HPA axis related genes and response to psychological therapies: genetics and epigenetics

Background Hypothalamic–pituitary–adrenal (HPA) axis functioning has been implicated in the development of stress-related psychiatric diagnoses and response to adverse life experiences. This study aimed to investigate the association between genetic and epigenetics in HPA axis and response to cognitive behavior therapy (CBT). Methods Children with anxiety disorders were recruited into the Genes for Treatment project (GxT, N = 1,152). Polymorphisms of FKBP5 and GR were analyzed for association with response to CBT. Percentage DNA methylation at the FKBP5 and GR promoter regions was measured before and after CBT in a subset (n = 98). Linear mixed effect models were used to investigate the relationship between genotype, DNA methylation, and change in primary anxiety disorder severity (treatment response). Results Treatment response was not associated with FKBP5 and GR polymorphisms, or pretreatment percentage DNA methylation. However, change in FKBP5 DNA methylation was nominally significantly associated with treatment response. Participants who demonstrated the greatest reduction in severity decreased in percentage DNA methylation during treatment, whereas those with little/no reduction in severity increased in percentage DNA methylation. This effect was driven by those with one or more FKBP5 risk alleles, with no association seen in those with no FKBP5 risk alleles. No significant association was found between GR methylation and response. Conclusions Allele-specific change in FKBP5 methylation was associated with treatment response. This is the largest study to date investigating the role of HPA axis related genes in response to a psychological therapy. Furthermore, this is the first study to demonstrate that DNA methylation changes may be associated with response to psychological therapies in a genotype-dependent manner

Testing the Asteroseismic Mass Scale Using Metal-Poor Stars Characterized with APOGEE and Kepler

Fundamental stellar properties, such as mass, radius, and age, can be inferred using asteroseismology. Cool stars with convective envelopes have turbulent motions that can stochastically drive and damp pulsations. The properties of the oscillation frequency power spectrum can be tied to mass and radius through solar-scaled asteroseismic relations. Stellar properties derived using these scaling relations need verification over a range of metallicities. Because the age and mass of halo stars are well-constrained by astrophysical priors, they provide an independent, empirical check on asteroseismic mass estimates in the low-metallicity regime. We identify nine metal-poor red giants (including six stars that are kinematically associated with the halo) from a sample observed by both the Kepler space telescope and the Sloan Digital Sky Survey-III APOGEE spectroscopic survey. We compare masses inferred using asteroseismology to those expected for halo and thick-disk stars. Although our sample is small, standard scaling relations, combined with asteroseismic parameters from the APOKASC Catalog, produce masses that are systematically higher (=0.17+/-0.05 Msun) than astrophysical expectations. The magnitude of the mass discrepancy is reduced by known theoretical corrections to the measured large frequency separation scaling relationship. Using alternative methods for measuring asteroseismic parameters induces systematic shifts at the 0.04 Msun level. We also compare published asteroseismic analyses with scaling relationship masses to examine the impact of using the frequency of maximum power as a constraint. Upcoming APOKASC observations will provide a larger sample of ~100 metal-poor stars, important for detailed asteroseismic characterization of Galactic stellar populations.Comment: 4 figures; 1 table. Accepted to ApJ

Rough titanium alloys regulate osteoblast production of angiogenic factors

Multiple biomaterials are clinically available to spine surgeons for performing interbody fusion. Poly-ether-ether-ketone (PEEK) is used frequently for lumbar spine interbody fusion, but alternative materials are also used, including titanium (Ti) alloys. Previously, we showed that osteoblasts exhibit a more differentiated phenotype when grown on machined or grit-blasted titanium aluminum vanadium (Ti6Al4V) alloys with micron-scale roughened surfaces than when grown on smoother Ti6Al4V surfaces or on tissue culture polystyrene (TCPS). We hypothesized that osteoblasts cultured on rough Ti alloy substrates would present a more mature osteoblast phenotype than cells cultured on PEEK, suggesting that textured Ti6Al4V implants may provide a more osteogenic surface for interbody fusion devices. PURPOSE: The aim of the present study was to compare osteoblast response to smooth Ti6Al4V (sTiAlV) and roughened Ti6Al4V (rTiAlV) with their response to PEEK with respect to differentiation and production of factors associated with osteogenesis. STUDY DESIGN: This in vitro study compared the phenotype of human MG63 osteoblast-like cells cultured on PEEK, sTiAlV, or rTiAlV surfaces and their production of bone morphogenetic proteins (BMPs). METHODS: Surface properties of PEEK, sTiAlV, and rTiAlV discs were determined. Human MG63 cells were grown on TCPS and the discs. Confluent cultures were harvested, and cell number, alkaline phosphatase–specific activity, and osteocalcin were measured as indicators of osteoblast maturation. Expression of messenger RNA (mRNA) for BMP2 and BMP4 was measuredMultiple biomaterials are clinically available to spine surgeons for performing interbody fusion. Poly-ether-ether-ketone (PEEK) is used frequently for lumbar spine interbody fusion, but alternative materials are also used, including titanium (Ti) alloys. Previously, we showed that osteoblasts exhibit a more differentiated phenotype when grown on machined or grit-blasted titanium aluminum vanadium (Ti6Al4V) alloys with micron-scale roughened surfaces than when grown on smoother Ti6Al4V surfaces or on tissue culture polystyrene (TCPS). We hypothesized that osteoblasts cultured on rough Ti alloy substrates would present a more mature osteoblast phenotype than cells cultured on PEEK, suggesting that textured Ti6Al4V implants may provide a more osteogenic surface for interbody fusion devices. PURPOSE: The aim of the present study was to compare osteoblast response to smooth Ti6Al4V (sTiAlV) and roughened Ti6Al4V (rTiAlV) with their response to PEEK with respect to differentiation and production of factors associated with osteogenesis. STUDY DESIGN: This in vitro study compared the phenotype of human MG63 osteoblast-like cells cultured on PEEK, sTiAlV, or rTiAlV surfaces and their production of bone morphogenetic proteins (BMPs). METHODS: Surface properties of PEEK, sTiAlV, and rTiAlV discs were determined. Human MG63 cells were grown on TCPS and the discs. Confluent cultures were harvested, and cell number, alkaline phosphatase–specific activity, and osteocalcin were measured as indicators of osteoblast maturation. Expression of messenger RNA (mRNA) for BMP2 and BMP4 was measure

Human Impacts on Forest Biodiversity in Protected Walnut-Fruit Forests in Kyrgyzstan

We used a spatially explicit model of forest dynamics, supported by empirical field data and socioeconomic data, to examine the impacts of human disturbances on a protected forest landscape in Kyrgyzstan. Local use of 27 fruit and nut species was recorded and modeled. Results indicated that in the presence of fuelwood cutting with or without grazing, species of high socioeconomic impor- tance such as Juglans regia, Malus spp., and Armeniaca vulgaris were largely eliminated from the landscape after 50–150 yr. In the absence of disturbance or in the presence of grazing only, decline of these species occurred at a much lower rate, owing to competi- tive interactions between tree species. This suggests that the current intensity of fuelwood harvesting is not sustainable. Conversely, cur- rent grazing intensities were found to have relatively little impact on forest structure and composition, and could potentially play a positive role in supporting regeneration of tree species. These results indicate that both positive and negative impacts on biodiversity can arise from human populations living within a protected area. Potentially, these could be reconciled through the development of participatory approaches to conservation management within this reserve, to ensure the maintenance of its high conservation value while meeting human needs

The Sloan Digital Sky Survey Reverberation Mapping Project : UV–optical accretion disk measurements with the Hubble Space Telescope

Funding: Y.H., J.R.T., and G.F.A. acknowledge support from NASA grants HST-GO-15650 and 18-2ADAP18-0177 and NSF grant CAREER-1945546. K.H. acknowledges support from STFC grant ST/R000824/1. C.J.G. acknowledges support from NSF grant AST-2009949. Y.S. acknowledges support from NSF grants AST-1715579 and AST-2009947. P.H. acknowledges support from the Natural Sciences and Engineering Research Council of Canada (NSERC), funding reference number 2017-05983. L.C.H. was supported by the National Science Foundation of China (11721303, 11991052) and the National Key R&D Program of China (2016YFA0400702).We present accretion-disk structure measurements from UV–optical reverberation mapping (RM) observations of a sample of eight quasars at 0.24 < z < 0.85. Ultraviolet photometry comes from two cycles of Hubble Space Telescope monitoring, accompanied by multiband optical monitoring by the Las Cumbres Observatory network and Liverpool Telescopes. The targets were selected from the Sloan Digital Sky Survey Reverberation Mapping project sample with reliable black hole mass measurements from Hβ RM results. We measure significant lags between the UV and various optical griz bands using JAVELIN and CREAM methods. We use the significant lag results from both methods to fit the accretion-disk structure using a Markov Chain Monte Carlo approach. We study the accretion disk as a function of disk normalization, temperature scaling, and efficiency. We find direct evidence for diffuse nebular emission from Balmer and Fe ii lines over discrete wavelength ranges. We also find that our best-fit disk color profile is broadly consistent with the Shakura & Sunyaev disk model. We compare our UV–optical lags to the disk sizes inferred from optical–optical lags of the same quasars and find that our results are consistent with these quasars being drawn from a limited high-lag subset of the broader population. Our results are therefore broadly consistent with models that suggest longer disk lags in a subset of quasars, for example, due to a nonzero size of the ionizing corona and/or magnetic heating contributing to the disk response.Publisher PDFPeer reviewe

The Sloan Digital Sky Survey Reverberation Mapping Project : the MBH–host relations at 0.2 ∼< z ∼< 0.6 from reverberation mapping and Hubble Space Telescope imaging

Funding: Y.S. acknowledges support from an Alfred P. Sloan Research Fellowship and NSF grants AST-1715579, AST-2009947. Support for Program number HST-GO-14109 was provided through a grant from the STScI under NASA contract NAS5-26555. L.C.H. was supported by the National Key R&D Program of China (2016YFA0400702) and the National Science Foundation of China (11721303, 11991052). E.D.B. is supported by Padua University grants DOR1715817/17, DOR1885254/18, and DOR1935272/19 and by MIUR grant PRIN 201720173ML3WW_001. J.V.H.S.and K.H. acknowledge funds from a Science and Technology Facilities Council grant ST/R000824/1.We present the results of a pilot Hubble Space Telescope (HST) imaging study of the host galaxies of ten quasars from the Sloan Digital Sky Survey Reverberation Mapping (SDSS-RM) project. Probing more than an order of magnitude in BH and stellar masses, our sample is the first statistical sample to study the BH-host correlations beyond z>0.3 with reliable BH masses from reverberation mapping rather than from single-epoch spectroscopy. We perform image decomposition in two HST bands (UVIS-F606W and IR-F110W) to measure host colors and estimate stellar masses using empirical relations between broad-band colors and the mass-to-light ratio. The stellar masses of our targets are mostly dominated by a bulge component. The BH masses and stellar masses of our sample broadly follow the same correlations found for local RM AGN and quiescent bulge-dominant galaxies, with no strong evidence of evolution in the MBH-M*bulge relation to z~0.6. We further compare the host light fraction from HST imaging decomposition to that estimated from spectral decomposition. We found a good correlation between the host fractions derived with both methods. However, the host fraction derived from spectral decomposition is systematically smaller than that from imaging decomposition by ~30%, indicating different systematics in both approaches. This study paves the way for upcoming more ambitious host galaxy studies of quasars with direct RM-based BH masses at high redshift.PostprintPeer reviewe

Genetic variation in the endocannabinoid system and response to cognitive behavioural therapy for child anxiety disorders

Extinction learning is an important mechanism in the successful psychological treatment of anxiety. Individual differences in response and relapse following Cognitive Behavior Therapy may in part be explained by variability in the ease with which fears are extinguished or the vulnerability of these fears to re-emerge. Given the role of the endocannabinoid system in fear extinction, this study investigates whether genetic variation in the endocannabinoid system explains individual differences in response to CBT. Children (N = 1,309) with a primary anxiety disorder diagnosis were recruited. We investigated the relationship between variation in the CNR1, CNR2, and FAAH genes and change in primary anxiety disorder severity between pre- and post-treatment and during the follow-up period in the full sample and a subset with fear-based anxiety disorder diagnoses. Change in symptom severity during active treatment was nominally associated (P < 0.05) with two SNPs. During the follow-up period, five SNPs were nominally associated with a poorer treatment response (rs806365 [CNR1]; rs2501431 [CNR2]; rs2070956 [CNR2]; rs7769940 [CNR1]; rs2209172 [FAAH]) and one with a more favorable response (rs6928813 [CNR1]). Within the fear-based subset, the effect of rs806365 survived multiple testing corrections (P < 0.0016). We found very limited evidence for an association between variants in endocannabinoid system genes and treatment response once multiple testing corrections were applied. Larger, more homogenous cohorts are needed to allow the identification of variants of small but statistically significant effect and to estimate effect sizes for these variants with greater precision in order to determine their potential clinical utility

Simultaneous quantification of 12 different nucleotides and nucleosides released from renal epithelium and in human urine samples using ion-pair reversed-phase HPLC

Nucleotides and nucleosides are not only involved in cellular metabolism but also act extracellularly via P1 and P2 receptors, to elicit a wide variety of physiological and pathophysiological responses through paracrine and autocrine signalling pathways. For the first time, we have used an ion-pair reversed-phase high-performance liquid chromatography ultraviolet (UV)-coupled method to rapidly and simultaneously quantify 12 different nucleotides and nucleosides (adenosine triphosphate, adenosine diphosphate, adenosine monophosphate, adenosine, uridine triphosphate, uridine diphosphate, uridine monophosphate, uridine, guanosine triphosphate, guanosine diphosphate, guanosine monophosphate, guanosine): (1) released from a mouse renal cell line (M1 cortical collecting duct) and (2) in human biological samples (i.e., urine). To facilitate analysis of urine samples, a solid-phase extraction step was incorporated (overall recovery rate ? 98 %). All samples were analyzed following injection (100 ?l) into a Synergi Polar-RP 80 Å (250 × 4.6 mm) reversed-phase column with a particle size of 10 ?m, protected with a guard column. A gradient elution profile was run with a mobile phase (phosphate buffer plus ion-pairing agent tetrabutylammonium hydrogen sulfate; pH 6) in 2-30 % acetonitrile (v/v) for 35 min (including equilibration time) at 1 ml min(-1) flow rate. Eluted compounds were detected by UV absorbance at 254 nm and quantified using standard curves for nucleotide and nucleoside mixtures of known concentration. Following validation (specificity, linearity, limits of detection and quantitation, system precision, accuracy, and intermediate precision parameters), this protocol was successfully and reproducibly used to quantify picomolar to nanomolar concentrations of nucleosides and nucleotides in isotonic and hypotonic cell buffers that transiently bathed M1 cells, and urine samples from normal subjects and overactive bladder patients

The Sloan Digital Sky Survey Reverberation Mapping Project : how broad emission line widths change when luminosity changes

Funding: National Science Foundation of China (11721303, 11890693, 11991052) and the National Key R&D Program of China (2016YFA0400702, 2016YFA0400703). YS acknowledges support from an Alfred P. Sloan Research Fellowship and NSF grant AST-1715579. CJG, WNB, JRT, and DPS acknowledge support from NSF grants AST-1517113 and AST-1516784. KH acknowledges support from STFC grant ST/R000824/1. PBH acknowledges support from NSERC grant 2017-05983. YH acknowledges support from NASA grant HST-GO-15650.Quasar broad emission lines are largely powered by photoionization from the accretion continuum. Increased central luminosity will enhance line emissivity in more distant clouds, leading to increased average distance of the broad-line-emitting clouds and decreased averaged line width, known as the broad-line region (BLR) "breathing". However, different lines breathe differently, and some high-ionization lines, such as C IV, can even show "anti-breathing" where the line broadens when luminosity increases. Using multi-year photometric and spectroscopic monitoring data from the Sloan Digital Sky Survey Reverberation Mapping project, we quantify the breathing effect (Δlog W=αΔlog L) of broad Hα, Hβ, Mg II, C IV,and C III] for statistical quasar samples over z≈0.1−2.5. We found that Hβ displays the most consistent normal breathing expected from the virial relation (α∼−0.25), Mg II and Hα on average show no breathing (α∼0), and C IV (and similarly C III] and Si IV mostly shows anti-breathing (α>0). The anti-breathing of C IV can be well understood by the presence of a non-varying core component in addition to a reverberating broad-base component, consistent with earlier findings. The deviation from canonical breathing introduces extra scatter (aluminosity-dependent bias) in single-epoch virial BH mass estimates due to intrinsic quasar variability, which underlies the long argued caveats of C IV single-epoch masses. Using the line dispersion instead of FWHM leads to less, albeit still substantial, deviations from canonical breathing in most cases. Our results strengthen the need for reverberation mapping to provide reliable quasar BH masses, and quantify the level of variability-induced bias in single-epoch BH masses based on various lines.PostprintPeer reviewe

Sensorimotor Plasticity after Music-Supported Therapy in Chronic Stroke Patients Revealed by Transcranial Magnetic Stimulation

BACKGROUND: Several recently developed therapies targeting motor disabilities in stroke sufferers have shown to be more effective than standard neurorehabilitation approaches. In this context, several basic studies demonstrated that music training produces rapid neuroplastic changes in motor-related brain areas. Music-supported therapy has been recently developed as a new motor rehabilitation intervention. METHODS AND RESULTS: In order to explore the plasticity effects of music-supported therapy, this therapeutic intervention was applied to twenty chronic stroke patients. Before and after the music-supported therapy, transcranial magnetic stimulation was applied for the assessment of excitability changes in the motor cortex and a 3D movement analyzer was used for the assessment of motor performance parameters such as velocity, acceleration and smoothness in a set of diadochokinetic movement tasks. Our results suggest that the music-supported therapy produces changes in cortical plasticity leading the improvement of the subjects' motor performance. CONCLUSION: Our findings represent the first evidence of the neurophysiological changes induced by this therapy in chronic stroke patients, and their link with the amelioration of motor performance. Further studies are needed to confirm our observations