33 resultados para 111501 Basic Pharmacology

em CentAUR: Central Archive University of Reading - UK


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Integrations of a fully-coupled climate model with and without flux adjustments in the equatorial oceans are performed under 2×CO2 conditions to explore in more detail the impact of increased greenhouse gas forcing on the monsoon-ENSO system. When flux adjustments are used to correct some systematic model biases, ENSO behaviour in the modelled future climate features distinct irregular and periodic (biennial) regimes. Comparison with the observed record yields some consistency with ENSO modes primarily based on air-sea interaction and those dependent on basinwide ocean wave dynamics. Simple theory is also used to draw analogies between the regimes and irregular (stochastically forced) and self-excited oscillations respectively. Periodic behaviour is also found in the Asian-Australian monsoon system, part of an overall biennial tendency of the model under these conditions related to strong monsoon forcing and increased coupling between the Indian and Pacific Oceans. The tropospheric biennial oscillation (TBO) thus serves as a useful descriptor for the coupled monsoon-ENSO system in this case. The presence of obvious regime changes in the monsoon-ENSO system on interdecadal timescales, when using flux adjustments, suggests there may be greater uncertainty in projections of future climate, although further modelling studies are required to confirm the realism and cause of such changes.

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The impact of doubled CO2 concentration on the Asian summer monsoon is studied using a coupled ocean-atmosphere model. Both the mean seasonal precipitation and interannual monsoon variability are found to increase in the future climate scenario presented. Systematic biases in current climate simulations of the coupled system prevent accurate representation of the monsoon-ENSO teleconnection, of prime importance for seasonal prediction and for determining monsoon interannual variability. By applying seasonally varying heat flux adjustments to the tropical Pacific and Indian Ocean surface in the future climate simulation, some assessment can be made of the impact of systematic model biases on future climate predictions. In simulations where the flux adjustments are implemented, the response to climate change is magnified, with the suggestion that systematic biases may be masking the true impact of increased greenhouse gas forcing. The teleconnection between ENSO and the Asian summer monsoon remains robust in the future climate, although the Indo-Pacific takes on more of a biennial character for long periods of the flux-adjusted simulation. Assessing the teleconnection across interdecadal timescales shows wide variations in its amplitude, despite the absence of external forcing. This suggests that recent changes in the observed record cannot be distinguished from internal variations and as such are not necessarily related to climate change.

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The impact of systematic model errors on a coupled simulation of the Asian Summer monsoon and its interannual variability is studied. Although the mean monsoon climate is reasonably well captured, systematic errors in the equatorial Pacific mean that the monsoon-ENSO teleconnection is rather poorly represented in the GCM. A system of ocean-surface heat flux adjustments is implemented in the tropical Pacific and Indian Oceans in order to reduce the systematic biases. In this version of the GCM, the monsoon-ENSO teleconnection is better simulated, particularly the lag-lead relationships in which weak monsoons precede the peak of El Nino. In part this is related to changes in the characteristics of El Nino, which has a more realistic evolution in its developing phase. A stronger ENSO amplitude in the new model version also feeds back to further strengthen the teleconnection. These results have important implications for the use of coupled models for seasonal prediction of systems such as the monsoon, and suggest that some form of flux correction may have significant benefits where model systematic error compromises important teleconnections and modes of interannual variability.

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In the Eady model, where the meridional potential vorticity (PV) gradient is zero, perturbation energy growth can be partitioned cleanly into three mechanisms: (i) shear instability, (ii) resonance, and (iii) the Orr mechanism. Shear instability involves two-way interaction between Rossby edge waves on the ground and lid, resonance occurs as interior PV anomalies excite the edge waves, and the Orr mechanism involves only interior PV anomalies. These mechanisms have distinct implications for the structural and temporal linear evolution of perturbations. Here, a new framework is developed in which the same mechanisms can be distinguished for growth on basic states with nonzero interior PV gradients. It is further shown that the evolution from quite general initial conditions can be accurately described (peak error in perturbation total energy typically less than 10%) by a reduced system that involves only three Rossby wave components. Two of these are counterpropagating Rossby waves—that is, generalizations of the Rossby edge waves when the interior PV gradient is nonzero—whereas the other component depends on the structure of the initial condition and its PV is advected passively with the shear flow. In the cases considered, the three-component model outperforms approximate solutions based on truncating a modal or singular vector basis.

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This article describes the development and evaluation of the U.K.’s new High-Resolution Global Environmental Model (HiGEM), which is based on the latest climate configuration of the Met Office Unified Model, known as the Hadley Centre Global Environmental Model, version 1 (HadGEM1). In HiGEM, the horizontal resolution has been increased to 0.83° latitude × 1.25° longitude for the atmosphere, and 1/3° × 1/3° globally for the ocean. Multidecadal integrations of HiGEM, and the lower-resolution HadGEM, are used to explore the impact of resolution on the fidelity of climate simulations. Generally, SST errors are reduced in HiGEM. Cold SST errors associated with the path of the North Atlantic drift improve, and warm SST errors are reduced in upwelling stratocumulus regions where the simulation of low-level cloud is better at higher resolution. The ocean model in HiGEM allows ocean eddies to be partially resolved, which dramatically improves the representation of sea surface height variability. In the Southern Ocean, most of the heat transports in HiGEM is achieved by resolved eddy motions, which replaces the parameterized eddy heat transport in the lower-resolution model. HiGEM is also able to more realistically simulate small-scale features in the wind stress curl around islands and oceanic SST fronts, which may have implications for oceanic upwelling and ocean biology. Higher resolution in both the atmosphere and the ocean allows coupling to occur on small spatial scales. In particular, the small-scale interaction recently seen in satellite imagery between the atmosphere and tropical instability waves in the tropical Pacific Ocean is realistically captured in HiGEM. Tropical instability waves play a role in improving the simulation of the mean state of the tropical Pacific, which has important implications for climate variability. In particular, all aspects of the simulation of ENSO (spatial patterns, the time scales at which ENSO occurs, and global teleconnections) are much improved in HiGEM.

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Understanding and predicting changes in storm tracks over longer time scales is a challenging problem, particularly in the North Atlantic. This is due in part to the complex range of forcings (land–sea contrast, orography, sea surface temperatures, etc.) that combine to produce the structure of the storm track. The impact of land–sea contrast and midlatitude orography on the North Atlantic storm track is investigated through a hierarchy of GCM simulations using idealized and “semirealistic” boundary conditions in a high-resolution version of the Hadley Centre atmosphere model (HadAM3). This framework captures the large-scale essence of features such as the North and South American continents, Eurasia, and the Rocky Mountains, enabling the results to be applied more directly to realistic modeling situations than was possible with previous idealized studies. The physical processes by which the forcing mechanisms impact the large-scale flow and the midlatitude storm tracks are discussed. The characteristics of the North American continent are found to be very important in generating the structure of the North Atlantic storm track. In particular, the southwest–northeast tilt in the upper tropospheric jet produced by southward deflection of the westerly flow incident on the Rocky Mountains leads to enhanced storm development along an axis close to that of the continent’s eastern coastline. The approximately triangular shape of North America also enables a cold pool of air to develop in the northeast, intensifying the surface temperature contrast across the eastern coastline, consistent with further enhancements of baroclinicity and storm growth along the same axis.

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Hydrogels are defined as three-dimensionally cross-linked networks of hydrophilic polymers capable of imbibing large amounts of water or biological fluids.They can be prepared from any water-soluble polymer or monomer, encompassing a wide range of chemical compositions and bulk physical properties. In the swollen state hydrogels are soft, wet and elastic materials that resemble natural living tissue, which makes them candidates for developing various biomaterials and dosage forms. This article provides a brief introduction to hydrogels, methods of their synthesis and properties

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We previously identified the function of the hepatitis C virus (HCV) p7 protein as an ion channel in artificial lipid bilayers and demonstrated that this in vitro activity is inhibited by amantadine. Here we show that the ion channel activity of HCV p7 expressed in mammalian cells can substitute for that of influenza virus M2 in a cell-based assay. This was also the case for the p7 from the related virus, bovine viral diarrhoea virus (BVDV). Moreover, amantadine was shown to abrogate HCV p7 function in this assay at a concentration that specifically inhibits M2. Mutation of a conserved basic loop located between the two predicted trans-membrane alpha helices rendered HCV p7 non-functional as an ion channel. The intracellular localization of p7 was unaffected by this mutation and was found to overlap significantly with membranes associated with mitochondria. Demonstration of p7 ion channel activity in cellular membranes and its inhibition by amantadine affirm the protein as a target for future anti-viral chemotherapy.

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Resistant strains of Plasmodium falciparum and the unavailability of useful antimalarial vaccines reinforce the need to develop new efficacious antimalarials. This study details a pharmacophore model that has been used to identify a potent, soluble, orally bioavailable antimalarial bisquinoline, metaquine (N,N'-bis(7-chloroquinolin-4-yl)benzene-1,3-diamine) (dihydrochloride), which is active against Plasmodium berghei in vivo (oral ID50 of 25 mu mol/kg) and multidrug-resistant Plasmodium falciparum K1 in vitro (0.17 mu M). Metaquine shows strong affinity for the putative antimalarial receptor, heme at pH 7.4 in aqueous DMSO. Both crystallographic analyses and quantum mechanical calculations (HF/6-31+G*) reveal important regions of protonation and bonding thought to persist at parasitic vacuolar pH concordant with our receptor model. Formation of drug-heme adduct in solution was confirmed using high-resolution positive ion electrospray mass spectrometry. Metaquine showed strong binding with the receptor in a 1: 1 ratio (log K = 5.7 +/- 0.1) that was predicted by molecular mechanics calculations. This study illustrates a rational multidisciplinary approach for the development of new 4-aminoquinoline antimalarials, with efficacy superior to chloroquine, based on the use of a pharmacophore model.

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The internal partitioning, which is frequently introduced in open-space planning due to its flexibility, was tested to study its effects on the room air quality as well as ventilation performance. For the study, physical tests using a small model room and numerical modeling using CFD computation were utilized to evaluate different test conditions employing mixing ventilation from the ceiling. The partition parameters, such as its location, height, and the gap underneath, as well as contaminant source location were tested under isothermal conditions. This paper summarizes the results from the study.

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Over the last 25 years, the effects of fatty acids on the immune system have been characterized using in vitro, animal and human studies. Advances in fatty acid biochemistry and molecular techniques have recently suggested new mechanisms by which fatty acids could potentially modify immune responses, including modification of the organization of cellular lipids and interaction with nuclear receptors. Possibilities for the clinical applications of n-3 PUFA are now developing. The present review focuses on the hypothesis that the anti-inflammatory properties of n-3 PUFA in the arterial wall may contribute to the protective effects of n-3 PUFA in CVD, as suggested by epidemiological and secondary prevention studies. Studies are just beginning to show that dietary n-3 PUFA can be incorporated into plaque lipid in human subjects, where they may influence the morphology and stability of the atherosclerotic lesion.