Improving Stellar and Planetary Parameters of Transiting Planet Systems: The Case of TrES-2

We report on a spectroscopic determination of the atmospheric parameters and chemical abundance of the parent star of the recently discovered transiting planet TrES-2. A detailed LTE analysis of a set of Fe I and Fe II lines from our Keck spectra yields T_(eff) = 5850 ± 50 K, log g = 4.4 ± 0.1, and [Fe/H] = -0.15 ± 0.10. Several independent checks (e.g., additional spectroscopy, line-depth ratios) confirm the reliability of our spectroscopic T_(eff) estimate. The mass and radius of the star, needed to determine the properties of the planet, are traditionally inferred by comparison with stellar evolution models using T_(eff) and some measure of the stellar luminosity, such as the spectroscopic surface gravity. We apply here a new method in which we use instead of log g the normalized separation a/R_* (related to the stellar density), directly measurabele from the light curves of transiting planets with much greater precision. With the a/R_* value from the light-curve analysis of Holman and coworkers and our T_(eff) estimate, we obtain M_* = 0.980 ± 0.062 M_☉ and R_* = 1.000^(+0.036)_(-0.033) R_☉, and an evolutionary age of 5.1^(+2.7)_(-2.3) Gyr, in good agreement with other constraints (Ca II H and K line cores, lithium abundance, and rotation). The new stellar parameters yield improved values for the planetary mass and radius of M_p = 1.198 ± 0.053 M_J and R_p = 1.220^(+0.045)_(-0.042) R_J, confirming that TrES-2 is the most massive among the currently known nearby (d ≲ 300 pc) transiting hot Jupiters. The surface gravity of the planet, log g_p = 3.299 ± 0.016, can be derived independently of the knowledge of the stellar parameters (i.e., directly from observations), and with a very high precision rivaling that of the best known double-lined eclipsing binaries

A Mendelian randomization study of the causal association between anxiety phenotypes and schizophrenia

Schizophrenia shows a genetic correlation with both anxiety disorder and neuroticism, a trait strongly associated with anxiety. However, genetic correlations do not discern causality from genetic confounding. We therefore aimed to investigate whether anxiety-related phenotypes lie on the causal pathway to schizophrenia using Mendelian randomization (MR). Four MR methods, each with different assumptions regarding instrument validity, were used to investigate casual associations of anxiety and neuroticism related phenotypes on schizophrenia, and vice versa: inverse variance weighted (IVW), weighted median, weighted mode, and, when appropriate, MR Egger regression. MR provided evidence of a causal effect of neuroticism on schizophrenia (IVW odds ratio [OR]: 1.33, 95% confidence interval [CI]: 1.12-1.59), but only weak evidence of a causal effect of anxiety on schizophrenia (IVW OR: 1.10, 95% CI: 1.01-1.19). There was also evidence of a causal association from schizophrenia liability to anxiety disorder (IVW OR: 1.28, 95% CI: 1.18-1.39) and worry (IVW beta: 0.05, 95% CI: 0.03-0.07), but effect estimates from schizophrenia to neuroticism were inconsistent in the main analysis. The evidence of neuroticism increasing schizophrenia risk provided by our results supports future efforts to evaluate neuroticism- or anxiety-based therapies to prevent onset of psychotic disorders

TrES-2: The First Transiting Planet in the Kepler Field

We announce the discovery of the second transiting hot Jupiter discovered by the Trans-atlantic Exoplanet Survey. The planet, which we dub TrES-2, orbits the nearby star GSC 03549-02811 every 2.47063 days. From high-resolution spectra, we determine that the star has T_eff = 5960 +/- 100 K and log(g) = 4.4 +/- 0.2, implying a spectral type of G0V and a mass of 1.08 +0.11/-0.05 M_sun. High-precision radial-velocity measurements confirm a sinusoidal variation with the period and phase predicted by the photometry, and rule out the presence of line-bisector variations that would indicate that the spectroscopic orbit is spurious. We estimate a planetary mass of 1.28 +0.09/-0.04 M_Jup. We model B, r, R, and I photometric timeseries of the 1.4%-deep transits and find a planetary radius of 1.24 +0.09/-0.06 R_Jup. This planet lies within the field of view of the NASA Kepler mission, ensuring that hundreds of upcoming transits will be monitored with exquisite precision and permitting a host of unprecedented investigations.Comment: Accepted for publication in ApJL. 15 pages, 2 figure

A New Spectroscopic and Photometric Analysis of the Transiting Planet Systems TrES-3 and TrES-4

We report new spectroscopic and photometric observations of the parent stars of the recently discovered transiting planets TrES-3 and TrES-4. A detailed abundance analysis based on high-resolution spectra yields [Fe/H] = –0.19 ± 0.08, T_(eff) = 5650 ± 75 K, and log g = 4.4 ± 0.1 for TrES-3, and [Fe/H] = +0.14 ± 0.09, T_(eff) = 6200 ± 75 K, and log g = 4.0 ± 0.1 for TrES-4. The accuracy of the effective temperatures is supported by a number of independent consistency checks. The spectroscopic orbital solution for TrES-3 is improved with our new radial velocity measurements of that system, as are the light-curve parameters for both systems based on newly acquired photometry for TrES-3 and a reanalysis of existing photometry for TrES-4. We have redetermined the stellar parameters taking advantage of the strong constraint provided by the light curves in the form of the normalized separation a/R_* (related to the stellar density) in conjunction with our new temperatures and metallicities. The masses and radii we derive are M_* = 0.928^(+0.028)_(–0.048) M_⊙, R_* = 0.829^(+0.015)_(–0.022) R_⊙, and M_* = 1.404^(+0.066)_(–0.134) M_⊙, R_* = 1.846^(+0.096)_(–0.087) R_⊙ for TrES-3 and TrES-4, respectively. With these revised stellar parameters, we obtain improved values for the planetary masses and radii. We find M_p = 1.910^(+0.075)_(–0.080) M_(Jup), R_p = 1.336^(+0.031)_(–0.036) R_(Jup) for TrES-3, and M_p = 0.925 ± 0.082 M_(Jup), R_p = 1.783^(+0.093)_(–0.086) R_(Jup) for TrES-4. We confirm TrES-4 as the planet with the largest radius among the currently known transiting hot Jupiters

PP2A inhibition overcomes acquired resistance to HER2 targeted therapy

Background: HER2 targeted therapies including trastuzumab and more recently lapatinib have significantly improved the prognosis for HER2 positive breast cancer patients. However, resistance to these agents is a significant clinical problem. Although several mechanisms have been proposed for resistance to trastuzumab, the mechanisms of lapatinib resistance remain largely unknown. In this study we generated new models of acquired resistance to HER2 targeted therapy and investigated mechanisms of resistance using phospho-proteomic profiling. Results: Long-term continuous exposure of SKBR3 cells to low dose lapatinib established a cell line, SKBR3-L, which is resistant to both lapatinib and trastuzumab. Phospho-proteomic profiling and immunoblotting revealed significant alterations in phospho-proteins involved in key signaling pathways and molecular events. In particular, phosphorylation of eukaryotic elongation factor 2 (eEF2), which inactivates eEF2, was significantly decreased in SKBR3-L cells compared to the parental SKBR3 cells. SKBR3-L cells exhibited significantly increased activity of protein phosphatase 2A (PP2A), a phosphatase that dephosphorylates eEF2. SKBR3-L cells showed increased sensitivity to PP2A inhibition, with okadaic acid, compared to SKBR3 cells. PP2A inhibition significantly enhanced response to lapatinib in both the SKBR3 and SKBR3-L cells. Furthermore, treatment of SKBR3 parental cells with the PP2A activator, FTY720, decreased sensitivity to lapatinib. The alteration in eEF2 phosphorylation, PP2A activity and sensitivity to okadaic acid were also observed in a second HER2 positive cell line model of acquired lapatinib resistance, HCC1954-L. Conclusions: Our data suggests that decreased eEF2 phosphorylation, mediated by increased PP2A activity, contributes to resistance to HER2 inhibition and may provide novel targets for therapeutic intervention in HER2 positive breast cancer which is resistant to HER2 targeted therapies

Associations between schizophrenia genetic risk, anxiety disorders and manic/hypomanic episode in a longitudinal population cohort study.

BACKGROUND: Studies involving clinically recruited samples show that genetic liability to schizophrenia overlaps with that for several psychiatric disorders including bipolar disorder, major depression and, in a population study, anxiety disorder and negative symptoms in adolescence.AimsWe examined whether, at a population level, association between schizophrenia liability and anxiety disorders continues into adulthood, for specific anxiety disorders and as a group. We explored in an epidemiologically based cohort the nature of adult psychopathology sharing liability to schizophrenia. METHOD: Schizophrenia polygenic risk scores (PRSs) were calculated for 590 European-descent individuals from the Christchurch Health and Development Study. Logistic regression was used to examine associations between schizophrenia PRS and four anxiety disorders (social phobia, specific phobia, panic disorder and generalised anxiety disorder), schizophrenia/schizophreniform disorder, manic/hypomanic episode, alcohol dependence, major depression, and - using linear regression - total number of anxiety disorders. A novel population-level association with hypomania was tested in a UK birth cohort (Avon Longitudinal Study of Parents and Children). RESULTS: Schizophrenia PRS was associated with total number of anxiety disorders and with generalised anxiety disorder and panic disorder. We show a novel population-level association between schizophrenia PRS and manic/hypomanic episode. CONCLUSIONS: The relationship between schizophrenia liability and anxiety disorders is not restricted to psychopathology in adolescence but is present in adulthood and specifically linked to generalised anxiety disorder and panic disorder. We suggest that the association between schizophrenia liability and hypomanic/manic episodes found in clinical samples may not be due to bias.Declarations of interestNone

Changes to the Oligosaccharide Profile of Bovine Milk at the Onset of Lactation

peer-reviewedNumerous bioactive components exist in human milk including free oligosaccharides, which represent some of the most important, and provide numerous health benefits to the neonate. Considering the demonstrated value of these compounds, much interest lies in characterising structurally similar oligosaccharides in the dairy industry. In this study, the impacts of days post-parturition and parity of the cows on the oligosaccharide and lactose profiles of their milk were evaluated. Colostrum and milk samples were obtained from 18 cows 1–5 days after parturition. Three distinct phases were identified using multivariate analysis: colostrum (day 0), transitional milk (days 1–2) and mature milk (days 3–5). LS-tetrasaccharide c, lacto-N-neotetraose, disialyllacto-N-tetraose, 3’-sial-N-acetyllactosamine, 3’-sialyllactose, lacto-N-neohexaose and disialyllactose were found to be highly affiliated with colostrum. Notably, levels of lactose were at their lowest concentration in the colostrum and substantially increased 1-day post-parturition. The cow’s parity was also shown to have a significant effect on the oligosaccharide profile, with first lactation cows containing more disialyllacto-N-tetraose, 6’-sialyllactose and LS-tetrasaccharide compared to cows in their second or third parity. Overall, this study identifies key changes in oligosaccharide and lactose content that clearly distinguish colostrum from transitional and mature milk and may facilitate the collection of specific streams with divergent biological functions

Evolution of the bovine milk fatty acid profile – From colostrum to milk five days post parturition

peer-reviewedMilk was collected from each of 18 cows (presenting an even spread of 1st, 2nd and 3rd lactation): colostrum on the day of calving and subsequent morning milk 1–5 days post parturition. Days post parturition significantly affected the fatty acid profile of colostrum and transition milk samples. The colostrum fatty acid profile was distinctly different from that of mature milk, with significantly higher levels of polyunsaturated and saturated fatty acids. Parity of the cow had a significant effect on the fatty acid profile of colostrum and transition milk samples; conjugated linoleic acid was significantly higher in cows entering their 1st lactation than in those in their 3rd lactation, while multiparous cows produced significantly higher concentrations of C16:0. The changing composition of the fatty acid profile can be classed into three distinct phases: colostrum (D0), transition milk (D1 and D2 post parturition) and mature milk (D3–D5).Teagasc, the Irish Agriculture and Food Development Authority

Pharmacogenomic variants and drug interactions identified through the genetic analysis of clozapine metabolism

Objective: Clozapine is the only effective medication for treatment-resistant schizophrenia, but its worldwide use is still limited because of its complex titration protocols. While the discovery of pharmacogenomic variants of clozapine metabolism may improve clinical management, no robust findings have yet been reported. This study is the first to adopt the framework of genome-wide association studies (GWASs) to discover genetic markers of clozapine plasma concentrations in a large sample of patients with treatment-resistant schizophrenia. Methods: The authors used mixed-model regression to combine data from multiple assays of clozapine metabolite plasma concentrations from a clozapine monitoring service and carried out a genome-wide analysis of clozapine, norclozapine, and their ratio on 10,353 assays from 2,989 individuals. These analyses were adjusted for demographic factors known to influence clozapine metabolism, although it was not possible to adjust for all potential mediators given the available data. GWAS results were used to pinpoint specific enzymes and metabolic pathways and compounds that might interact with clozapine pharmacokinetics. Results: The authors identified four distinct genome-wide significant loci that harbor common variants affecting the metabolism of clozapine or its metabolites. Detailed examination pointed to coding and regulatory variants at several CYP* and UGT* genes as well as corroborative evidence for interactions between the metabolism of clozapine, coffee, and tobacco. Individual effects of single single-nucleotide polymorphisms (SNPs) fine-mapped from these loci were large, such as the minor allele of rs2472297, which was associated with a reduction in clozapine concentrations roughly equivalent to a decrease of 50 mg/day in clozapine dosage. On their own, these single SNPs explained from 1.15% to 9.48% of the variance in the plasma concentration data. Conclusions: Common genetic variants with large effects on clozapine metabolism exist and can be found via genome-wide approaches. Their identification opens the way for clinical studies assessing the use of pharmacogenomics in the clinical management of patients with treatment-resistant schizophrenia