and a meta-analytical approach, our findings point towards a link between prefrontal thinning and negative symptom severity in schizophrenia. This finding provides further insight into the relationship between structural brain abnormalities and negative symptoms in schizophrenia.
OH, HO2, total and partially speciated RO2, and OH reactivity (kOH′) were measured during the July 2015 ICOZA (Integrated Chemistry of OZone in the Atmosphere) project that took place at a coastal ...site in north Norfolk, UK. Maximum measured daily OH, HO2 and total RO2 radical concentrations were in the range 2.6–17 × 106, 0.75–4.2 × 108 and 2.3–8.0 × 108 molec. cm−3, respectively. kOH′ ranged from 1.7 to 17.6 s−1, with a median value of 4.7 s−1. ICOZA data were split by wind direction to assess differences in the radical chemistry between air that had passed over the North Sea (NW–SE sectors) and that over major urban conurbations such as London (SW sector). A box model using the Master Chemical Mechanism (MCMv3.3.1) was in reasonable agreement with the OH measurements, but it overpredicted HO2 observations in NW–SE air in the afternoon by a factor of ∼ 2–3, although slightly better agreement was found for HO2 in SW air (factor of ∼ 1.4–2.0 underprediction). The box model severely underpredicted total RO2 observations in both NW–SE and SW air by factors of ∼ 8–9 on average. Measured radical and kOH′ levels and measurement–model ratios displayed strong dependences on NO mixing ratios, with the results suggesting that peroxy radical chemistry is not well understood under high-NOx conditions. The simultaneous measurement of OH, HO2, total RO2 and kOH′ was used to derive experimental (i.e. observationally determined) budgets for all radical species as well as total ROx (i.e. OH + HO2 + RO2). In NW–SE air, the ROx budget could be closed during the daytime within experimental uncertainty, but the rate of OH destruction exceeded the rate of OH production, and the rate of HO2 production greatly exceeded the rate of HO2 destruction, while the opposite was true for RO2. In SW air, the ROx budget analysis indicated missing daytime ROx sources, but the OH budget was balanced, and the same imbalances were found with the HO2 and RO2 budgets as in NW–SE air. For HO2 and RO2, the budget imbalances were most severe at high-NO mixing ratios, and the best agreement between HO2 and RO2 rates of production and destruction rates was found when the RO2 + NO rate coefficient was reduced by a factor of 5. A photostationary-steady-state (PSS) calculation underpredicted daytime OH in NW–SE air by ∼ 35 %, whereas agreement (∼ 15 %) was found within instrumental uncertainty (∼ 26 % at 2σ) in SW air. The rate of in situ ozone production (P(Ox)) was calculated from observations of ROx, NO and NO2 and compared to that calculated from MCM-modelled radical concentrations. The MCM-calculated P(Ox) significantly underpredicted the measurement-calculated P(Ox) in the morning, and the degree of underprediction was found to scale with NO.
A substantial proportion of patients with heart failure have preserved left ventricular ejection fraction (HF-PEF). Previous studies have reported mixed results whether survival is similar to those ...patients with heart failure and reduced EF (HF-REF).
We compared survival in patients with HF-PEF with that in patients with HF-REF in a meta-analysis using individual patient data. Preserved EF was defined as an EF ≥ 50%. The 31 studies included 41 972 patients: 10 347 with HF-PEF and 31 625 with HF-REF. Compared with patients with HF-REF, those with HF-PEF were older (mean age 71 vs. 66 years), were more often women (50 vs. 28%), and have a history of hypertension (51 vs. 41%). Ischaemic aetiology was less common (43 vs. 59%) in patients with HF-PEF. There were 121 95% confidence interval (CI): 117, 126 deaths per 1000 patient-years in those with HF-PEF and 141 (95% CI: 138, 144) deaths per 1000 patient-years in those with HF-REF. Patients with HF-PEF had lower mortality than those with HF-REF (adjusted for age, gender, aetiology, and history of hypertension, diabetes, and atrial fibrillation); hazard ratio 0.68 (95% CI: 0.64, 0.71). The risk of death did not increase notably until EF fell below 40%.
Patients with HF-PEF have a lower risk of death than patients with HF-REF, and this difference is seen regardless of age, gender, and aetiology of HF. However, absolute mortality is still high in patients with HF-PEF highlighting the need for a treatment to improve prognosis.
Background and Purpose
Epilepsy is the most prevalent neurological disease and is characterized by recurrent seizures. Here, we investigate (i) the anticonvulsant profiles of cannabis‐derived ...botanical drug substances (BDSs) rich in cannabidivarin (CBDV) and containing cannabidiol (CBD) in acute in vivo seizure models and (ii) the binding of CBDV BDSs and their components at cannabinoid CB1 receptors.
Experimental Approach
The anticonvulsant profiles of two CBDV BDSs (50–422 mg·kg−1) were evaluated in three animal models of acute seizure. Purified CBDV and CBD were also evaluated in an isobolographic study to evaluate potential pharmacological interactions. CBDV BDS effects on motor function were also investigated using static beam and grip strength assays. Binding of CBDV BDSs to cannabinoid CB1 receptors was evaluated using displacement binding assays.
Key Results
CBDV BDSs exerted significant anticonvulsant effects in the pentylenetetrazole (≥100 mg·kg−1) and audiogenic seizure models (≥87 mg·kg−1), and suppressed pilocarpine‐induced convulsions (≥100 mg·kg−1). The isobolographic study revealed that the anticonvulsant effects of purified CBDV and CBD were linearly additive when co‐administered. Some motor effects of CBDV BDSs were observed on static beam performance; no effects on grip strength were found. The Δ9‐tetrahydrocannabinol and Δ9‐tetrahydrocannabivarin content of CBDV BDS accounted for its greater affinity for CB1 cannabinoid receptors than purified CBDV.
Conclusions and Implications
CBDV BDSs exerted significant anticonvulsant effects in three models of seizure that were not mediated by the CB1 cannabinoid receptor and were of comparable efficacy with purified CBDV. These findings strongly support the further clinical development of CBDV BDSs for the treatment of epilepsy.
Background There is a genetic contribution to the risk of ventricular arrhythmias in survivors of acute coronary syndromes (ACS). We wished to explore the role of 33 candidate single nucleotide ...polymorphisms (SNPs) in prolonged repolarization and sudden death in patients surviving ACS. Methods A total of 2,139 patients (1680 white ethnicity) surviving an admission for ACS were enrolled in the prospective Coronary Disease Cohort Study. Extensive clinical, echocardiographic, and neurohormonal data were collected for 12 months, and clinical events were recorded for a median of 5 years. Each SNP was assessed for association with sudden cardiac death (SCD)/cardiac arrest (CA) and prolonged repolarization at 3 time-points: index admission, 1 month, and 12 months postdischarge. Results One hundred six SCD/CA events occurred during follow-up (6.3%). Three SNPs from 3 genes (rs17779747 KCNJ2 , rs876188 C14orf64 , rs3864180 GPC5 ) were significantly associated with SCD/CA in multivariable models (after correction for multiple testing); the minor allele of rs17779747 with a decreased risk (hazard ratio HR 0.68 per copy of the minor allele, 95% CI 0.50-0.92, P = .012), and rs876188 and rs386418 with an increased risk (HR 1.52 95% CI 1.10-2.09, P = .011 and HR 1.34 95% CI 1.04-1.82, P = .023, respectively). At 12 months postdischarge, rs10494366 and rs12143842 ( NOS1AP ) were significant predictors of prolonged repolarization (HR 1.32 95% CI 1.04-1.67, P = .022 and HR 1.30 95% CI 1.01-1.66, P = .038, respectively), but not at earlier time-points. Conclusion Three SNPs were associated with SCD/CA. Repolarization time was associated with variation in the NOS1AP gene. This study demonstrates a possible role for SNPs in risk stratification for arrhythmic events after ACS.
Shoot growth in wheat is sensitive to high soil strength, but as high strength and drying tend to occur together it has proved difficult to separate the effects of water stress and mechanical ...impedance. The results of two field experiments in 2003 and 2004, where soil strength was manipulated by compaction and irrigation, demonstrated that the yield of wheat (Triticum aestivum L.) was sensitive to physical stress in the root zone. We obtained linear relationships between yield and soil strength and between yield and accumulated soil moisture data (accumulation analogous to thermal time), with similar slopes for both seasons. We were unable to detect root-sourced signals of xylem-sap ABA concentration, despite changes in stomatal conductance. When mechanical impedance and matric potential were varied independently in controlled environments, the growth of wheat was sensitive to mechanical impedance, but not to small changes in matric potential. While the response of stomatal conductance to soil drying in the field could be interpreted as evidence of hydraulic signalling, we suggest that the role of high soil strength, in limiting growth rates on moderately dry soil, requires further research.
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