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

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

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

Ice sheet model dependency of the simulated Greenland Ice Sheet in the mid-Pliocene

The understanding of the nature and behavior of ice sheets in past warm periods is important for constraining the potential impacts of future climate change. The Pliocene warm period (between 3.264 and 3.025 Ma) saw global temperatures similar to those projected for future climates; nevertheless, Pliocene ice locations and extents are still poorly constrained. We present results from the efforts to simulate mid-Pliocene Greenland Ice Sheets by means of the international Pliocene Ice Sheet Modeling Intercomparison Project (PLISMIP). We compare the performance of existing numerical ice sheet models in simulating modern control and mid-Pliocene ice sheets with a suite of sensitivity experiments guided by available proxy records. We quantify equilibrated ice sheet volume on Greenland, identifying a potential range in sea level contributions from warm Pliocene scenarios. A series of statistical measures are performed to quantify the confidence of simulations with focus on inter-model and inter-scenario differences. We find that Pliocene Greenland Ice Sheets are less sensitive to differences in ice sheet model configurations and internal physical quantities than to changes in imposed climate forcing. We conclude that Pliocene ice was most likely to be limited to the highest elevations in eastern and southern Greenland as simulated with the highest confidence and by synthesizing available regional proxies; however, the extent of those ice caps needs to be further constrained by using a range of general circulation model (GCM) climate forcings

Magnetic levitation stabilized by streaming fluid flows

We demonstrate that the ubiquitous laboratory magnetic stirrer provides a simple passive method of magnetic levitation, in which the so-called “flea” levitates indefinitely. We study the onset of levitation and quantify the flea’s motion (a combination of vertical oscillation, spinning and “waggling”), finding excellent agreement with a mechanical analytical model. The waggling motion drives recirculating flow, producing a centripetal reaction force that stabilized the flea. Our findings have implications for the locomotion of artificial swimmers and the development of bidirectional microfluidic pumps, and they provide an alternative to sophisticated commercial levitators

Interpreting the forced responses of a two-degree-of-freedom nonlinear oscillator using backbone curves

In this paper the backbone curves of a two-degree-of-freedom nonlinear oscillator are used to interpret its behaviour when subjected to external forcing. The backbone curves describe the loci of dynamic responses of a system when unforced and undamped, and are represented in the frequency-amplitude projection. In this study we provide an analytical method for relating the backbone curves, found using the second-order normal form technique, to the forced responses. This is achieved using an energy-based analysis to predict the resonant crossing points between the forced responses and the backbone curves. This approach is applied to an example system subjected to two different forcing cases: one in which the forcing is applied directly to an underlying linear mode and the other subjected to forcing in both linear modes. Additionally, a method for assessing the accuracy of the prediction of the resonant crossing points is then introduced, and these predictions are then compared to responses found using numerical continuation