Isolation of 10 cyclosporine metabolites from human bile

Ten metabolites of cyclosporine were isolated from the ethyl ether extract of bile from four liver transplant patients receiving cyclosporine. Two of the metabolites were unique and previously unidentified. Liquid-liquid partitioning into diethyl ether with subsequent defatting with n-hexane was used for the initial extraction form bile. Separation of the individual metabolites (A-J) was performed using a Sephadex LH-20 column and a gradient high performance liquid chromatographic method. The molecular weights of the isolated metabolites were determined by fast atom bombardment/mass spectrometry. Gas chromatography with mass spectrometic amino acid analysis was also used to identify the amino acid composition and the hydroxylation position of metabolites A, B, C, D, and G. Proton nuclear magnetic resonance spectra were utilized to disinguish the chemical shifts of N-CH3 singlets and NH doublets of metabolites A, B, C, and D. Metabolites A, E, F, H, I, and J were reported previously in human urine and animal bile. Metabolites C and D are dihydroxylated compounds which cannot be clearly described as previously isolated compounds. Metabolites B and G are novel metabolites with a mass fragment which corresponded to a loss of 131 Da from the protonated molecular ion (MH+) in the fast atom bombardment/mass spectrometry, suggesting that the double bond in amino acid 1 has been modified. Metabolites B and G were primarily isolated from the bile of one of the liver transplant patients which contained abnormally high concentrations of these two metabolites. The method described is an efficient procedure for isolating milligram quantities of the major metabolites with greater than 95% purity

A study of risk factors of maternity outcomes using large, routinely-collected electronic datasets

Background: In the UK, almost all maternity care (>99% of births) is delivered via the National Health Service, which serves a varied population (approximately 22% from ethnic minority groups) according to a set of agreed standards and guidelines with common training pathways for maternity professionals. This makes the UK a useful high-income context in which to investigate maternity care and outcomes. Increasing availability of electronic health record data for women giving birth has made it possible to understand risk factors for adverse outcomes and the impacts of policy change in maternity care more closely. Furthermore, there is growing attention to ethnic and socioeconomic inequalities in outcomes of maternity care. The overall aim of this thesis is to demonstrate how data collected during maternity care can be used to understand determinants of maternity outcomes. In particular, I look at the association between women’s socioeconomic and ethnic background and their maternity outcomes. Methods: In this thesis, observational epidemiological studies using national patient-level datasets address four related issues in maternity care in England and Wales. First, the quality of coding of ethnicity is evaluated in a cross-validation study comparing two sources of ethnicity data for women giving birth. Second, risk factors for adverse pregnancy outcomes (postpartum haemorrhage, maternal intensive care admission, and preterm birth) are examined using multivariable logistic regression models adjusting for clinical risk factors and care received. Third, the performance of the risk-classification system used to determine women’s choice of birthplace, using the National Institute for Care Excellence guideline for Intrapartum Care, is evaluated by calculating the proportion of women in each risk group who experience a complicated birth requiring obstetric or neonatal assistance. Fourth, the proportion of adverse pregnancy outcomes (stillbirth, preterm birth, and fetal growth restriction) attributable to socioeconomic and ethnic inequality is estimated using population attributable fractions. Results: First, cross-validation of ethnicity data between datasets supports the use of ethnicity collapsed into groups, with caution over results for women with mixed ethnicity, for whom the most inconsistencies are observed. Second, studies examining risk factors for severe maternal morbidity (maternal intensive care admission and postpartum haemorrhage) demonstrate evidence that these outcomes are more common for Black women than women from other ethnic groups; this association persists following adjustment for clinical characteristics and differences in care given. Furthermore, detailed evaluation of risk factors for preterm birth demonstrates that different groups of women experience iatrogenic (provider-initiated) and spontaneous preterm birth, and these should be measured separately. Third, giving more weight to parity and history of previous caesarean improves the risk assessment of women giving birth at term in comparison to currently used classification methods. Finally, ethnic and socioeconomic inequalities are responsible for a substantial proportion of stillbirths, preterm births and babies born with fetal growth restriction; while socioeconomic inequalities are partially attenuated by adjustment for the modifiable maternal risk factors BMI and smoking, ethnic inequalities are not. Conclusions: Increasing availability of clinical data have made it possible to evaluate maternity care in more depth, demonstrating lessons for clinical risk assessment and care, avenues for further research development, and potential targets for political and public health interventions to improve the health and circumstances of women before and during pregnancy. As electronic records become more widespread and comprehensive, the quantity and sophistication of questions it will be possible to answer will expand, encompassing a wider reach of women’s healthcare before, during and after birth. This thesis demonstrates that such data, if handled carefully, can support our understanding of individual risk factors, risk classification, and healthcare systems and policy, and be used to develop recommendations to improve both healthcare policy and clinical care for women and their families

Climatic Controls on the Spring Phytoplankton Growing Season in a Temperate Shelf Sea

The Northwest European Shelf is positioned directly beneath the North Atlantic Storm Track, within which the frequency and intensity of transient storms are modulated by large-scale climatic oscillations. In temperate shelf seas, the impact of storms on the physical environment has received considerable attention, but the effect on biogeochemistry is less studied. Here, we use output from a multidecadal (1982–2015) coupled physical-biogeochemical model supported by observations from ocean gliders to investigate phytoplankton growth throughout the winter-spring transition. We define two separate phytoplankton growth events: the spring bloom, defined as the exponential growth following seasonal stratification, and the prebloom, occurring before stratification, and accounting for up to 22% of the total spring growth. Our results support the paradigm that light is a first-order control, with the spring bloom initiating up to 22 days after stratification onset should light levels be too low to trigger the bloom. The prebloom is heavily influenced by the phase of the Atlantic Multidecadal Oscillation (AMO), demonstrated by an acceleration in the rate of increase of total chlorophyll concentrations (±90% confidence limit) from 7.6 ± 2.8 mg m−2 d−1 (during a positive AMO) to 13.1 ± 4.3 mg m−2 d−1 (negative AMO), due to modulation of periods of ephemeral stratification that occur between successive storms. We propose that phytoplankton growth in prebloom events might help buffer the lag between phytoplankton supply and larval recruitment, particularly during years when the spring bloom is delayed

Durà, Antoni; Camonita, Francesco; Berzi, Matteo i Noferini, Andrea (2018). Euroregions, excellence and innovation across EU borders : A Catalogue of good practices. Barcelona: UAB. Departament de Geografia

Obra ressenyada: Antoni DURÀ; Francesco CAMONITA; Matteo BERZI i Andrea NOFERINI, Euroregions, excellence and innovation across EU borders: a Catalogue of good practices. Barcelona: UAB. Departament de Geografia, 2018

Probing the short range spin dependent interactions by polarized 3^{3} 3 He atom beams

Experiments using polarized 3He atom beams to search for short range spin dependent forces are proposed. High intensity, high polarization, small beam size 3He atom beams have been successfully produced and used in surface science researches. By incorporating background reduction designs as combination shielding by µ-metal and superconductor and double beam paths, the precision of spin rotation angle per unit length could be improved by a factor of ~104. By this precision, in combination with a high density and low magnetic susceptibility sample source mass, and reversing one beam path if necessary, sensitivities on three different types of spin dependent interactions could be improved by as much as ~102 to ~108 over the current experiments at the millimeter range

A characteristics framework for Semantic Information Systems Standards

Semantic Information Systems (IS) Standards play a critical role in the development of the networked economy. While their importance is undoubted by all stakeholders—such as businesses, policy makers, researchers, developers—the current state of research leaves a number of questions unaddressed. Terminological confusion exists around the notions of “business semantics”, “business-to-business interoperability”, and “interoperability standards” amongst others. And, moreover, a comprehensive understanding about the characteristics of Semantic IS Standards is missing. The paper addresses this gap in literature by developing a characteristics framework for Semantic IS Standards. Two case studies are used to check the applicability of the framework in a “real-life” context. The framework lays the foundation for future research in an important field of the IS discipline and supports practitioners in their efforts to analyze, compare, and evaluate Semantic IS Standard

Cell salvage and donor blood transfusion during cesarean section: A pragmatic, multicentre randomised controlled trial (SALVO)

BACKGROUND: Excessive haemorrhage at cesarean section requires donor (allogeneic) blood transfusion. Cell salvage may reduce this requirement. METHODS AND FINDINGS: We conducted a pragmatic randomised controlled trial (at 26 obstetric units; participants recruited from 4 June 2013 to 17 April 2016) of routine cell salvage use (intervention) versus current standard of care without routine salvage use (control) in cesarean section among women at risk of haemorrhage. Randomisation was stratified, using random permuted blocks of variable sizes. In an intention-to-treat analysis, we used multivariable models, adjusting for stratification variables and prognostic factors identified a priori, to compare rates of donor blood transfusion (primary outcome) and fetomaternal haemorrhage ≥2 ml in RhD-negative women with RhD-positive babies (a secondary outcome) between groups. Among 3,028 women randomised (2,990 analysed), 95.6% of 1,498 assigned to intervention had cell salvage deployed (50.8% had salvaged blood returned; mean 259.9 ml) versus 3.9% of 1,492 assigned to control. Donor blood transfusion rate was 3.5% in the control group versus 2.5% in the intervention group (adjusted odds ratio [OR] 0.65, 95% confidence interval [CI] 0.42 to 1.01, p = 0.056; adjusted risk difference -1.03, 95% CI -2.13 to 0.06). In a planned subgroup analysis, the transfusion rate was 4.6% in women assigned to control versus 3.0% in the intervention group among emergency cesareans (adjusted OR 0.58, 95% CI 0.34 to 0.99), whereas it was 2.2% versus 1.8% among elective cesareans (adjusted OR 0.83, 95% CI 0.38 to 1.83) (interaction p = 0.46). No case of amniotic fluid embolism was observed. The rate of fetomaternal haemorrhage was higher with the intervention (10.5% in the control group versus 25.6% in the intervention group, adjusted OR 5.63, 95% CI 1.43 to 22.14, p = 0.013). We are unable to comment on long-term antibody sensitisation effects. CONCLUSIONS: The overall reduction observed in donor blood transfusion associated with the routine use of cell salvage during cesarean section was not statistically significant. TRIAL REGISTRATION: This trial was prospectively registered on ISRCTN as trial number 66118656 and can be viewed on http://www.isrctn.com/ISRCTN66118656

Comprehensive evaluation of matrix factorization methods for the analysis of DNA microarray gene expression data

<p>Abstract</p> <p>Background</p> <p>Clustering-based methods on gene-expression analysis have been shown to be useful in biomedical applications such as cancer subtype discovery. Among them, Matrix factorization (MF) is advantageous for clustering gene expression patterns from DNA microarray experiments, as it efficiently reduces the dimension of gene expression data. Although several MF methods have been proposed for clustering gene expression patterns, a systematic evaluation has not been reported yet.</p> <p>Results</p> <p>Here we evaluated the clustering performance of orthogonal and non-orthogonal MFs by a total of nine measurements for performance in four gene expression datasets and one well-known dataset for clustering. Specifically, we employed a non-orthogonal MF algorithm, BSNMF (Bi-directional Sparse Non-negative Matrix Factorization), that applies bi-directional sparseness constraints superimposed on non-negative constraints, comprising a few dominantly co-expressed genes and samples together. Non-orthogonal MFs tended to show better clustering-quality and prediction-accuracy indices than orthogonal MFs as well as a traditional method, K-means. Moreover, BSNMF showed improved performance in these measurements. Non-orthogonal MFs including BSNMF showed also good performance in the functional enrichment test using Gene Ontology terms and biological pathways.</p> <p>Conclusions</p> <p>In conclusion, the clustering performance of orthogonal and non-orthogonal MFs was appropriately evaluated for clustering microarray data by comprehensive measurements. This study showed that non-orthogonal MFs have better performance than orthogonal MFs and <it>K</it>-means for clustering microarray data.</p

Reproducible and relocatable regional ocean modelling: fundamentals and practices

In response to an increasing demand for bespoke or tailored regional ocean modelling configurations, we outline fundamental principles and practices that can expedite the process to generate new configurations. The paper develops the principle of reproducibility and advocates adherence by presenting benefits to the community and user. The elements of this principle are reproducible workflows and standardised assessment, with additional effort over existing working practices being balanced against the added value generated. The paper then decomposes the complex build process, for a new regional ocean configuration, into stages and presents guidance, advice and insight for each component. This advice is compiled from across the NEMO (Nucleus for European Modelling of the Ocean) user community and sets out principles and practises that encompass regional ocean modelling with any model. With detailed and region-specific worked examples in Sects. 3 and 4, the linked companion repositories and DOIs all target NEMOv4. The aim of this review and perspective paper is to broaden the user community skill base and to accelerate development of new configurations in order to increase the time available for exploiting the configurations

Parallel Evolution of a Type IV Secretion System in Radiating Lineages of the Host-Restricted Bacterial Pathogen Bartonella

Adaptive radiation is the rapid origination of multiple species from a single ancestor as the result of concurrent adaptation to disparate environments. This fundamental evolutionary process is considered to be responsible for the genesis of a great portion of the diversity of life. Bacteria have evolved enormous biological diversity by exploiting an exceptional range of environments, yet diversification of bacteria via adaptive radiation has been documented in a few cases only and the underlying molecular mechanisms are largely unknown. Here we show a compelling example of adaptive radiation in pathogenic bacteria and reveal their genetic basis. Our evolutionary genomic analyses of the α-proteobacterial genus Bartonella uncover two parallel adaptive radiations within these host-restricted mammalian pathogens. We identify a horizontally-acquired protein secretion system, which has evolved to target specific bacterial effector proteins into host cells as the evolutionary key innovation triggering these parallel adaptive radiations. We show that the functional versatility and adaptive potential of the VirB type IV secretion system (T4SS), and thereby translocated Bartonella effector proteins (Beps), evolved in parallel in the two lineages prior to their radiations. Independent chromosomal fixation of the virB operon and consecutive rounds of lineage-specific bep gene duplications followed by their functional diversification characterize these parallel evolutionary trajectories. Whereas most Beps maintained their ancestral domain constitution, strikingly, a novel type of effector protein emerged convergently in both lineages. This resulted in similar arrays of host cell-targeted effector proteins in the two lineages of Bartonella as the basis of their independent radiation. The parallel molecular evolution of the VirB/Bep system displays a striking example of a key innovation involved in independent adaptive processes and the emergence of bacterial pathogens. Furthermore, our study highlights the remarkable evolvability of T4SSs and their effector proteins, explaining their broad application in bacterial interactions with the environment