Use of Di- and Tripropionate substrate analogs to probe the active site of human recombinant coproporphyrinogen oxidase

Background: Defects in the enzyme coproporphyrinogen oxidase result in accumulation of porphyrins which may affect the severity of a subset of porphyrias. Thus evaluation of this enzyme for substrate selectivity is of value. Kinetic evaluations of recombinant human coproporphyrinogen oxidase have been undertaken using six di- and tripropionate analogs of the natural substrate coproporphyrinogen-III. These Substrate analogs were modified by having alkyl groups in place of one or both of the ring 13- or 17-propionate moieties. Material/Methods: Cloned human enzyme was incubated with analogs under apparent first order conditions and with various substrate concentrations. The kinetic values, K-m and V-max, were determined. Results: Relative to the authentic substrate, the K-m values for the 13-ethyl, dimethyl and diethyl porphyrinogens were very comparable whereas the K-m values were much higher using dipropyl and dibutyl porphyrinogen and much lower for the 17-ethyl analog. For the dipropionate analogs, the V-max values were an apparent function of the carbon length of the substituent. on the C and D rings, with longer carbon length severely reducing product formation by some 4-5 orders of magnitude. Also, the two isomeric tripropionates that were tested indicated that it was more detrimental to have an ethyl group at the 13-position for both binding and catalysis. Conclusions: This work extends our understanding of porphyrin ring substituent effects reported by Cooper et al. (2005). The substituents on both the C and D rings have significant effects on both the substrate binding and catalysis by this important enzyme

A polarity reversal in the large-scale magnetic field of the rapidly rotating Sun HD 190771

Aims. We investigate the long-term evolution of the large-scale photospheric magnetic field geometry of the solar-type star HD 190771. With fundamental parameters very close to those of the Sun except for a shorter rotation period of 8.8 d, HD 190771 provides us with a first insight into the specific impact of the rotation rate in the dynamo generation of magnetic fields in 1 $M_\odot$ stars. Methods. We use circularly polarized, high-resolution spectra obtained with the NARVAL spectropolarimeter (Observatoire du Pic du Midi, France) and compute cross-correlation line profiles with high signal-to-noise ratio to detect polarized Zeeman signatures. From three phase-resolved data sets collected during the summers of 2007, 2008, and 2009, we model the large-scale photospheric magnetic field of the star by means of Zeeman-Doppler imaging and follow its temporal evolution. Results. The comparison of the magnetic maps shows that a polarity reversal of the axisymmetric component of the large-scale magnetic field occurred between 2007 and 2008, this evolution being observed in both the poloidal and toroidal magnetic components. Between 2008 and 2009, another type of global evolution occured, characterized by a sharp decrease of the fraction of magnetic energy stored in the toroidal component. These changes were not accompanied by significant evolution in the total photospheric magnetic energy. Using our spectra to perform radial velocity measurements, we also detect a very low-mass stellar companion to HD 190771.Comment: Accepted by Astronomy and Astrophysics (Letter to the Editor

The rapid rotation and complex magnetic field geometry of Vega

The recent discovery of a weak surface magnetic field on the normal intermediate-mass star Vega raises the question of the origin of this magnetism in a class of stars that was not known to host magnetic fields. We aim to confirm the field detection and provide additional observational constraints about the field characteristics, by modelling the magnetic geometry of the star and by investigating the seasonal variability of the reconstructed field. We analyse a total of 799 circularly-polarized spectra collected with the NARVAL and ESPaDOnS spectropolarimeters during 2008 and 2009. We employ a cross-correlation procedure to compute, from each spectrum, a mean polarized line profile with a signal-to-noise ratio of about 20,000. The technique of Zeeman-Doppler Imaging is then used to determine the rotation period of the star and reconstruct the large-scale magnetic geometry of Vega at two different epochs. We confirm the detection of circularly polarized signatures in the mean line profiles. The amplitude of the signatures is larger when spectral lines of higher magnetic sensitivity are selected for the analysis, as expected for a signal of magnetic origin. The short-term evolution of polarized signatures is consistent with a rotational period of 0.732 \pm 0.008 d. The reconstructed magnetic topology unveils a magnetic region of radial field orientation, closely concentrated around the rotation pole. This polar feature is accompanied by a small number of magnetic patches at lower latitudes. No significant variability in the field structure is observed over a time span of one year. The repeated observation of a weak photospheric magnetic field on Vega suggests that a previously unknown type of magnetic stars exists in the intermediate-mass domain. Vega may well be the first confirmed member of a much larger, as yet unexplored, class of weakly-magnetic stars.Comment: Accepted by Astronomy & Astrophysics. Abstract shortened to respect the arXiv limit of 1920 character

A dominant magnetic dipole for the evolved Ap star candidate EK Eridani

EK Eri is one of the most slowly rotating active giants known, and has been proposed to be the descendant of a strongly magnetic Ap star. We have performed a spectropolarimetric study of EK Eri over 4 photometric periods with the aim of inferring the topology of its magnetic field. We used the NARVAL spectropolarimeter at the Bernard Lyot telescope at the Pic du Midi Observatory, along with the least-squares deconvolution method, to extract high signal-to-noise ratio Stokes V profiles from a timeseries of 28 polarisation spectra. We have derived the surface-averaged longitudinal magnetic field Bl. We fit the Stokes V profiles with a model of the large-scale magnetic field and obtained Zeeman Doppler images of the surface magnetic strength and geometry. Bl variations of up to about 80 G are observed without any reversal of its sign, and which are in phase with photometric ephemeris. The activity indicators are shown to vary smoothly on a timescale compatible with the rotational period inferred from photometry (308.8 d.), however large deviations can occur from one rotation to another. The surface magnetic field variations of EK Eri appear to be dominated by a strong magnetic spot (of negative polarity) which is phased with the dark (cool) photometric spot. Our modeling shows that the large-scale magnetic field of EK Eri is strongly poloidal. For a rotational axis inclination of i = 60{\deg}, we obtain a model that is almost purely dipolar. In the dipolar model, the strong magnetic/photometric spot corresponds to the negative pole of the dipole, which could be the remnant of that of an Ap star progenitor of EK Eri. Our observations and modeling conceptually support this hypothesis, suggesting an explanation of the outstanding magnetic properties of EK Eri as the result of interaction between deep convection and the remnant of an Ap star magnetic dipole.Comment: 8 pages, 6 figures, accepted for publication in Astronomy & Astrophysic

Sex differences in the association between plasma copeptin and incident type 2 diabetes: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study

AIMS/HYPOTHESIS: Vasopressin plays a role in osmoregulation, glucose homeostasis and inflammation. Therefore, plasma copeptin, the stable C-terminal portion of the precursor of vasopressin, has strong potential as a biomarker for the cardiometabolic syndrome and diabetes. Previous results were contradictory, which may be explained by differences between men and women in responsiveness of the vasopressin system. The aim of this study was to evaluate the usefulness of copeptin for prediction of future type 2 diabetes in men and women separately. METHODS: From the Prevention of Renal and Vascular Endstage Disease (PREVEND) study, 4,063 women and 3,909 men without diabetes at baseline were included. A total of 208 women and 288 men developed diabetes during a median follow-up of 7.7 years. RESULTS: In multivariable-adjusted models, we observed a stronger association of copeptin with risk of future diabetes in women (OR 1.49 [95% CI 1.24, 1.79]) than in men (OR 1.01 [95% CI 0.85, 1.19]) (p (interaction) < 0.01). The addition of copeptin to the Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) clinical model improved the discriminative value (C-statistic,+0.007, p = 0.02) and reclassification (integrated discrimination improvement [IDI] = 0.004, p < 0.01) in women. However, we observed no improvement in men. The additive value of copeptin in women was maintained when other independent predictors, such as glucose, high sensitivity C-reactive protein (hs-CRP) and 24 h urinary albumin excretion (UAE), were included in the model. CONCLUSIONS/INTERPRETATION: The association of plasma copeptin with the risk of developing diabetes was stronger in women than in men. Plasma copeptin alone, and along with existing biomarkers (glucose, hs-CRP and UAE), significantly improved the risk prediction for diabetes in women

Circulating Precursor Levels of Endothelin-1 and Adrenomedullin, Two Endothelium-Derived, Counteracting Substances, in Sepsis

Plasma levels of endothelin-1 (ET-1) and adrenomedullin (ADM), two opposingly acting peptides, correlate with mortality in endotoxemia, but their measurement is cumbersome. New sandwich assays have been introduced that measure more stable precursor fragments. The objective of this study was to investigate the counterplay of their precursor peptides in septic patients and to compare them with disease severity and other biomarkers. Blood samples of an observational study in 95 consecutive critically ill patients admitted to the intensive care unit (ICU) were analyzed. CT-proET-1 and MR-proADM concentrations on admission were measured using new sandwich immunoassays. Depending on the clinical severity of the infection, both CT-proET-1 and MR-proADM levels exhibited a gradual increase from Systemic Inflammatory Response Syndrome (SIRS) to sepsis and septic shock (p < .001). Compared to the group of survivors, the group of non-survivors had higher median values of MR-proADM (5.7 nmol/L [range 0.4 to 21.0] versus 1.9 nmol/L [range 0.3 to 17.1], p < .02) and similar CT-proET-1 levels (56.0pmol/L [range 0.5 to 271.0] versus 54.1pmol/L [range 1.0 to 506.0], p = .86). Receiver operating characteristics (ROC) curve analysis showed a higher prognostic accuracy of the calculated ratio of both counteracting substances as compared to CT-proET-1 (p = 0.001) and C-reactive protein (CRP) (p = .001) and in the range of MR-proADM (p = .51), procalcitonin (p = 0.22), and the APACHE II score (p = .61). Endothelin-1 and adrenomedullin precursor peptides gradually increase with increasing severities of infection in critically ill patients. The ratio of the two counteracting peptides correlates with mortality and shows aprognostic accuracy to predict adverse outcome comparable to the APACHE II score

Comparison of collapsing methods for the statistical analysis of rare variants

Novel technologies allow sequencing of whole genomes and are considered as an emerging approach for the identification of rare disease-associated variants. Recent studies have shown that multiple rare variants can explain a particular proportion of the genetic basis for disease. Following this assumption, we compare five collapsing approaches to test for groupwise association with disease status, using simulated data provided by Genetic Analysis Workshop 17 (GAW17). Variants are collapsed in different scenarios per gene according to different minor allele frequency (MAF) thresholds and their functionality. For comparing the different approaches, we consider the family-wise error rate and the power. Most of the methods could maintain the nominal type I error levels well for small MAF thresholds, but the power was generally low. Although the methods considered in this report are common approaches for analyzing rare variants, they performed poorly with respect to the simulated disease phenotype in the GAW17 data set

Copeptin is associated with mortality and outcome in patients with acute intracerebral hemorrhage

Spontaneous intracerebral hemorrhage (ICH) accounts for a high mortality and morbidity. Early prediction of outcome is crucial for optimized care and treatment decision. Copeptin, the C-terminal part of provasopressin, has emerged as a new prognostic marker in a variety of diseases, but its prognostic value in ICH is unknown