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

Improving the measurement of QALYs in dementia: developing patient- and carer-reported health state classification systems using Rasch analysis

Objectives: Cost-utility analysis is increasingly used to inform resource allocation. This requires a means of valuing health states before and after intervention. Although generic measures are typically used to generate values, these do not perform well with people with dementia. We report the development of a health state classification system amenable to valuation for use in studies of dementia, derived from the DEMQOL system, a measure of health-related quality of life in dementia by patient self-report (DEMQOL) and carer proxy-report (DEMQOL-Proxy). Methods: Factor analysis was used to determine the dimensional structure of DEMQOL and DEMQOL-Proxy. Rasch analysis was subsequently used to investigate item performance across factors in terms of item-level ordering, functioning across subgroups, model fit and severity-range coverage. This enabled the selection of one item from each factor for the classification system. A sample of people with a diagnosis of mild/moderate dementia (n=644) and a sample of carers of those with mild/moderate dementia (n=683) were used. Results: Factor analysis found different 5-factor solutions for DEMQOL and DEMQOL-Proxy. Following item reduction and selection using Rasch analysis, a 5-dimension classification for DEMQOL and a 4-dimension classification for DEMQOL-Proxy were developed. Each item contained 4 health state levels. Conclusion: Combining Rasch and classical psychometric analysis is a valid method of selecting items for dementia health state classifications from both the patient and carer perspectives. The next stage is to obtain preference weights so that the measure can be used in the economic evaluation of treatment, care and support arrangements for dementia.quality adjusted life years; health related quality of life; Rasch analysis; preference-based measures of health; health states; dementia

Using Rasch analysis to form plausible health states amenable to valuation: the development of CORE-6D from CORE-OM in order to elicit preferences for common mental health problems

Purpose: To describe a new approach for deriving a preference-based index from a condition specific measure that uses Rasch analysis to develop health states. Methods: CORE-OM is a 34-item instrument monitoring clinical outcomes of people with common mental health problems. CORE-OM is characterised by high correlation across its domains. Rasch analysis was used to reduce the number of items and response levels in order to produce a set of unidimensionally-behaving items, and to generate a credible set of health states corresponding to different levels of symptom severity using the Rasch item threshold map. Results: The proposed methodology resulted in the development of CORE-6D, a 2-dimensional health state description system consisting of a unidimensionally-behaving 5-item emotional component and a physical symptom item. Inspection of the Rasch item threshold map of the emotional component helped identify a set of 11 plausible health states, which, combined with the physical symptom item levels, will be used for the valuation of the instrument, resulting in the development of a preference-based index. Conclusions: This is a useful new approach to develop preference-based measures where the domains of a measure are characterised by high correlation. The CORE-6D preference-based index will enable calculation of Quality Adjusted Life Years in people with common mental health problems

Warped Riemannian metrics for location-scale models

The present paper shows that warped Riemannian metrics, a class of Riemannian metrics which play a prominent role in Riemannian geometry, are also of fundamental importance in information geometry. Precisely, the paper features a new theorem, which states that the Rao-Fisher information metric of any location-scale model, defined on a Riemannian manifold, is a warped Riemannian metric, whenever this model is invariant under the action of some Lie group. This theorem is a valuable tool in finding the expression of the Rao-Fisher information metric of location-scale models defined on high-dimensional Riemannian manifolds. Indeed, a warped Riemannian metric is fully determined by only two functions of a single variable, irrespective of the dimension of the underlying Riemannian manifold. Starting from this theorem, several original contributions are made. The expression of the Rao-Fisher information metric of the Riemannian Gaussian model is provided, for the first time in the literature. A generalised definition of the Mahalanobis distance is introduced, which is applicable to any location-scale model defined on a Riemannian manifold. The solution of the geodesic equation is obtained, for any Rao-Fisher information metric defined in terms of warped Riemannian metrics. Finally, using a mixture of analytical and numerical computations, it is shown that the parameter space of the von Mises-Fisher model of $n$-dimensional directional data, when equipped with its Rao-Fisher information metric, becomes a Hadamard manifold, a simply-connected complete Riemannian manifold of negative sectional curvature, for $n = 2,\ldots,8$. Hopefully, in upcoming work, this will be proved for any value of $n$.Comment: first version, before submissio

A new interpretation of total column BrO during Arctic spring

Emission of bromine from sea-salt aerosol, frost flowers, ice leads, and snow results in the nearly complete removal of surface ozone during Arctic spring. Regions of enhanced total column BrO observed by satellites have traditionally been associated with these emissions. However, airborne measurements of BrO and O3 within the convective boundary layer (CBL) during the ARCTAS and ARCPAC field campaigns at times bear little relation to enhanced column BrO. We show that the locations of numerous satellite BrO "hotspots" during Arctic spring are consistent with observations of total column ozone and tropopause height, suggesting a stratospheric origin to these regions of elevated BrO. Tropospheric enhancements of BrO large enough to affect the column abundance are also observed, with important contributions originating from above the CBL. Closure of the budget for total column BrO, albeit with significant uncertainty, is achieved by summing observed tropospheric partial columns with calculated stratospheric partial columns provided that natural, short-lived biogenic bromocarbons supply between 5 and 10 ppt of bromine to the Arctic lowermost stratosphere. Proper understanding of bromine and its effects on atmospheric composition requires accurate treatment of geographic variations in column BrO originating from both the stratosphere and troposphere. Copyright 2010 by the American Geophysical Union

A Global SU(5) F-theory model with Wilson line breaking

We engineer compact SU(5) Grand Unified Theories in F-theory in which GUT-breaking is achieved by a discrete Wilson line. Because the internal gauge field is flat, these models avoid the high scale threshold corrections associated with hypercharge flux. Along the way, we exemplify the `local-to-global' approach in F-theory model building and demonstrate how the Tate divisor formalism can be used to address several challenges of extending local models to global ones. These include in particular the construction of G-fluxes that extend non-inherited bundles and the engineering of U(1) symmetries. We go beyond chirality computations and determine the precise (charged) massless spectrum, finding exactly three families of quarks and leptons but excessive doublet and/or triplet pairs in the Higgs sector (depending on the example) and vector-like exotics descending from the adjoint of SU(5)_{GUT}. Understanding why vector-like pairs persist in the Higgs sector without an obvious symmetry to protect them may shed light on new solutions to the mu problem in F-theory GUTs.Comment: 95 pages (71 pages + 1 Appendix); v2 references added, minor correction

Structural insights into Clostridium perfringens delta toxin pore formation

Clostridium perfringens Delta toxin is one of the three hemolysin-like proteins produced by C. perfringens type C and possibly type B strains. One of the others, NetB, has been shown to be the major cause of Avian Nectrotic Enteritis, which following the reduction in use of antibiotics as growth promoters, has become an emerging disease of industrial poultry. Delta toxin itself is cytotoxic to the wide range of human and animal macrophages and platelets that present GM2 ganglioside on their membranes. It has sequence similarity with Staphylococcus aureus β-pore forming toxins and is expected to heptamerize and form pores in the lipid bilayer of host cell membranes. Nevertheless, its exact mode of action remains undetermined. Here we report the 2.4 Å crystal structure of monomeric Delta toxin. The superposition of this structure with the structure of the phospholipid-bound F component of S. aureus leucocidin (LukF) revealed that the glycerol molecules bound to Delta toxin and the phospholipids in LukF are accommodated in the same hydrophobic clefts, corresponding to where the toxin is expected to latch onto the membrane, though the binding sites show significant differences. From structure-based sequence alignment with the known structure of staphylococcal α-hemolysin, a model of the Delta toxin pore form has been built. Using electron microscopy, we have validated our model and characterized the Delta toxin pore on liposomes. These results highlight both similarities and differences in the mechanism of Delta toxin (and by extension NetB) cytotoxicity from that of the staphylococcal pore-forming toxins

Biodiversity Loss and the Taxonomic Bottleneck: Emerging Biodiversity Science

Human domination of the Earth has resulted in dramatic changes to global and local patterns of biodiversity. Biodiversity is critical to human sustainability because it drives the ecosystem services that provide the core of our life-support system. As we, the human species, are the primary factor leading to the decline in biodiversity, we need detailed information about the biodiversity and species composition of specific locations in order to understand how different species contribute to ecosystem services and how humans can sustainably conserve and manage biodiversity. Taxonomy and ecology, two fundamental sciences that generate the knowledge about biodiversity, are associated with a number of limitations that prevent them from providing the information needed to fully understand the relevance of biodiversity in its entirety for human sustainability: (1) biodiversity conservation strategies that tend to be overly focused on research and policy on a global scale with little impact on local biodiversity; (2) the small knowledge base of extant global biodiversity; (3) a lack of much-needed site-specific data on the species composition of communities in human-dominated landscapes, which hinders ecosystem management and biodiversity conservation; (4) biodiversity studies with a lack of taxonomic precision; (5) a lack of taxonomic expertise and trained taxonomists; (6) a taxonomic bottleneck in biodiversity inventory and assessment; and (7) neglect of taxonomic resources and a lack of taxonomic service infrastructure for biodiversity science. These limitations are directly related to contemporary trends in research, conservation strategies, environmental stewardship, environmental education, sustainable development, and local site-specific conservation. Today’s biological knowledge is built on the known global biodiversity, which represents barely 20% of what is currently extant (commonly accepted estimate of 10 million species) on planet Earth. Much remains unexplored and unknown, particularly in hotspots regions of Africa, South Eastern Asia, and South and Central America, including many developing or underdeveloped countries, where localized biodiversity is scarcely studied or described. ‘‘Backyard biodiversity’’, defined as local biodiversity near human habitation, refers to the natural resources and capital for ecosystem services at the grassroots level, which urgently needs to be explored, documented, and conserved as it is the backbone of sustainable economic development in these countries. Beginning with early identification and documentation of local flora and fauna, taxonomy has documented global biodiversity and natural history based on the collection of ‘‘backyard biodiversity’’ specimens worldwide. However, this branch of science suffered a continuous decline in the latter half of the twentieth century, and has now reached a point of potential demise. At present there are very few professional taxonomists and trained local parataxonomists worldwide, while the need for, and demands on, taxonomic services by conservation and resource management communities are rapidly increasing. Systematic collections, the material basis of biodiversity information, have been neglected and abandoned, particularly at institutions of higher learning. Considering the rapid increase in the human population and urbanization, human sustainability requires new conceptual and practical approaches to refocusing and energizing the study of the biodiversity that is the core of natural resources for sustainable development and biotic capital for sustaining our life-support system. In this paper we aim to document and extrapolate the essence of biodiversity, discuss the state and nature of taxonomic demise, the trends of recent biodiversity studies, and suggest reasonable approaches to a biodiversity science to facilitate the expansion of global biodiversity knowledge and to create useful data on backyard biodiversity worldwide towards human sustainability

Spacelike Singularities and Hidden Symmetries of Gravity

We review the intimate connection between (super-)gravity close to a spacelike singularity (the "BKL-limit") and the theory of Lorentzian Kac-Moody algebras. We show that in this limit the gravitational theory can be reformulated in terms of billiard motion in a region of hyperbolic space, revealing that the dynamics is completely determined by a (possibly infinite) sequence of reflections, which are elements of a Lorentzian Coxeter group. Such Coxeter groups are the Weyl groups of infinite-dimensional Kac-Moody algebras, suggesting that these algebras yield symmetries of gravitational theories. Our presentation is aimed to be a self-contained and comprehensive treatment of the subject, with all the relevant mathematical background material introduced and explained in detail. We also review attempts at making the infinite-dimensional symmetries manifest, through the construction of a geodesic sigma model based on a Lorentzian Kac-Moody algebra. An explicit example is provided for the case of the hyperbolic algebra E10, which is conjectured to be an underlying symmetry of M-theory. Illustrations of this conjecture are also discussed in the context of cosmological solutions to eleven-dimensional supergravity.Comment: 228 pages. Typos corrected. References added. Subject index added. Published versio