Perigenual anterior cingulate morphology covaries with perceived social standing

Low socioeconomic status (SES) increases the risk for developing psychiatric and chronic medical disorders. A stress-related pathway by which low SES may affect mental and physical health is through the perception of holding a low social standing, termed low subjective social status. This proposal implicates overlapping brain regions mediating stress reactivity and socioemotional behaviors as neuroanatomical substrates that could plausibly link subjective social status to health-related outcomes. In a test of this proposal, we used a computational structural neuroimaging method (voxel-based morphometry) in a healthy community sample to examine the relationships between reports of subjective social status and regional gray matter volume. Results showed that after accounting for potential demographic confounds, subclinical depressive symptoms, dispositional forms of negative emotionality and conventional indicators of SES, self-reports of low subjective social status uniquely covaried with reduced gray matter volume in the perigenual area of the anterior cingulate cortex (pACC)—a brain region involved in experiencing emotions and regulating behavioral and physiological reactivity to psychosocial stress. The pACC may represent a neuroanatomical substrate by which perceived social standing relates to mental and physical health

Circulating CD34+ Cell Count is Associated with Extent of Subclinical Atherosclerosis in Asymptomatic Amish Men, Independent of 10-Year Framingham Risk

Background Bone-marrow derived progenitor cells (PCs) may play a role in maintaining vascular health by actively repairing damaged endothelium. The purpose of this study in asymptomatic Old Order Amish men (n = 90) without hypertension or diabetes was to determine if PC count, as determined by CD34+ cell count in peripheral blood, was associated with 10-year risk of cardiovascular disease (CVD) and measures of subclinical atherosclerosis. Methods and Results CD34+ cell count by fluorescence-activated cell sorting, coronary artery calcification (CAC) by electron beam computed tomography, and CVD risk factors were obtained. Carotid intimal-medial thickness (CIMT) also was obtained in a subset of 57 men. After adjusting for 10-year CVD risk, CD34+ cell count was significantly associated with CAC quantity ( p =0.03) and CIMT ( p < 0.0001). A 1-unit increase in natural-log transformed CD34+ cell count was associated with an estimated 55.2% decrease (95% CI: −77.8% to −9.3%) in CAC quantity and an estimated 14.3% decrease (95% CI: −20.1% to −8.1%) in CIMT. Conclusions Increased CD34+ cell count was associated with a decrease in extent of subclinical atherosclerosis in multiple arterial beds, independent of 10-year CVD risk. Further investigations of associations of CD34+ cell count with subclinical atherosclerosis in asymptomatic individuals could provide mechanistic insights into the atherosclerotic process

A Hydrophobic Gate in an Ion Channel: The Closed State of the Nicotinic Acetylcholine Receptor

The nicotinic acetylcholine receptor (nAChR) is the prototypic member of the `Cys-loop' superfamily of ligand-gated ion channels which mediate synaptic neurotransmission, and whose other members include receptors for glycine, gamma-aminobutyric acid, and serotonin. Cryo-electron microscopy has yielded a three dimensional structure of the nAChR in its closed state. However, the exact nature and location of the channel gate remains uncertain. Although the transmembrane pore is constricted close to its center, it is not completely occluded. Rather, the pore has a central hydrophobic zone of radius about 3 A. Model calculations suggest that such a constriction may form a hydrophobic gate, preventing movement of ions through a channel. We present a detailed and quantitative simulation study of the hydrophobic gating model of the nicotinic receptor, in order to fully evaluate this hypothesis. We demonstrate that the hydrophobic constriction of the nAChR pore indeed forms a closed gate. Potential of mean force (PMF) calculations reveal that the constriction presents a barrier of height ca. 10 kT to the permeation of sodium ions, placing an upper bound on the closed channel conductance of 0.3 pS. Thus, a 3 A radius hydrophobic pore can form a functional barrier to the permeation of a 1 A radius Na+ ion. Using a united atom force field for the protein instead of an all atom one retains the qualitative features but results in differing conductances, showing that the PMF is sensitive to the detailed molecular interactions.Comment: Accepted by Physical Biology; includes a supplement and a supplementary mpeg movie can be found at http://sbcb.bioch.ox.ac.uk/oliver/download/Movies/watergate.mp

Does centrality in a cross-sectional network suggest intervention targets for social anxiety disorder?

Objective: Network analysis allows us to identify the most interconnected (i.e., central) symptoms, and multiple authors have suggested that these symptoms might be important treatment targets. This is because change in central symptoms (relative to others) should have greater impact on change in all other symptoms. It has been argued that networks derived from cross-sectional data may help identify such important symptoms. We tested this hypothesis in social anxiety disorder. Method: We first estimated a state-of-the-art regularized partial correlation network based on participants with social anxiety disorder (n = 910) to determine which symptoms were more central. Next, we tested whether change in these central symptoms were indeed more related to overall symptom change in a separate dataset of participants with social anxiety disorder who underwent a variety of treatments (n = 244). We also tested whether relatively superficial item properties (infrequency of endorsement and variance of items) might account for any effects shown for central symptoms. Results: Centrality indices successfully predicted how strongly changes in items correlated with change in the remainder of the items. Findings were limited to the measure used in the network and did not generalize to three other measures related to social anxiety severity. In contrast, infrequency of endorsement showed associations across all measures. Conclusions: The transfer of recently published results from cross-sectional network analyses to treatment data is unlikely to be straightforward. (PsycINFO Database Record (c) 2018 APA, all rights reserved)FSW – Publicaties zonder aanstelling Universiteit Leide

Pharmacometabolomics reveals that serotonin is implicated in aspirin response variability.

While aspirin is generally effective for prevention of cardiovascular disease, considerable variation in drug response exists, resulting in some individuals displaying high on-treatment platelet reactivity. We used pharmacometabolomics to define pathways implicated in variation of response to treatment. We profiled serum samples from healthy subjects pre- and postaspirin (14 days, 81 mg/day) using mass spectrometry. We established a strong signature of aspirin exposure independent of response (15/34 metabolites changed). In our discovery (N = 80) and replication (N = 125) cohorts, higher serotonin levels pre- and postaspirin correlated with high, postaspirin, collagen-induced platelet aggregation. In a third cohort, platelets from subjects with the highest levels of serotonin preaspirin retained higher reactivity after incubation with aspirin than platelets from subjects with the lowest serotonin levels preaspirin (72 ± 8 vs. 61 ± 11%, P = 0.02, N = 20). Finally, ex vivo, serotonin strongly increased platelet reactivity after platelet incubation with aspirin (+20%, P = 4.9 × 10(-4), N = 12). These results suggest that serotonin is implicated in aspirin response variability.Analytical BioScience

Multisite Investigation of Outcomes With Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention

OBJECTIVES: This multicenter pragmatic investigation assessed outcomes following clinical implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention (PCI). BACKGROUND: CYP2C19 loss-of-function alleles impair clopidogrel effectiveness after PCI. METHODS: After clinical genotyping, each institution recommended alternative antiplatelet therapy (prasugrel, ticagrelor) in PCI patients with a loss-of-function allele. Major adverse cardiovascular events (defined as myocardial infarction, stroke, or death) within 12 months of PCI were compared between patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy. Risk was also compared between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy. Cox regression was performed, adjusting for group differences with inverse probability of treatment weights. RESULTS: Among 1,815 patients, 572 (31.5%) had a loss-of-function allele. The risk for major adverse cardiovascular events was significantly higher in patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy (23.4 vs. 8.7 per 100 patient-years; adjusted hazard ratio: 2.26; 95% confidence interval: 1.18 to 4.32; p = 0.013). Similar results were observed among 1,210 patients with acute coronary syndromes at the time of PCI (adjusted hazard ratio: 2.87; 95% confidence interval: 1.35 to 6.09; p = 0.013). There was no difference in major adverse cardiovascular events between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy (adjusted hazard ratio: 1.14; 95% confidence interval: 0.69 to 1.88; p = 0.60). CONCLUSIONS: These data from real-world observations demonstrate a higher risk for cardiovascular events in patients with a CYP2C19 loss-of-function allele if clopidogrel versus alternative therapy is prescribed. A future randomized study of genotype-guided antiplatelet therapy may be of value

Space telescope and optical reverberation mapping project. IV. Anomalous behavior of the broad ultraviolet emission lines in NGC 5548

During an intensive Hubble Space Telescope (HST) Cosmic Origins Spectrograph (COS) UV monitoring campaign of the Seyfert 1 galaxy NGC 5548 performed from 2014 February to July, the normally highly correlated far UV continuum and broad emission line variations decorrelated for ∼60-70 days, starting ∼75 days after the first HST/COS observation. Following this anomalous state, the flux and variability of the broad emission lines returned to a more normal state. This transient behavior, characterized by significant deficits in flux and equivalent width of the strong broad UV emission lines, is the first of its kind to be unambiguously identified in an active galactic nucleus reverberation mapping campaign. The largest corresponding emission line flux deficits occurred for the high ionization, collisionally excited lines C iv and Si iv(+O iv]), and also He ii(+O iii]), while the anomaly in Lywas substantially smaller. This pattern of behavior indicates a depletion in the flux of photons with Eph > 54 eV relative to those near 13.6 eV. We suggest two plausible mechanisms for the observed behavior: (i) temporary obscuration of the ionizing continuum incident upon broad line region (BLR) clouds by a moving veil of material lying between the inner accretion disk and inner (BLR), perhaps resulting from an episodic ejection of material from the disk, or (ii) a temporary change in the intrinsic ionizing continuum spectral energy distribution resulting in a deficit of ionizing photons with energies >54 eV, possibly due to a transient restructuring of the Comptonizing atmosphere above the disk. Current evidence appears to favor the latter explanation.Publisher PDFPeer reviewe

Space Telescope and Optical Reverberation Mapping Project. VI. : reverberating disk models for NGC 5548

D.A.S. and K.D.H. acknowledge support from the UK Science and Technology Facilities Council through grant ST/K502339/1 and ST/J001651/1.We conduct a multiwavelength continuum variability study of the Seyfert 1 galaxy NGC 5548 to investigate the temperature structure of its accretion disk. The 19 overlapping continuum light curves (1158 Å to 9157 Å) combine simultaneous Hubble Space Telescope, Swift, and ground-based observations over a 180 day period from 2014 January to July. Light-curve variability is interpreted as the reverberation response of the accretion disk to irradiation by a central time-varying point source. Our model yields the disk inclination i = 36° ± 10°, temperature T1 =(44 ± 6) x 103 K at 1 light day from the black hole, and a temperature–radius slope (T α r-α) of α = 0.99 ± 0.03. We also infer the driving light curve and find that it correlates poorly with both the hard and soft X-ray light curves, suggesting that the X-rays alone may not drive the ultraviolet and optical variability over the observing period. We also decompose the light curves into bright, faint, and mean accretion-disk spectra. These spectra lie below that expected for a standard blackbody accretion disk accreting at L/LEdd=0.1.PostprintPeer reviewe

Space Telescope and Optical Reverberation Mapping Project.VI. Reverberating Disk Models for NGC 5548

We conduct a multiwavelength continuum variability study of the Seyfert 1 galaxy NGC 5548 to investigate the temperature structure of its accretion disk. The 19 overlapping continuum light curves ($1158\,\mathring{\rm A}$ to $9157\,\mathring{\rm A}$) combine simultaneous Hubble Space Telescope, Swift, and ground-based observations over a 180 day period from 2014 January to July. Light-curve variability is interpreted as the reverberation response of the accretion disk to irradiation by a central time-varying point source. Our model yields the disk inclination $i=36^\circ \pm 10^\circ$, temperature ${T}_{1}=(44\pm 6)\times {10}^{3}$ K at 1 light day from the black hole, and a temperature–radius slope ($T\propto {r}^{-\alpha }$) of $\alpha =0.99\pm 0.03$. We also infer the driving light curve and find that it correlates poorly with both the hard and soft X-ray light curves, suggesting that the X-rays alone may not drive the ultraviolet and optical variability over the observing period. We also decompose the light curves into bright, faint, and mean accretion-disk spectra. These spectra lie below that expected for a standard blackbody accretion disk accreting at $L/{L}_{\mathrm{Edd}}=0.1$.<br/