Using principal component analysis to understand the variability of PDS 456

We present a spectral-variability analysis of the low-redshift quasar PDS 456 using principal component analysis. In the XMM-Newton data, we find a strong peak in the first principal component at the energy of the Fe absorption line from the highly blueshifted outflow. This indicates that the absorption feature is more variable than the continuum, and that it is responding to the continuum. We find qualitatively different behaviour in the Suzaku data, which is dominated by changes in the column density of neutral absorption. In this case, we find no evidence of the absorption produced by the highly ionized gas being correlated with this variability. Additionally, we perform simulations of the source variability, and demonstrate that PCA can trivially distinguish between outflow variability correlated, anti-correlated, and un-correlated with the continuum flux. Here, the observed anti-correlation between the absorption line equivalent width and the continuum flux may be due to the ionization of the wind responding to the continuum. Finally, we compare our results with those found in the narrow-line Seyfert 1 IRAS 13224-3809. We find that the Fe K UFO feature is sharper and more prominent in PDS 456, but that it lacks the lower energy features from lighter elements found in IRAS 13224-3809, presumably due to differences in ionization

A New Relativistic Component of the Accretion Disk Wind in PDS 456

Past X-ray observations of the nearby luminous quasar PDS 456 (at z = 0.184) have revealed a wide angle accretion disk wind, with an outflow velocity of ∼−0.25 c . Here, we unveil a new, relativistic component of the wind through hard X-ray observations with NuSTAR and XMM-Newton , obtained in 2017 March when the quasar was in a low-flux state. This very fast wind component, with an outflow velocity of −0.46 ± 0.02 c , is detected in the iron K band, in addition to the −0.25 c wind zone. The relativistic component may arise from the innermost disk wind, launched from close to the black hole at a radius of ∼10 gravitational radii. The opacity of the fast wind also increases during a possible obscuration event lasting for 50 ks. We suggest that the very fast wind may only be apparent during the lowest X-ray flux states of PDS 456, becoming overly ionized as the luminosity increases. Overall, the total wind power may even approach the Eddington value

Evidence for a radiatively driven disc-wind in PDS 456?

We present a newly discovered correlation between the wind outflow velocity and the X-ray luminosity in the luminous ($L_{\rm bol}\sim10^{47}\,\rm erg\,s^{-1}$) nearby ($z=0.184$) quasar PDS\,456. All the contemporary XMM-Newton, NuSTAR and Suzaku observations from 2001--2014 were revisited and we find that the centroid energy of the blueshifted Fe\,K absorption profile increases with luminosity. This translates into a correlation between the wind outflow velocity and the hard X-ray luminosity (between 7--30\,keV) where we find that $v_{\rm w}/c \propto L_{7-30}^{\gamma}$ where $\gamma=0.22\pm0.04$. We also show that this is consistent with a wind that is predominately radiatively driven, possibly resulting from the high Eddington ratio of PDS\,456

Risk factors for ductal and lobular breast cancer: results from the nurses' health study

Introduction Ductal and lobular carcinomas are the two most common types of invasive breast cancer. Whether well-established risk factors are differentially associated with risk on the basis of histologic subtype is not clear. We prospectively investigated the association between a number of hormonal and nonhormonal exposures and risk defined by histologic subtype among 4,655 ductal and 659 lobular cases of postmenopausal breast cancer from the Nurses\u27 Health Study. Methods Multivariate Cox proportional hazards regression stratified by histologic subtype and time period was used to examine the association between risk factors and the incidence of ductal and lobular subtypes. For each exposure, we calculated the P value for heterogeneity using a likelihood ratio test comparing models with separate estimates for the two subtypes versus a single estimate across subtypes. Results The associations with age at menarche (P-heterogeneity (het) = 0.03), age at first birth (P-het \u3c 0.001) and postmenopausal hormone use (P-het \u3c 0.001) were more strongly associated with lobular cancers. The associations with age, nulliparity, parity, age at menopause, type of menopause, alcohol intake, adult body mass index (BMI), BMI at age 18, family history of breast cancer and personal history of benign breast disease did not vary by subtype (P-het ≥ 0.08). Results were similar when we restricted the analyses to estrogen receptor-positive and progesterone receptor-positive tumors. Conclusions These data indicate that breast cancer is a heterogeneous disease, and the differential association with a number of risk factors is suggestive of etiologically distinct tumors. Epidemiological analyses should continue to take into account a modifying role of histology

Galaxy evolution: black hole feedback in the luminous quasar PDS 456

The evolution of galaxies is connected to the growth of supermassive black holes in their centers. During the quasar phase, a huge luminosity is released as matter falls onto the black hole, and radiation-driven winds can transfer most of this energy back to the host galaxy. Over five different epochs, we detected the signatures of a nearly spherical stream of highly ionized gas in the broadband x-ray spectra of the luminous quasar PDS 456. This persistent wind is expelled at relativistic speeds from the inner accretion disk, and its wide aperture suggests an effective coupling with the ambient gas. The outflow's kinetic power larger than 10(46) ergs per second is enough to provide the feedback required by models of black hole and host galaxy coevolution

FLORA: a novel method to predict protein function from structure in diverse superfamilies

Predicting protein function from structure remains an active area of interest, particularly for the structural genomics initiatives where a substantial number of structures are initially solved with little or no functional characterisation. Although global structure comparison methods can be used to transfer functional annotations, the relationship between fold and function is complex, particularly in functionally diverse superfamilies that have evolved through different secondary structure embellishments to a common structural core. The majority of prediction algorithms employ local templates built on known or predicted functional residues. Here, we present a novel method (FLORA) that automatically generates structural motifs associated with different functional sub-families (FSGs) within functionally diverse domain superfamilies. Templates are created purely on the basis of their specificity for a given FSG, and the method makes no prior prediction of functional sites, nor assumes specific physico-chemical properties of residues. FLORA is able to accurately discriminate between homologous domains with different functions and substantially outperforms (a 2–3 fold increase in coverage at low error rates) popular structure comparison methods and a leading function prediction method. We benchmark FLORA on a large data set of enzyme superfamilies from all three major protein classes (α, β, αβ) and demonstrate the functional relevance of the motifs it identifies. We also provide novel predictions of enzymatic activity for a large number of structures solved by the Protein Structure Initiative. Overall, we show that FLORA is able to effectively detect functionally similar protein domain structures by purely using patterns of structural conservation of all residues

Background risk of breast cancer and the association between physical activity and mammographic density

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Downregulation of the central noradrenergic system by Toxoplasma gondii infection

Toxoplasma gondii is associated with physiological effects in the host. Dysregulation of catecholamines in the central nervous system has previously been observed in chronically-infected animals. In the study described here, the noradrenergic system was found to be suppressed with decreased levels of norepinephrine (NE) in brains of infected animals and in infected human and rat neural cells in vitro. The mechanism responsible for the NE suppression was found to be down-regulation of dopamine β-hydroxylase (DBH) gene expression, encoding the enzyme that synthesizes norepinephrine from dopamine with down-regulation observed in vitro and in infected brain tissue, particularly in the dorsal locus coeruleus/pons region. The down-regulation was sex-specific with males expressing reduced DBH mRNA levels whereas females were unchanged. Rather, DBH expression correlated with estrogen receptor in the female rat brains for this estrogen-regulated gene. DBH silencing was not a general response of neurons to infection as human cytomegalovirus (CMV) did not down-regulate DBH expression. The noradrenergic-linked behaviors of sociability and arousal were altered in chronically-infected animals, with a high correlation between DBH expression and infection intensity. A decrease in DBH expression in noradrenergic neurons can elevate dopamine levels which provides a possible explanation for mixed observations of changes in this neurotransmitter with infection. Decreased NE is consistent with the loss of coordination and motor impairments associated with toxoplasmosis. Further, the altered norepinephrine synthesis observed here may, in part, explain behavioural effects of infection and associations with mental illness

Oestradiol-17β plasma concentrations after intramuscular injection of oestradiol benzoate or oestradiol cypionate in llamas (Lama glama)

<p>Abstract</p> <p>Background</p> <p>Llamas (<it>Lama glama</it>) are induced ovulators and the process of ovulation depends on dominant follicular size. In addition, a close relationship between behavioural estrus and ovulation is not registered in llamas. Therefore, the exogenous control of follicular development with hormones aims to predict the optimal time to mate. Oestradiol-17β (E₂) and its esters are currently used in domestic species, including camelids, in synchronization treatments. But, in llamas, there is no reports regarding the appropriate dosages to be used and most protocols have been designed by extrapolation from those recommended for other ruminants. The aim of the present study was to characterize plasma E₂concentrations in intact female llamas following a single intramuscular (i.m.) injection of two oestradiol esters: oestradiol benzoate (EB) and oestradiol cypionate (ECP).</p> <p>Methods</p> <p>Twelve non pregnant and non lactating sexually mature llamas were i.m. injected on day 0 with 2.5 mg of EB (EB group, n = 6) or ECP (ECP group, n = 6). Blood samples were collected immediately before injection, at 1, 6, 12, 24 h after treatment and then daily until day 14 post injection. Changes in hormone concentrations with time were analyzed in each group by analysis of variance (ANOVA) using a repeated measures (within-SS) design. Plasma E₂concentrations and area under the concentration-time curve (AUC) values were compared between groups by ANOVA. In all cases a Least-Significant Difference test (LSD) was used to determine differences between means. Hormonal and AUC data are expressed as mean ± S.E.M.</p> <p>Results</p> <p>Peak plasma E₂concentrations were achieved earlier and were higher in EB group than in ECP group. Thereafter, E₂returned to physiological concentrations earlier in EB group (day 5) than in ECP group (day 9). Although plasma E₂profiles differed over time among groups there were no differences between them on AUC values.</p> <p>Conclusions</p> <p>The i.m. injection of a single dose of both oestradiol esters resulted in plasma E₂concentrations exceeding physiological values for a variable period. Moreover, the plasma E₂profiles observed depended on the derivative of oestradiol administered. This basic information becomes relevant at defining treatment protocols including oestrogens in llamas.</p

Identification of NAD interacting residues in proteins

Background: Small molecular cofactors or ligands play a crucial role in the proper functioning of cells. Accurate annotation of their target proteins and binding sites is required for the complete understanding of reaction mechanisms. Nicotinamide adenine dinucleotide (NAD+ or NAD) is one of the most commonly used organic cofactors in living cells, which plays a critical role in cellular metabolism, storage and regulatory processes. In the past, several NAD binding proteins (NADBP) have been reported in the literature, which are responsible for a wide-range of activities in the cell. Attempts have been made to derive a rule for the binding of NAD+ to its target proteins. However, so far an efficient model could not be derived due to the time consuming process of structure determination, and limitations of similarity based approaches. Thus a sequence and non-similarity based method is needed to characterize the NAD binding sites to help in the annotation. In this study attempts have been made to predict NAD binding proteins and their interacting residues (NIRs) from amino acid sequence using bioinformatics tools. Results: We extracted 1556 proteins chains from 555 NAD binding proteins whose structure is available in Protein Data Bank. Then we removed all redundant protein chains and finally obtained 195 non-redundant NAD binding protein chains, where no two chains have more than 40% sequence identity. In this study all models were developed and evaluated using five-fold cross validation technique on the above dataset of 195 NAD binding proteins. While certain type of residues are preferred (e.g. Gly, Tyr, Thr, His) in NAD interaction, residues like Ala, Glu, Leu, Lys are not preferred. A support vector machine (SVM) based method has been developed using various window lengths of amino acid sequence for predicting NAD interacting residues and obtained maximum Matthew's correlation coefficient (MCC) 0.47 with accuracy 74.13% at window length 17. We also developed a SVM based method using evolutionary information in the form of position specific scoring matrix (PSSM) and obtained maximum MCC 0.75 with accuracy 87.25%. Conclusion: For the first time a sequence-based method has been developed for the prediction of NAD binding proteins and their interacting residues, in the absence of any prior structural information. The present model will aid in the understanding of NAD+ dependent mechanisms of action in the cell. To provide service to the scientific community, we have developed a user-friendly web server, which is available from URL http://www.imtech.res.in/raghava/nadbinder/