Common promoter variant in cyclooxygenase-2 represses gene expression: evidence of role in acute-phase inflammatory response

Objective: Cyclooxygenase (COX)-2 is a key regulatory enzyme in the synthesis of prostanoids associated with trauma and inflammation. We investigated the COX-2 gene for functional variants that may influence susceptibility to disease. Methods and results: The promoter of COX-2 was screened for variants in healthy subjects by use of polymerase chain reaction-based methods. Promoter activity was investigated by using reporter expression experiments in human lung fibroblasts. Patients undergoing coronary artery bypass graft surgery, with measurements of plasma markers linked to COX-2 activity, were genotyped for association studies. A common COX-2 promoter variant, -765G>C, was found and shown to be carried by >25% of a group of healthy UK subjects. The -765C allele had significantly lower promoter activity compared with -765G, basally (28±3% lower, P<0.005) and in serum-stimulated cells (31±2% lower, P<0.005). In patients subjected to coronary artery bypass graft surgery, the magnitude of rise in levels of C-reactive protein (CRP) was strongly genotype dependent. Compared with -765G homozygotes, patients carrying the -765C allele had significantly lower plasma CRP levels at 1 to 4 days after surgery (14% lower at the peak of CRP levels on day 3, P<0.05 for all time points). Conclusions: For several acute and chronic inflammatory diseases, -765G>C may influence the variability of response observed

Comparing the direct normal form method with harmonic balance and the method of multiple scales

Approximate analytical methods have been used extensively for finding approximate solutions to nonlinear ordinary differential equations. In this paper we compare the recently developed direct normal form transformation with two other very well known and long standing methods, harmonic balance and the method of multiple scales. We will show that the direct normal form method combines some of the key advantages of harmonic balance and multiple scales whilst reducing some of the limitations

Electrodynamics of quasi-two-dimensional BEDT-TTF charge transfer salts

We consider the millimeter-wave electrodynamics specific to quasi-two-dimensional conductors and superconductors based on the organic donor molecule BEDT-TTF. Using realistic physical parameters, we examine the current polarizations that result for different oscillating (GHz) electric and magnetic field polarizations. We show that, in general, it is possible to discriminate between effects (dissipation and dispersion) due to in-plane and interlayer ac currents. However, we also show that it is not possible to selectively probe any single component of the in-plane conductivity tensor, and that excitation of interlayer currents is strongly influenced by the sample geometry and the electromagnetic field polarization.Comment: 5 pages including 3 figures Minor correction to figure

Isoform-selective susceptibility of DISC1/phosphodiesterase-4 complexes to dissociation by elevated intracellular cAMP levels

Disrupted-in-schizophrenia 1 (DISC1) is a genetic susceptibility factor for schizophrenia and related severe psychiatric conditions. DISC1 is a multifunctional scaffold protein that is able to interact with several proteins, including the independently identified schizophrenia risk factor phosphodiesterase-4B (PDE4B). Here we report that the 100 kDa full-length DISC1 isoform (fl-DISC1) can bind members of each of the four gene, cAMP-specific PDE4 family. Elevation of intracellular cAMP levels, so as to activate protein kinase A, caused the release of PDE4D3 and PDE4C2 isoforms from fl-DISC1 while not affecting binding of PDE4B1 and PDE4A5 isoforms. Using a peptide array strategy, we show that PDE4D3 binds fl-DISC1 through two regions found in common with PDE4B isoforms, the interaction of which is supplemented because of the presence of additional PDE4B-specific binding sites. We propose that the additional binding sites found in PDE4B1 underpin its resistance to release during cAMP elevation. We identify, for the first time, a functional distinction between the 100 kDa long DISC1 isoform and the short 71 kDa isoform. Thus, changes in the expression pattern of DISC1 and PDE4 isoforms offers a means to reprogram their interaction and to determine whether the PDE4 sequestered by DISC1 is released after cAMP elevation. The PDE4B-specific binding sites encompass point mutations in mouse Disc1 that confer phenotypes related to schizophrenia and depression and that affect binding to PDE4B. Thus, genetic variation in DISC1 and PDE4 that influence either isoform expression or docking site functioning may directly affect psychopathology

Diabatic and Adiabatic Collective Motion in a Model Pairing System

Large amplitude collective motion is investigated for a model pairing Hamiltonian containing an avoided level crossing. A classical theory of collective motion for the adiabatic limit is applied utilising either a time-dependent mean-field theory or a direct parametrisation of the time-dependent Schr\"odinger equation. A modified local harmonic equation is formulated to take account of the Nambu-Goldstone mode. It turns out that in some cases the system selects a diabatic path. Requantizing the collective Hamiltonian, a reasonable agreement with an exact calculation for the low-lying levels are obtained for both weak and strong pairing force. This improves on results of the conventional Born-Oppenheimer approximation.Comment: 23 pages, 7 ps figures. Latex, uses revtex and graphic

The EBR-II Probabilistic Risk Assessment: Results and insights

This paper summarizes the results from the recently completed EBR-II Probabilistic Risk Assessment (PRA) and provides an analysis of the source of risk of the operation of EBR-II from both internal and external initiating events. The EBR-II PRA explicitly accounts for the role of reactivity feedbacks in reducing fuel damage. The results show that the expected core damage frequency from internal initiating events at EBR-II is very low, 1. 6 10[sup [minus]6] yr[sup [minus]1], even with a wide definition of core damage (essentially that of exceeding Technical Specification limits). The probability of damage, primarily due to liquid metal fires, from externally initiated events (excluding earthquake) is 3.6 10[sup [minus]6] yr[sup [minus]1]. overall these results are considerably better than results for other research reactors and the nuclear industry in general and stem from three main sources: low likelihood of loss of coolant due to low system pressure and top entry double, vessels; low likelihood of loss of decay heat removal due to reliance on passive means; and low likelihood of power/flow mismatch due to both passive feedbacks and reliability of rod scram capability

An analytical method for the optimisation of weakly nonlinear systems

In this paper we discuss how backbone curves can be used to guide the design and optimisation of weakly nonlinear systems with multiple degrees-of-freedom. Aft er decomposing the system using the modes of the equivalent linear system (the linear modes), we show how the backbone curves of the unforced, undamped equivalent system can be calculated. These consist of pure responses in each of the linear modes and, in certain parameter regimes, responses which are a combination of two or more linear modes - a feature which can be linked to internal resonance. Using an example system we will investigate how these backbone curves can be used to describe particular characteristics of the response. An energy balancing technique is also employed to relate the backbone curves to the response of the forced and damped system, and anticipate the conditions for which a particular characteristic will be seen. Finally, we discuss how the analytical nature of these techniques enables us to precisely design and optimise characteristics of such systems and how this can be expanded to systems with a greater number of degrees-of-freedom

The use of high-throughput sequencing to investigate an outbreak of glycopeptide-resistant Enterococcus faecium with a novel quinupristin-dalfopristin resistance mechanism.

High-throughput sequencing (HTS) has successfully identified novel resistance genes in enterococci and determined clonal relatedness in outbreak analysis. We report the use of HTS to investigate two concurrent outbreaks of glycopeptide-resistant Enterococcus faecium (GRE) with an uncharacterised resistance mechanism to quinupristin-dalfopristin (QD).Seven QD-resistant and five QD-susceptible GRE isolates from a two-centre outbreak were studied. HTS was performed to identify genes or predicted proteins that were associated with the QD-resistant phenotype. MLST and SNP typing on HTS data was used to determine clonal relatedness.Comparative genomic analysis confirmed this GRE outbreak involved two distinct clones (ST80 and ST192). HTS confirmed the absence of known QD resistance genes, suggesting a novel mechanism was conferring resistance. Genomic analysis identified two significant genetic determinants with explanatory power for the high level of QD resistance in the ST80 QD-resistant clone: an additional 56aa leader sequence at the N-terminus of the lsaE gene and a transposon containing seven genes encoding proteins with possible drug or drug-target modification activities. However, HTS was unable to conclusively determine the QD resistance mechanism and did not reveal any genetic basis for QD resistance in the ST192 clone. This study highlights the usefulness of HTS in deciphering the degree of relatedness in two concurrent GRE outbreaks. Although HTS was able to reveal some genetic candidates for uncharacterised QD resistance, this study demonstrates the limitations of HTS as a tool for identifying putative determinants of resistance to QD