Cofactor regeneration by a soluble pyridine nucleotide transhydrogenase for biological production of hydromorphone

We have applied the soluble pyridine nucleotide transhydrogenase of Pseudomonas fluorescens to a cell-free system for the regeneration of the nicotinamide cofactors NAD and NADP in the biological production of the important semisynthetic opiate drug hydromorphone. The original recombinant whole-cell system suffered from cofactor depletion resulting from the action of an NADP(+)-dependent morphine dehydrogenase and an NADH-dependent morphinone reductase. By applying a soluble pyridine nucleotide transhydrogenase, which can transfer reducing equivalents between NAD and NADP, we demonstrate with a cell-free system that efficient cofactor cycling in the presence of catalytic amounts of cofactors occurs, resulting in high yields of hydromorphone. The ratio of morphine dehydrogenase, morphinone reductase, and soluble pyridine nucleotide transhydrogenase is critical for diminishing the production of the unwanted by-product dihydromorphine and for optimum hydromorphone yields. Application of the soluble pyridine nucleotide transhydrogenase to the whole-cell system resulted in an improved biocatalyst with an extended lifetime. These results demonstrate the usefulness of the soluble pyridine nucleotide transhydrogenase and its wider application as a tool in metabolic engineering and biocatalysis

The Dilemma of Foraging Herbivores: Dealing with Food and Fear

For foraging herbivores, both food quality and predation risk vary across the landscape. Animals should avoid low-quality food patches in favour of high-quality ones, and seek safe patches while avoiding risky ones. Herbivores often face the foraging dilemma, however, of choosing between high-quality food in risky places or low-quality food in safe places. Here, we explore how and why the interaction between food quality and predation risk affects foraging decisions of mammalian herbivores, focusing on browsers confronting plant toxins in a landscape of fear. We draw together themes of plant–herbivore and predator–prey interactions, and the roles of animal ecophysiology, behaviour and personality. The response of herbivores to the dual costs of food and fear depends on the interplay of physiology and behaviour. We discuss detoxification physiology in dealing with plant toxins, and stress physiology associated with perceived predation risk. We argue that behaviour is the interface enabling herbivores to stay or quit food patches in response to their physiological tolerance to these risks. We hypothesise that generalist and specialist herbivores perceive the relative costs of plant defence and predation risk differently and intra-specifically, individuals with different personalities and physiologies should do so too, creating individualised landscapes of food and fear. We explore the ecological significance and emergent impacts of these individual-based foraging outcomes on populations and communities, and offer predictions that can be clearly tested. In doing so, we provide an integrated platform advancing herbivore foraging theory with food quality and predation risk at its core

Understanding IFNλ in rheumatoid arthritis

Unraveling the mechanisms underlying the inflammatory response in rheumatoid arthritis is crucial in order to better understand the disease and to develop novel therapeutic approaches. Although the effect of type I interferons on fibroblasts and in the context of rheumatoid arthritis has been described for some time, little is known on the effects of the type III interferons, also known as IFNλ. In a previous issue, Xu and colleagues demonstrate that one of the members of the IFNλ family, IFNλ1, enhances Toll-like receptor expression and consequently promotes the production of proinflammatory cytokines known to be involved in initiating and maintaining the inflammatory responses in rheumatoid arthritis

Self-Organization in Urban Regeneration: A Two-Case Comparative Research

Urban regeneration processes in which local stakeholders take the lead are interesting for realizing tailor made and sustainable urban regeneration, but are also faced with serious difficulties. We use the concept of self-organization from complexity theory to examine the relationship between local stakeholders’ initiatives and vital urban regeneration processes. We conducted a two-case comparative research, Caterham Barracks and Broad Street Business Improvement Districts Birmingham (UK), in which local stakeholders take the lead. We analyse the evolution of these regeneration processes by using two different manifestations of self-organization: autopoietic and dissipative self-organization. We found that a balanced interplay between autopoietic and dissipative self-organization of local stakeholders is important for vital urban regeneration processes to establish. We elaborate four explanatory conditions for this interplay. These conditions provide at the one hand stability and identity development, but also the needed connections with established actors and institutions around urban regeneration and flexibility to adjust to evolving demands during the process of regeneration. However, consolidation of such initiatives does mean a challenge for existing structures for the government, market and society that will need to adapt and change their roles to new governance realities. In this way self-organizing processes become meaningful in the regeneration of urban areas

Generalized Conformal Quantum Mechanics of D0-brane

We study the generalized conformal quantum mechanics of the probe D0-brane in the near horizon background of the bound state of source D0-branes. We elaborate on the relationship of such model to the M theory in the light cone frame.Comment: 14 pages, RevTeX, revised version with added references to appear in Phys. Rev.

Microstructural and physical aspects of heat treated wood, part 1: softwood

Heat treatment of wood is an effective method to improve the dimensional stability and durability against biodegradation. Optimisation of a two-stage heat treatment process at relatively mild conditions (<200°C) and its effect on the anatomical structure of softwoods were investigated by means of a light and scanning electron microscopic analysis. Heat treatment did have an effect on the anatomical structure of wood, although this depends on the wood species considered and on the process method and conditions used. Softwood species with narrow annual rings and/or an abrupt transition from earlywood into latewood were sensitive to tangential cracks in the latewood section. Radial cracks occurred mainly in impermeable wood species such as Norway spruce, caused by large stresses in the wood structure during treatment. Sapwood of treated pine species revealed some damage to parenchyma cells in the rays and epithelial cells around resin canals, whereas this phenomenon has not been noticed in the heartwood section. Treated radiata pine resulted in a very open and permeable wood structure limiting the applications of this species. Broken cell walls perpendicular to the fibre direction resulting in transverse ruptures have been noticed in treated softwood species. This contributes to abrupt fractures of treated wood as observed in bending tests which can lead to considerably different failure behavior after impact or mechanical stress. In some treated softwood species maceration (small cracks between tracheids) was noticed after heat treatment. Heat treatment did not cause damage to the ray parenchyma pit membranes, bordered pits and large window pit membranes; the margo fibrils appeared without damage. Compared to the other softwood timbers tested European grown Douglas fir was the timber that stands heat treatment the best

The Gaugings of Maximal D=6 Supergravity

We construct the most general gaugings of the maximal D=6 supergravity. The theory is (2,2) supersymmetric, and possesses an on-shell SO(5,5) duality symmetry which plays a key role in determining its couplings. The field content includes 16 vector fields that carry a chiral spinor representation of the duality group. We utilize the embedding tensor method which determines the appropriate combinations of these vectors that participate in gauging of a suitable subgroup of SO(5,5). The construction also introduces the magnetic duals of the 5 two-form potentials and 16 vector fields.Comment: 34 pages, latex, reference added, typo's corrected and minor improvements mad

The Conformal Penrose Limit and the Resolution of the pp-curvature Singularities

We consider the exact solutions of the supergravity theories in various dimensions in which the space-time has the form M_{d} x S^{D-d} where M_{d} is an Einstein space admitting a conformal Killing vector and S^{D-d} is a sphere of an appropriate dimension. We show that, if the cosmological constant of M_{d} is negative and the conformal Killing vector is space-like, then such solutions will have a conformal Penrose limit: M^{(0)}_{d} x S^{D-d} where M^{(0)}_{d} is a generalized d-dimensional AdS plane wave. We study the properties of the limiting solutions and find that M^{(0)}_{d} has 1/4 supersymmetry as well as a Virasoro symmetry. We also describe how the pp-curvature singularity of M^{(0)}_{d} is resolved in the particular case of the D6-branes of D=10 type IIA supergravity theory. This distinguished case provides an interesting generalization of the plane waves in D=11 supergravity theory and suggests a duality between the SU(2) gauged d=8 supergravity of Salam and Sezgin on M^{(0)}_{8} and the d=7 ungauged supergravity theory on its pp-wave boundary.Comment: 20 pages, LaTeX; typos corrected, journal versio

Tests for Gene-Environment Interactions and Joint Effects with Exposure Misclassification

The number of methods for genome-wide testing of gene-environment interactions (GEI) continues to increase with the hope of discovering new genetic risk factors and obtaining insight into the disease-gene-environment relationship. The relative performance of these methods based on family-wise type 1 error rate and power depends on underlying disease-gene-environment associations, estimates of which may be biased in the presence of exposure misclassification. This simulation study expands on a previously published simulation study of methods for detecting GEI by evaluating the impact of exposure misclassification. We consider seven single step and modular screening methods for identifying GEI at a genome-wide level and seven joint tests for genetic association and GEI, for which the goal is to discover new genetic susceptibility loci by leveraging GEI when present. In terms of statistical power, modular methods that screen based on the marginal disease-gene relationship are more robust to exposure misclassification. Joints tests that include main/marginal effects of a gene display a similar robustness, confirming results from earlier studies. Our results offer an increased understanding of the strengths and limitations of methods for genome-wide search for GEI and joint tests in presence of exposure misclassification. KEY WORDS: case-control; genome-wide association; gene discovery, gene-environment independence; modular methods; multiple testing; screening test; weighted hypothesis test. Abbreviations: CC, case-control; CC(EXP), CC in the exposed subgroup; CO, case-only; CT, cocktail; DF, degree of freedom; D-G, disease-gene; EB, empirical Bayes; EB(EXP), EB in the exposed subgroup; EDGxE, joint marginal/association screening; FWER, family-wise error rate; G-E, gene-environment; GEI, gene-environment interaction; GEWIS, Gene Environment Wide Interaction Study; H2, hybrid two-step; LR, likelihood ratio; MA, marginal; OR, odds ratio; SE, sensitivity; SP, specificity; TS, two-step gene-environment screening

Supergravity, Non-Conformal Field Theories and Brane-Worlds

We consider the supergravity dual descriptions of non-conformal super Yang-Mills theories realized on the world-volume of Dp-branes. We use the dual description to compute stress-energy tensor and current correlators. We apply the results to the study of dilatonic brane-worlds described by non-conformal field theories coupled to gravity. We find that brane-worlds based on D4 and D5 branes exhibit a localization of gauge and gravitational fields. We calculate the corrections to the Newton and Coulomb laws in these theories.Comment: 24 pages, Latex, 2 figure