The topography of transmembrane segment six is altered during the catalytic cycle of P-glycoprotein

Structural evidence has demonstrated that P-glycoprotein (P-gp) undergoes considerable conformational changes during catalysis, and these alterations are important in drug interaction. Knowledge of which regions in P-gp undergo conformational alterations will provide vital information to elucidate the locations of drug binding sites and the mechanism of coupling. A number of investigations have implicated transmembrane segment six (TM6) in drug-P-gp interactions, and a cysteine-scanning mutagenesis approach was directed to this segment. Introduction of cysteine residues into TM6 did not disturb basal or drug-stimulated ATPase activity per se. Under basal conditions the hydrophobic probe coumarin maleimide readily labeled all introduced cysteine residues, whereas the hydrophilic fluorescein maleimide only labeled residue Cys-343. The amphiphilic BODIPY-maleimide displayed a more complex labeling profile. The extent of labeling with coumarin maleimide did not vary during the catalytic cycle, whereas fluorescein maleimide labeling of F343C was lost after nucleotide binding or hydrolysis. BODIPY-maleimide labeling was markedly altered during the catalytic cycle and indicated that the adenosine 5'-(beta,gamma-imino)triphosphate-bound and ADP/vanadate-trapped intermediates were conformationally distinct. Our data are reconciled with a recent atomic scale model of P-gp and are consistent with a tilting of TM6 in response to nucleotide binding and ATP hydrolysis

The Growth of Massive Galaxies Since z=2

We study the growth of massive galaxies from z=2 to the present using data from the NEWFIRM Medium Band Survey. The sample is selected at a constant number density of n=2x10^-4 Mpc^-3, so that galaxies at different epochs can be compared in a meaningful way. We show that the stellar mass of galaxies at this number density has increased by a factor of ~2 since z=2, following the relation log(M)=11.45-0.15z. In order to determine at what physical radii this mass growth occurred we construct very deep stacked rest-frame R-band images at redshifts z=0.6, 1.1, 1.6, and 2.0. These image stacks of typically 70-80 galaxies enable us to characterize the stellar distribution to surface brightness limits of ~28.5 mag/arcsec^2. We find that massive galaxies gradually built up their outer regions over the past 10 Gyr. The mass within a radius of r=5 kpc is nearly constant with redshift whereas the mass at 5-75 kpc has increased by a factor of ~4 since z=2. Parameterizing the surface brightness profiles we find that the effective radius and Sersic n parameter evolve as r_e~(1+z)^-1.3 and n~(1+z)^-1.0 respectively. The data demonstrate that massive galaxies have grown mostly inside-out, assembling their extended stellar halos around compact, dense cores with possibly exponential radial density distributions. Comparing the observed mass evolution to the average star formation rates of the galaxies we find that the growth is likely dominated by mergers, as in-situ star formation can only account for ~20% of the mass build-up from z=2 to z=0. The main uncertainties in this study are possible redshift-dependent systematic errors in the total stellar masses and the conversion from light-weighted to mass-weighted radial profiles.Comment: Accepted for publication in the Astrophysical Journal. 26 pages, 13 figures in main tex

Expensive Egos: Narcissistic Males Have Higher Cortisol

Background: Narcissism is characterized by grandiosity, low empathy, and entitlement. There has been limited research regarding the hormonal correlates of narcissism, despite the potential health implications. This study examined the role of participant narcissism and sex on basal cortisol concentrations in an undergraduate population. Methods and Findings: Participants were 106 undergraduate students (79 females, 27 males, mean age 20.1 years) from one Midwestern and one Southwestern American university. Narcissism was assessed using the Narcissistic Personality Inventory, and basal cortisol concentrations were collected from saliva samples in a laboratory setting. Regression analyses examined the effect of narcissism and sex on cortisol (log). There were no sex differences in basal cortisol, F(1,97) =.20, p =.65, and narcissism scores, F(1,97) =.00, p =.99. Stepwise linear regression models of sex and narcissism and their interaction predicting cortisol concentrations showed no main effects when including covariates, but a significant interaction, b =.27, p =.04. Narcissism was not related to cortisol in females, but significantly predicted cortisol in males. Examining the effect of unhealthy versus healthy narcissism on cortisol found that unhealthy narcissism was marginally related to cortisol in females, b =.27, p =.06, but significantly predicted higher basal cortisol in males, b =.72, p =.01, even when controlling for potential confounds. No relationship was found between sex, narcissism, or their interaction on selfreported stress

Does inequality erode generalized trust? Evidence from Romanian youths

Generalized trust is a critical component of liberal democratic citizenship. We evaluate the extent to which exposure to socioeconomic inequality erodes trust among Romanian youths. Using national survey data of Romanian eighth-grade and high school students, we evaluate this effect as a product of socioeconomic diversity within the classroom, controlling for the social status of the students as well as socioeconomic inequality within the community where the school is located. Our analysis shows that generalized trust is higher for students in higher grades. However, despite this maturing effect, students exposed to greater levels of socioeconomic diversity have significantly lower levels of trust. The effect is particularly acute for students in the ninth grade. This finding holds when controlling for socioeconomic diversity and polarization in the community. The result reinforces the idea that generalized trust develops early in one’s life and is quite stable, although a major life transformation, such as entering high school, may alter trust depending on the social context

Homodyne-based quantum random number generator at 2.9 Gbps secure against quantum side-information

Quantum random number generators promise perfectly unpredictable random numbers. A popular approach to quantum random number generation is homodyne measurements of the vacuum state, the ground state of the electro-magnetic field. Here we experimentally implement such a quantum random number generator, and derive a security proof that considers quantum side-information instead of classical side-information only. Based on the assumptions of Gaussianity and stationarity of noise processes, our security analysis furthermore includes correlations between consecutive measurement outcomes due to finite detection bandwidth, as well as analog-to-digital converter imperfections. We characterize our experimental realization by bounding measured parameters of the stochastic model determining the min-entropy of the system’s measurement outcomes, and we demonstrate a real-time generation rate of 2.9 Gbit/s. Our generator follows a trusted, device-dependent, approach. By treating side-information quantum mechanically an important restriction on adversaries is removed, which usually was reserved to semi-device-independent and device-independent schemes

The NANOGrav 15-year Data Set: Search for Anisotropy in the Gravitational-Wave Background

The North American Nanohertz Observatory for Gravitational Waves (NANOGrav) has reported evidence for the presence of an isotropic nanohertz gravitational wave background (GWB) in its 15 yr dataset. However, if the GWB is produced by a population of inspiraling supermassive black hole binary (SMBHB) systems, then the background is predicted to be anisotropic, depending on the distribution of these systems in the local Universe and the statistical properties of the SMBHB population. In this work, we search for anisotropy in the GWB using multiple methods and bases to describe the distribution of the GWB power on the sky. We do not find significant evidence of anisotropy, and place a Bayesian $95\%$ upper limit on the level of broadband anisotropy such that $(C_{l>0} / C_{l=0}) < 20\%$. We also derive conservative estimates on the anisotropy expected from a random distribution of SMBHB systems using astrophysical simulations conditioned on the isotropic GWB inferred in the 15-yr dataset, and show that this dataset has sufficient sensitivity to probe a large fraction of the predicted level of anisotropy. We end by highlighting the opportunities and challenges in searching for anisotropy in pulsar timing array data.Comment: 19 pages, 11 figures; submitted to Astrophysical Journal Letters as part of Focus on NANOGrav's 15-year Data Set and the Gravitational Wave Background. For questions or comments, please email [email protected]

The NANOGrav 15-Year Data Set: Detector Characterization and Noise Budget

Pulsar timing arrays (PTAs) are galactic-scale gravitational wave detectors. Each individual arm, composed of a millisecond pulsar, a radio telescope, and a kiloparsecs-long path, differs in its properties but, in aggregate, can be used to extract low-frequency gravitational wave (GW) signals. We present a noise and sensitivity analysis to accompany the NANOGrav 15-year data release and associated papers, along with an in-depth introduction to PTA noise models. As a first step in our analysis, we characterize each individual pulsar data set with three types of white noise parameters and two red noise parameters. These parameters, along with the timing model and, particularly, a piecewise-constant model for the time-variable dispersion measure, determine the sensitivity curve over the low-frequency GW band we are searching. We tabulate information for all of the pulsars in this data release and present some representative sensitivity curves. We then combine the individual pulsar sensitivities using a signal-to-noise-ratio statistic to calculate the global sensitivity of the PTA to a stochastic background of GWs, obtaining a minimum noise characteristic strain of $7\times 10^{-15}$ at 5 nHz. A power law-integrated analysis shows rough agreement with the amplitudes recovered in NANOGrav's 15-year GW background analysis. While our phenomenological noise model does not model all known physical effects explicitly, it provides an accurate characterization of the noise in the data while preserving sensitivity to multiple classes of GW signals.Comment: 67 pages, 73 figures, 3 tables; published in Astrophysical Journal Letters as part of Focus on NANOGrav's 15-year Data Set and the Gravitational Wave Background. For questions or comments, please email [email protected]

The NANOGrav 15 yr Data Set: Search for Transverse Polarization Modes in the Gravitational-wave Background

Recently we found compelling evidence for a gravitational-wave background with Hellings and Downs (HD) correlations in our 15 yr data set. These correlations describe gravitational waves as predicted by general relativity, which has two transverse polarization modes. However, more general metric theories of gravity can have additional polarization modes, which produce different interpulsar correlations. In this work, we search the NANOGrav 15 yr data set for evidence of a gravitational-wave background with quadrupolar HD and scalar-transverse (ST) correlations. We find that HD correlations are the best fit to the data and no significant evidence in favor of ST correlations. While Bayes factors show strong evidence for a correlated signal, the data does not strongly prefer either correlation signature, with Bayes factors ∼2 when comparing HD to ST correlations, and ∼1 for HD plus ST correlations to HD correlations alone. However, when modeled alongside HD correlations, the amplitude and spectral index posteriors for ST correlations are uninformative, with the HD process accounting for the vast majority of the total signal. Using the optimal statistic, a frequentist technique that focuses on the pulsar-pair cross-correlations, we find median signal-to-noise ratios of 5.0 for HD and 4.6 for ST correlations when fit for separately, and median signal-to-noise ratios of 3.5 for HD and 3.0 for ST correlations when fit for simultaneously. While the signal-to-noise ratios for each of the correlations are comparable, the estimated amplitude and spectral index for HD are a significantly better fit to the total signal, in agreement with our Bayesian analysis

The NANOGrav 15-year data set: Search for Transverse Polarization Modes in the Gravitational-Wave Background

Recently we found compelling evidence for a gravitational wave background with Hellings and Downs (HD) correlations in our 15-year data set. These correlations describe gravitational waves as predicted by general relativity, which has two transverse polarization modes. However, more general metric theories of gravity can have additional polarization modes which produce different interpulsar correlations. In this work we search the NANOGrav 15-year data set for evidence of a gravitational wave background with quadrupolar Hellings and Downs (HD) and Scalar Transverse (ST) correlations. We find that HD correlations are the best fit to the data, and no significant evidence in favor of ST correlations. While Bayes factors show strong evidence for a correlated signal, the data does not strongly prefer either correlation signature, with Bayes factors $\sim 2$ when comparing HD to ST correlations, and $\sim 1$ for HD plus ST correlations to HD correlations alone. However, when modeled alongside HD correlations, the amplitude and spectral index posteriors for ST correlations are uninformative, with the HD process accounting for the vast majority of the total signal. Using the optimal statistic, a frequentist technique that focuses on the pulsar-pair cross-correlations, we find median signal-to-noise-ratios of 5.0 for HD and 4.6 for ST correlations when fit for separately, and median signal-to-noise-ratios of 3.5 for HD and 3.0 for ST correlations when fit for simultaneously. While the signal-to-noise-ratios for each of the correlations are comparable, the estimated amplitude and spectral index for HD are a significantly better fit to the total signal, in agreement with our Bayesian analysis.Comment: 11 pages, 5 figure