Ribosomal oxygenases are structurally conserved from prokaryotes to humans

2-Oxoglutarate (2OG)-dependent oxygenases have important roles in the regulation of gene expression via demethylation of N-methylated chromatin components1,2 and in the hydroxylation of transcription factors3 and splicing factor proteins4. Recently, 2OG-dependent oxygenases that catalyse hydroxylation of transfer RNA5,6,7 and ribosomal proteins8 have been shown to be important in translation relating to cellular growth, TH17-cell differentiation and translational accuracy9,10,11,12. The finding that ribosomal oxygenases (ROXs) occur in organisms ranging from prokaryotes to humans8 raises questions as to their structural and evolutionary relationships. In Escherichia coli, YcfD catalyses arginine hydroxylation in the ribosomal protein L16; in humans, MYC-induced nuclear antigen (MINA53; also known as MINA) and nucleolar protein 66 (NO66) catalyse histidine hydroxylation in the ribosomal proteins RPL27A and RPL8, respectively. The functional assignments of ROXs open therapeutic possibilities via either ROX inhibition or targeting of differentially modified ribosomes. Despite differences in the residue and protein selectivities of prokaryotic and eukaryotic ROXs, comparison of the crystal structures of E. coli YcfD and Rhodothermus marinus YcfD with those of human MINA53 and NO66 reveals highly conserved folds and novel dimerization modes defining a new structural subfamily of 2OG-dependent oxygenases. ROX structures with and without their substrates support their functional assignments as hydroxylases but not demethylases, and reveal how the subfamily has evolved to catalyse the hydroxylation of different residue side chains of ribosomal proteins. Comparison of ROX crystal structures with those of other JmjC-domain-containing hydroxylases, including the hypoxia-inducible factor asparaginyl hydroxylase FIH and histone Nε-methyl lysine demethylases, identifies branch points in 2OG-dependent oxygenase evolution and distinguishes between JmjC-containing hydroxylases and demethylases catalysing modifications of translational and transcriptional machinery. The structures reveal that new protein hydroxylation activities can evolve by changing the coordination position from which the iron-bound substrate-oxidizing species reacts. This coordination flexibility has probably contributed to the evolution of the wide range of reactions catalysed by oxygenases

Women's Preferences for Treatment of Perinatal Depression and Anxiety : A Discrete Choice Experiment

Perinatal depression and anxiety (PNDA) are an international healthcare priority, associated with significant short- and long-term problems for women, their children and families. Effective treatment is available but uptake is suboptimal: some women go untreated whilst others choose treatments without strong evidence of efficacy. Better understanding of women's preferences for treatment is needed to facilitate uptake of effective treatment. To address this issue, a discrete choice experiment (DCE) was administered to 217 pregnant or postnatal women in Australia, who were recruited through an online research company and had similar sociodemographic characteristics to Australian data for perinatal women. The DCE investigated preferences regarding cost, treatment type, availability of childcare, modality and efficacy. Data were analysed using logit-based models accounting for preference and scale heterogeneity. Predicted probability analysis was used to explore relative attribute importance and policy change scenarios, including how these differed by women's sociodemographic characteristics. Cost and treatment type had the greatest impact on choice, such that a policy of subsidising effective treatments was predicted to double their uptake compared with the base case. There were differences in predicted uptake associated with certain sociodemographic characteristics: for example, women with higher educational attainment were more likely to choose effective treatment. The findings suggest policy directions for decision makers whose goal is to reduce the burden of PNDA on women, their children and families

Design and study protocol of the maternal smoking cessation during pregnancy study, (M-SCOPE)

<p>Abstract</p> <p>Background</p> <p>Maternal smoking is the most significant cause of preventable complications during pregnancy, with smoking cessation during pregnancy shown to increase birth weight and reduce preterm birth among pregnant women who quit smoking. Taking into account the fact that the number of women who smoke in Greece has increased steadily throughout the previous decade and that the prevalence of smoking among Greek females is one of the highest in the world, smoking cessation should be a top priority among Greek health care professionals.</p> <p>Methods/Design</p> <p>The Maternal Smoking Cessation during Pregnancy Study (M-SCOPE), is a Randomized Control Trial (RCT) that aims to test whether offering Greek pregnant smokers a high intensity intervention increases smoking cessation during the third trimester of pregnancy, when compared to a low intensity intervention. Prospective participants will be pregnant smokers of more than 5 cigarettes per week, recruited up to the second trimester of pregnancy. Urine samples for biomarker analysis of cotinine will be collected at three time points: at baseline, at around the 32^ndweek of gestation and at six months post partum. The control group/low intensity intervention will include: brief advice for 5 minutes and a short leaflet, while the experimental group/intensive intervention will include: 30 minutes of individualized cognitive-behavioural intervention provided by a trained health professional and a self-help manual especially tailored for smoking cessation during pregnancy, while counselling will be based on the ''5 As.'' After childbirth, the infants' birth weight, gestational age and any other health related complications during pregnancy will be recorded. A six months post-partum a follow up will be performed in order to re-assess the quitters smoking status.</p> <p>Discussion</p> <p>If offering pregnant smokers a high intensity intervention for smoking cessation increases the rate of smoking cessation in comparison to a usual care low intensity intervention in Greek pregnant smokers, such a scheme if beneficial could be implemented successfully within clinical practice in Greece.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov Identifier <a href="http://www.clinicaltrials.gov/ct2/show/NCT01210118">NCT01210118</a></p

Missense mutations in the WD40 domain of AHI1 cause non-syndromic retinitis pigmentosa

Background: Recent findings suggesting that Abelson helper integration site 1 (AHI1) is involved in non-syndromic retinal disease have been debated, as the functional significance of identified missense variants was uncertain. We assessed whether AHI1 variants cause non-syndromic retinitis pigmentosa (RP). Methods: Exome sequencing was performed in three probands with RP. The effects of the identified missense variants in AHI1 were predicted by three-dimensional structure homology modelling. Ciliary parameters were evaluated in patient's fibroblasts, and recombinant mutant proteins were expressed in ciliated retinal pigmented epithelium cells. Results: In the three patients with RP, three sets of compound heterozygous variants were detected in AHI1 (c.2174G>A; p.Trp725* and c.2258A>T; p.Asp753Val, c.660delC; p.Ser221Glnfs*10 and c.2090C>T; p.Pro697Leu, c.2087A>G; p.His696Arg and c.2429C>T; p.Pro810Leu). All four missense variants were present in the conserved WD40 domain of Jouberin, the ciliary protein encoded by AHI1, with variable predicted implications for the domain structure. No significant changes in the percentage of ciliated cells, nor in cilium length or intraflagellar transport were detected. However, expression of mutant recombinant Jouberin in ciliated cells showed a significantly decreased enrichment at the ciliary base. Conclusions: This report confirms that mutations in AHI1 can underlie autosomal recessive RP. Moreover, it structurally and functionally validates the effect of the RP-associated AHI1 variants on protein function, thus proposing a new genotype-phenotype correlation for AHI1 mutation associated retinal ciliopathies

Modelling Eddy Current Brake emissions for electromagnetic compatibility with signaling devices in high speed railways

This paper presents a model that anticipates the emissions from eddy current brakes (ECBs) installed in high-speed trains. The emissions are computed in the 10 KHz-1.3 MHz range, where trackside signaling devices operate and issues related to electromagnetic compatibility have arisen, hindering ECB's promise of full deployment. The electromagnetic model provides a transfer function in the frequency domain between the nondesired harmonic currents produced by the train power supply and the subsequent radiated emissions by the ECBs at the trackside. The model includes the influence of the on-board ECB system's electric circuitry on the three-dimensional field computation of the electromagnets by a cosimulation approach (circuit and electromagnetic cross talk). After the data are postprocessed, the simulated results are compared with the results of an extensive measurement campaign on board a high-speed ICE 3 train equipped with ECBs. The high correlation makes it possible to anticipate ECB emissions in order to save costly on-track test runs, to suggest ECB design strategies and to provide safe limits when the worst cases occur

Modeling the impact on wheel sensor readouts by Eddy Current Brakes installed in high-speed trains

This paper presents a model to anticipate the impact of Eddy Current Brakes (ECBs) installed in high-speed trains on the readouts of rail-side wheel sensors. The purpose is to anticipate false positive readouts of train wheels when traversing, one of the main obstacles for full ECB deployment. The ECB type EWB 154 from Knorr-Bremse and Wheel Sensor types RSR180 and RSR123 from Frauscher Sensor Technology are represented in a comprehensive model, integrating LTSpice and CST Microwave Studio. The wheel sensor predicted readout error is 4% compared to measurements when DC current is not applied to the ECB (passive case). It is demonstrated that the RSR180 is not compatible with ECBs, whereas the RSR123 is. The impact of active (DC current fed) brakes is analyzed when performing running tests with a high-speed ICE 3 train equipped with ECBs. The model is adjusted to study the saturation of the rail and ECB pole cores. The extra damping of the wheel sensor fingerprint is modeled by an extra 6% drop that may well be applicable to passive tests in a laboratory setting to shift to active tests without actually performing them. In this way, cost and time would be saved. Based on the model outcomes, a test bench is recommended for laboratory tests to emulate active behavior