Composition and evolution of the continental crust: Retrospect and prospect

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Differential hormone-dependent transcriptional activation and -repression by naturally occurring human glucocorticoid receptor variants

The molecular mechanisms underlying primary glucocorticoid resistance or hypersensitivity are not well understood. Using transfected COS-1 cells as a model system, we studied gene regulation by naturally occurring mutants of the glucocorticoid receptor (GR) with single-point mutations in the regions encoding the ligand-binding domain or the N-terminal domain reflecting different phenotypic expression. We analyzed the capacity of these GR variants to regulate transcription from different promoters, either by binding directly to positive or negative glucocorticoid-response elements on the DNA or by interfering with protein-protein interactions. Decreased dexamethasone (DEX) binding to GR variants carrying mutations in the ligand-binding domain correlated well with decreased capacity to activate transcription from the mouse mammary tumor virus (MMTV) promoter. One variant, D641V, which suboptimally activated MMTV promoter-mediated transcription, repressed a PRL promoter element containing a negative glucocorticoid-response element with wild type activity. DEX-induced repression of transcription from elements of the intercellular adhesion molecule-1 promoter via nuclear factor-kappaB by the D641V variant was even more efficient compared with the wild type GR. We observed a general DEX-responsive AP-1-mediated transcriptional repression of the collagenase-1 promoter, even when receptor variants did not activate transcription from the MMTV promoter. Our findings indicate that different point mutations in the GR can affect separate pathways of gene regulation in a differential fashion, which can explain the various phenotypes observed

Glucocorticoid receptor gene polymorphisms do not affect growth in fetal and early postnatal life. The Generation R Study

Background: Glucocorticoids have an important role in early growth and development. Glucocorticoid receptor gene polymorphisms have been identified that contribute to the variability in glucocorticoid sensitivity. We examined whether these glucocorticoid receptor gene polymorphisms are associated with growth in fetal and early postnatal life.Methods: This study was embedded in a population-based prospective cohort study from fetal life onwards. The studied glucocorticoid receptor gene polymorphisms included BclI (rs41423247), TthIIII (rs10052957), GR-9β (rs6198), N363S (rs6195) and R23K (rs6789 and6190). Fetal growth was assessed by ultrasounds in second and third trimester of pregnancy. Anthropometric measurements in early childhood were performed at birth and at the ages of 6, 14 and 24 months postnatally. Analyses focused on weight, length and head circumference. Analyses were based on 2,414 healthy, Caucasian children.Results: Glucocorticoid receptor gene polymorphisms were not associated with fetal weight, birth weight and early postnatal weight. Also, no associations were found with length and head circumference. Neither were these polymorphisms associated with the risks of low birth weight or growth acceleration from birth to 24 months of age.Conclusions: We found in a large population-based cohort no evidence for an effect of known glucocorticoid receptor gene polymorphisms on fetal and early post

Glucocorticoid receptor mRNA levels are selectively decreased in neutrophils of children with sepsis

Objective: Corticosteroids are used in sepsis treatment to benefit outcome. However, discussion remains on which patients will benefit from treatment. Inter-individual variations in cortisol sensitivity, mediated through the glucocorticoid receptor, might play a role in the observed differences. Our aim was to study changes in mRNA levels of three glucocorticoid receptor splice variants in neutrophils of children with sepsis. Patients and design: Twenty-three children admitted to the pediatric intensive care unit with sepsis or septic shock were included. Neutrophils were isolated at days 0, 3 and 7, and after recovery (>3 months). mRNA levels of the glucocorticoid receptor splice variants GR-α (determining most of the cortisol effect), GR-P (increasing GR-α effect) and GR-β (inhibitor of GR-α) were measured quantitatively. Main results: Neutrophils from sepsis patients showed decreased levels of glucocorticoid receptor mRNA of the GR-α and GR-P splice variants on day 0 compared to after recovery. GR-α and GR-P mRNA levels showed a gradual recovery on days 3 and 7 and normalized after recovery. GR-β mRNA levels did not change significantly during sepsis. GR expression was negatively correlated to interleukin-6 (a measure of disease severity, r = -0.60, P = 0.009). Conclusions: Children with sepsis or septic shock showed a transient depression of glucocorticoid receptor mRNA in their neutrophils. This feature may represent a tissue-specific adaptation during sepsis leading to increased cortisol resistance of neutrophils. Our study adds to understanding the mechanism of cortisol sensitivity in immune cells. Future treatment strategies, aiming at timing and tissue specific regulation of glucocorticoids, might benefit patients with sepsis or septic shock

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Composition and evolution of the continental crust: Retrospect and prospect

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Primary cordierite with > 2.5 wt% CO2 from the UHT Bakhuis Granulite Belt, Surinam: CO2 fluid phase saturation during ultrahigh-temperature metamorphism

The Paleoproterozoic Bakhuis Granulite Belt (BGB) in Surinam, South America, shows ultrahigh-temperature metamorphism (UHTM) at temperatures of around 1000 °C which, unusually, produced peak-to-near-peak cordierite with sillimanite and, in some cases, Al-rich orthopyroxene on a regional scale. Mg-rich cordierite (Mg/(Mg + Fe) = 0.88) in a sillimanite-bearing metapelitic granulite has a maximum birefringence of second-order blue (ca. 0.020) indicative of a considerable amount of CO2 (> 2 wt%) within its structural channels. SIMS microanalysis confirms the presence of 2.57 ± 0.19 wt% CO2, the highest CO2 concentration found in natural cordierite. This high CO2 content has enabled the stability of cordierite to extend into UHT conditions at high pressures and very low to negligible H2O activity. Based on a modified calibration of the H2O–CO2 incorporation model of Harley et al. (J Metamorph Geol 20:71–86, 2002), this cordierite occupies a stability field that extends from 8.8 ± 0.6 kbar at 750 °C to 11.3 ± 0.65 kbar at 1050 °C. Volatile-saturated cordierite with 2.57 wt% CO2 and negligible H2O (0.04 wt%) indicates fluid-present carbonic conditions with a CO2 activity near 1.0 at peak or near-peak pressures of 10.5–11.3 kbar under UHT temperatures of 950–1050 °C. The measured H2O content of the cordierite in the metapelite is far too low to be consistent with partial melting at 1000–1050 °C, implying either that nearly all of any H2O originally in this cordierite under UHT conditions was lost during post-peak cooling or that the cordierite was formed after migmatization. The high level of CO2 required to ensure fluid saturation of the c. 11 kbar UHT cordierite is proposed to have been derived from an external, possibly mantle, source

Constraining the genesis of tungsten mineralization in the Jiaoxi deposit, Tibet: a fluid inclusion and H, O, S and Pb isotope investigation

The Jiaoxi deposit, located in the western part of the Lhasa terrane, is the first discovered Miocene (ca. 13 Ma) quartz vein-type tungsten deposit in this belt. Ore bodies mainly occur as wolframite-bearing veins hosted in the shales and granite. Three stages were identified for the formation of the Jiaoxi deposit, including the oxide stage (dominated by wolframite and quartz), the sulfide stage (quartz-sulfides veins) and the fluorite stage (late veins comprising fluorite, calcite, and quartz). Here, we investigate the genesis of this deposit based on fluid inclusion and H-O-S-Pb isotope studies. Fluid inclusion microthermometry and oxygen isotope data reveal that the wolframite precipitated from a moderate temperature (340–380°C), low salinity (2.1–7.5 wt% NaCl equivalent) hydrothermal fluid at a depth of ∼ 6 km. The sulfides from the oxide and sulfide stage have uniform δ34SCDT values (+2.5 to + 3.7‰), and consistent Pb isotope compositions with the coeval granites (206Pb/204Pb: 17.866–18.789; 207Pb/204Pb: 15.555–15.743; 208Pb/204Pb: 37.157–39.335). The δ18OVSMOW value of the hydrothermal fluid decreased from the oxide (δ18OVSMOW = +7.2 to +14.2‰) to the fluorite stage (δ18OVSMOW = +2.1 to +5.7‰), indicating that the exsolved magmatic hydrothermal fluid mixed with meteoric water. This is also suggested by the positive correlation between the salinity and homogenization temperature of the aqueous fluid inclusions. LA-ICP-MS analysis of individual fluid inclusion reveals that the W concentrations of ore-forming fluid in the oxide stage (1.2–70.2 ppm) are much higher than those in the sulfide and fluorite stage (1.1–2.2 ppm) and show positive correlations with the homogenization temperatures and the Cl concentrations. We propose that fluid dilution and cooling due to fluid mixing played an important role during the wolframite precipitation in the Jiaoxi deposit

A mathematical approach to the temporal stationarity of background noise in MEG/EEG measurements

The general spatiotemporal covariance matrix of the background noise in MEG/EEG signals is huge. To reduce the dimensionality of this matrix it is modeled as a Kronecker product of a spatial and a temporal covariance matrix. When the number of time samples is larger than, say, J = 500, the iterative Maximum Likelihood estimation of these two matrices is still too time-consuming to be useful on a routine basis. In this study we looked for methods to circumvent this computationally expensive procedure by using a parametric model with subject-dependent parameters. Such a model would additionally help with interpreting MEG/EEG signals. For the spatial covariance, models have been derived already and it has been shown that measured MEG/EEG signals can be understood spatially as random processes, generated by random dipoles. The temporal covariance, however, has not been modeled yet, therefore we studied the temporal covariance matrix in several subjects. For all subjects the temporal covariance shows an alpha oscillation and vanishes for large time lag. This gives rise to a temporal noise model consisting of two components: alpha activity and additional random noise. The alpha activity is modeled as randomly occurring waves with random phase and the covariance of the additional noise decreases exponentially with lag. This model requires only six parameters instead of 1/2J(J + 1). Theoretically, this model is stationary but in practice the stationarity of the matrix is highly influenced by the baseline correction. It appears that very good agreement between the data and the parametric model can be obtained when the baseline correction window is taken into account properly. This finding implies that the background noise is in principle a stationary process and that nonstationarities are mainly caused by the nature of the preprocessing method. When analyzing events at a fixed sample after the stimulus (e.g., the SEF N20 response) one can take advantage of this nonstationarity by optimizing the baseline window to obtain a low noise variance at this particular sample. © 2003 Elsevier Science (USA). All rights reserved