Novel polyvinylpyrrolidones to improve delivery of poorly-water soluble drugs; from design to synthesis and evaluation

Polyvinylpyrrolidone is a widely used in tablet formulations with the linear form acting as a wetting agent and disintegrant whereas the cross-linked form is a super-disintegrant. We have previously reported that simply mixing the commercial cross-linked polymer with ibuprofen disrupted drug crystallinity with consequent improvements in drug dissolution behavior. In this study, we have designed and synthesized novel cross-linking agents containing a range of oligoether moieties which have then be polymerized with vinylpyrrolidone to generate a suite of novel excipients with enhanced hydrogen-bonding capabilities. The polymers have a porous surface and swell in most common solvents and in water; properties which suggest their value as disintegrants. The polymers were evaluated in simple physical mixtures with ibuprofen as a model poorly-water soluble drug. The results show that the novel PVPs induce the drug to become “X-ray amorphous”, which increased dissolution to a greater extent than that seen with commercial cross-linked PVP. The polymers stabilize the amorphous drug with no evidence for recrystallization seen after 20 weeks storage.

Contribution of N Species and P Fractions to Stream Water Quality in Agricultural Catchments

The contribution from agricultural catchments to stream nitrogen and phosphorus concentrations was assessed by evaluation of the chemical composition of these nutrients in agricultural runoff for both surface and subsurface flow pathways. A range of land uses (grazed and ungrazed grassland, cereals, roots) in intensive agricultural systems was studied at scales from hillslope plots (0.5m2) to large catchment (>300km2). By fractionating the total nutrient load it was possible to establish that most of the phosphorus was transported in the unreactive (particulate and organic) fraction via surface runoff. This was true regardless of the scale of measurement. The form of the nitrogen load varied with land use and grazing intensity. High loads of dissolved inorganic nitrogen (with >90% transported as NH4-N) were recorded in surface runoff from heavily grazed land. In subsurface flow from small (2km2) subcatchments and in larger (>300 km2) catchments, organic nitrogen was found to be an important secondary constituent of the total nitrogen load, comprising 40% of the total annual load.

Heterogeneous surface expression of EspA translocon filaments by Escherichia coli O157:H7 is controlled at the posttranscriptional level

Type III secretion systems of enteric bacteria enable translocation of effector proteins into host cells. Secreted proteins of verotoxigenic Escherichia coli O157 strains include components of a translocation apparatus, EspA, -B, and -D, as well as "effectors" such as the translocated intimin receptor (Tir) and the mitochondrion-associated protein (Map). This research has investigated the regulation of LEE4 translocon proteins, in particular EspA. EspA filaments could not be detected on the bacterial cell surface when E. coli O157:H7 was cultured in M9 minimal medium but were expressed from only a proportion of the bacterial population when cultured in minimal essential medium modified with 25 mM HEPES. The highest proportions of EspA-filamented bacteria were detected in late exponential phase, after which filaments were lost rapidly from the bacterial cell surface. Our previous research had shown that human and bovine E. coli O157:H7 strains exhibit marked differences in EspD secretion levels. Here it is demonstrated that the proportion of the bacterial population expressing EspA filaments was associated with the level of EspD secretion. The ability of individual bacteria to express EspA filaments was not controlled at the level of LEE1-4 operon transcription, as demonstrated by using both beta-galactosidase and green fluorescent protein (GFP) promoter fusions. All bacteria, whether expressing EspA filaments or not, showed equivalent levels of GFP expression when LEEI-4 translational fusions were used. Despite this, the LEE4-espADB mRNA was more abundant from populations with a high proportion of nonsecreting bacteria (low secretors) than from populations with a high proportion of secreting and therefore filamented bacteria (high secretors). This research demonstrates that while specific environmental conditions are required to induce LEEI-4 expression, a further checkpoint exists before EspA filaments are produced on the bacterial surface and secretion of effector proteins occurs. This checkpoint in E. coli O157:H7 translocon expression is controlled by a posttranscriptional mechanism acting on LEE4-espADB mRNA. The heterogeneity in EspA filamentation could arise from phase-variable expression of regulators that control this posttranscriptional mechanism.

Land-atmosphere energy exchange in Arctic tundra and boreal forest: available data and feedbacks to climate

This paper summarizes and analyses available data on the surface energy balance of Arctic tundra and boreal forest. The complex interactions between ecosystems and their surface energy balance are also examined, including climatically induced shifts in ecosystem type that might amplify or reduce the effects of potential climatic change. High latitudes are characterized by large annual changes in solar input. Albedo decreases strongly from winter, when the surface is snow-covered, to summer, especially in nonforested regions such as Arctic tundra and boreal wetlands. Evapotranspiration (QE) of high-latitude ecosystems is less than from a freely evaporating surface and decreases late in the season, when soil moisture declines, indicating stomatal control over QE, particularly in evergreen forests. Evergreen conifer forests have a canopy conductance half that of deciduous forests and consequently lower QE and higher sensible heat flux (QH). There is a broad overlap in energy partitioning between Arctic and boreal ecosystems, although Arctic ecosystems and light taiga generally have higher ground heat flux because there is less leaf and stem area to shade the ground surface, and the thermal gradient from the surface to permafrost is steeper. Permafrost creates a strong heat sink in summer that reduces surface temperature and therefore heat flux to the atmosphere. Loss of permafrost would therefore amplify climatic warming. If warming caused an increase in productivity and leaf area, or fire caused a shift from evergreen to deciduous forest, this would increase QE and reduce QH. Potential future shifts in vegetation would have varying climate feedbacks, with largest effects caused by shifts from boreal conifer to shrubland or deciduous forest (or vice versa) and from Arctic coastal to wet tundra. An increase of logging activity in the boreal forests appears to reduce QE by roughly 50% with little change in QH, while the ground heat flux is strongly enhanced.

Sub-surface terahertz imaging through uneven surfaces: visualizing Neolithic wall paintings in Çatalhöyük

Pulsed terahertz imaging is being developed as a technique to image obscured mural paintings. Due to significant advances in terahertz technology, portable systems are now capable of operating in unregulated environments and this has prompted their use on archaeological excavations. August 2011 saw the first use of pulsed terahertz imaging at the archaeological site of Çatalhöyük, Turkey, where mural paintings dating from the Neolithic period are continuously being uncovered by archaeologists. In these particular paintings the paint is applied onto an uneven surface, and then covered by an equally uneven surface. Traditional terahertz data analysis has proven unsuccessful at sub-surface imaging of these paintings due to the effect of these uneven surfaces. For the first time, an image processing technique is presented, based around Gaussian beam-mode coupling, which enables the visualization of the obscured painting.

Growth rate and vertical propagation of the initial error in baroclinic models

The present study investigates the growth of error in baroclinic waves. It is found that stable or neutral waves are particularly sensitive to errors in the initial condition. Short stable waves are mainly sensitive to phase errors and the ultra long waves to amplitude errors. Analysis simulation experiments have indicated that the amplitudes of the very long waves become usually too small in the free atmosphere, due to the sparse and very irregular distribution of upper air observations. This also applies to the four-dimensional data assimilation experiments, since the amplitudes of the very long waves are usually underpredicted. The numerical experiments reported here show that if the very long waves have these kinds of amplitude errors in the upper troposphere or lower stratosphere the error is rapidly propagated (within a day or two) to the surface and to the lower troposphere.

Numerical modelling of the energy and water cycle of the Baltic Sea

This paper will introduce the Baltex research programme and summarize associated numerical modelling work which has been undertaken during the last five years. The research has broadly managed to clarify the main mechanisms determining the water and energy cycle in the Baltic region, such as the strong dependence upon the large scale atmospheric circulation. It has further been shown that the Baltic Sea has a positive water balance, albeit with large interannual variations. The focus on the modelling studies has been the use of limited area models at ultra-high resolution driven by boundary conditions from global models or from reanalysis data sets. The programme has further initiated a comprehensive integration of atmospheric, land surface and hydrological modelling incorporating snow, sea ice and special lake models. Other aspects of the programme include process studies such as the role of deep convection, air sea interaction and the handling of land surface moisture. Studies have also been undertaken to investigate synoptic and sub-synoptic events over the Baltic region, thus exploring the role of transient weather systems for the hydrological cycle. A special aspect has been the strong interests and commitments of the meteorological and hydrological services because of the potentially large societal interests of operational applications of the research. As a result of this interests special attention has been put on data-assimilation aspects and the use of new types of data such as SSM/I, GPS-measurements and digital radar. A series of high resolution data sets are being produced. One of those, a 1/6 degree daily precipitation climatology for the years 1996–1999, is such a unique contribution. The specific research achievements to be presented in this volume of Meteorology and Atmospheric Physics is the result of a cooperative venture between 11 European research groups supported under the EU-Framework programmes.

Observed and simulated precipitation responses in wet and dry regions 1850–2100

Global warming is expected to enhance fluxes of fresh water between the surface and atmosphere, causing wet regions to become wetter and dry regions drier, with serious implications for water resource management. Defining the wet and dry regions as the upper 30% and lower 70% of the precipitation totals across the tropics (30° S–30° N) each month we combine observations and climate model simulations to understand changes in the wet and dry regions over the period 1850–2100. Observed decreases in precipitation over dry tropical land (1950–2010) are also simulated by coupled atmosphere–ocean climate models (−0.3%/decade) with trends projected to continue into the 21st century. Discrepancies between observations and simulations over wet land regions since 1950 exist, relating to decadal fluctuations in El Niño southern oscillation, the timing of which is not represented by the coupled simulations. When atmosphere-only simulations are instead driven by observed sea surface temperature they are able to adequately represent this variability over land. Global distributions of precipitation trends are dominated by spatial changes in atmospheric circulation. However, the tendency for already wet regions to become wetter (precipitation increases with warming by 3% K−1 over wet tropical oceans) and the driest regions drier (precipitation decreases of −2% K−1 over dry tropical land regions) emerges over the 21st century in response to the substantial surface warming.

Diurnal warm-layer events in the western Mediterranean and European shelf seas

We characterize near-surface ocean diurnal warm-layer events, using satellite observations and fields from numerical weather forecasting. The study covers April to September, 2006, over the area 11°W to 17°E and 35°N to 57°N, with 0.1° cells. We use hourly satellite SSTs from which peak amplitudes of diurnal cycles in SST (dSSTs) can be estimated with error ∼0.3 K. The diurnal excursions of SST observed are spatially and temporally coherent. The largest dSSTs exceed 6 K, affect 0.01% of the surface, and are seen in the Mediterranean, North and Irish Seas. There is an anti-correlation between the magnitude and the horizontal length scale of dSST events. Events wherein dSST exceeds 4 K have length scales of ≤40 km. From the frequency distribution of different measures of wind-speed minima, we infer that extreme dSST maxima arise where conditions of low wind speed are sustained from early morning to mid afternoon.

Electronic charge transfer between ceria surfaces and gold adatoms: a GGA+U investigation

We use density functional theory calculations with Hubbard corrections (DFT+U) to investigate electronic aspects of the interaction between ceria surfaces and gold atoms. Our results show that Au adatoms at the (111) surface of ceria can adopt Au0, Au+ or Au� electronic configurations depending on the adsorption site. The strongest adsorption sites are on top of the surface oxygen and in a bridge position between two surface oxygen atoms, and in both cases charge transfer from the gold atom to one of the Ce cations at the surface is involved. Adsorption at other sites, including the hollow sites of the surface, and an O–Ce bridging site, is weaker and does not involve charge transfer. Adsorption at an oxygen vacancy site is very strong and involves the formation of an Au� anion. We argue that the ability of gold atoms to stabilise oxygen vacancies at the ceria surface by moving into the vacancy site and attracting the excess electrons of the defect could be responsible for the enhanced reducibility of ceria surfaces in the presence of gold. Finally, we rationalise the differences in charge transfer behaviour from site to site in terms of the electrostatic potential at the surface and the coordination of the species.

The Joint UK Land Environment Simulator (JULES), model description – part 1: energy and water fluxes

This manuscript describes the energy and water components of a new community land surface model called the Joint UK Land Environment Simulator (JULES). This is developed from the Met Office Surface Exchange Scheme (MOSES). It can be used as a stand alone land surface model driven by observed forcing data, or coupled to an atmospheric global circulation model. The JULES model has been coupled to the Met Office Unified Model (UM) and as such provides a unique opportunity for the research community to contribute their research to improve both world-leading operational weather forecasting and climate change prediction systems. In addition JULES, and its forerunner MOSES, have been the basis for a number of very high-profile papers concerning the land-surface and climate over the last decade. JULES has a modular structure aligned to physical processes, providing the basis for a flexible modelling platform.

A semi-distributed ntegrated itrogen model for multiple source assessment in tchments (INCA): Part I — model structure and process equations

A new model has been developed for assessing multiple sources of nitrogen in catchments. The model (INCA) is process based and uses reaction kinetic equations to simulate the principal mechanisms operating. The model allows for plant uptake, surface and sub-surface pathways and can simulate up to six land uses simultaneously. The model can be applied to catchment as a semi-distributed simulation and has an inbuilt multi-reach structure for river systems. Sources of nitrogen can be from atmospheric deposition, from the terrestrial environment (e.g. agriculture, leakage from forest systems etc.), from urban areas or from direct discharges via sewage or intensive farm units. The model is a daily simulation model and can provide information in the form of time series at key sites, or as profiles down river systems or as statistical distributions. The process model is described and in a companion paper the model is applied to the River Tywi catchment in South Wales and the Great Ouse in Bedfordshire.

The role of dust in climate changes today, at the last glacial maximum and in the future.

Natural mineral aerosol (dust) is an active component of the climate system and plays multiple roles in mediating physical and biogeochemical exchanges between the atmosphere, land surface and ocean. Changes in the amount of dust in the atmosphere are caused both by changes in climate (precipitation, wind strength, regional moisture balance) and changes in the extent of dust sources caused by either anthropogenic or climatically induced changes in vegetation cover. Models of the global dust cycle take into account the physical controls on dust deflation from prescribed source areas (based largely on soil wetness and vegetation cover thresholds), dust transport within the atmospheric column, and dust deposition through sedimentation and scavenging by precipitation. These models successfully reproduce the first-order spatial and temporal patterns in atmospheric dust loading under modern conditions. Atmospheric dust loading was as much as an order-of-magnitude larger than today during the last glacial maximum (LGM). While the observed increase in emissions from northern Africa can be explained solely in terms of climate changes (colder, drier and windier glacial climates), increased emissions from other regions appear to have been largely a response to climatically induced changes in vegetation cover and hence in the extent of dust source areas. Model experiments suggest that the increased dust loading in tropical regions had an effect on radiative forcing comparable to that of low glacial CO2 levels. Changes in land-use are already increasing the dust loading of the atmosphere. However, simulations show that anthropogenically forced climate changes substantially reduce the extent and productivity of natural dust sources. Positive feedbacks initiated by a reduction of dust emissions from natural source areas on both radiative forcing and atmospheric CO2 could substantially mitigate the impacts of land-use changes, and need to be considered in climate change assessments.

Freshwater and heat transports from global ocean synthesis

[1] An eddy-permitting ¼° global ocean reanalysis based on the Operational Met Office FOAM data assimilation system has been run for 1989–2010 forced by ERA-Interim meteorology. Freshwater and heat transports are compared with published estimates globally and in each basin, with special focus on the Atlantic. The meridional transports agree with observations within errors at most locations, but where eddies are active the transports by the mean flow are nearly always in better agreement than the total transports. Eddy transports are down gradient and are enhanced relative to a free run. They may oppose or reinforce mean transports and provide 40–50% of the total transport near midlatitude fronts, where eddies with time scales <1 month provide up to 15%. Basin-scale freshwater convergences are calculated with the Arctic/Atlantic, Indian, and Pacific oceans north of 32°S, all implying net evaporation of 0.33 ± 0.04 Sv, 0.65 ± 0.07 Sv, and 0.09 ± 0.04 Sv, respectively, within the uncertainty of observations in the Atlantic and Pacific. The Indian is more evaporative and the Southern Ocean has more precipitation (1.07 Sv). Air-sea fluxes are modified by assimilation influencing turbulent heat fluxes and evaporation. Generally, surface and assimilation fluxes together match the meridional transports, indicating that the reanalysis is close to a steady state. Atlantic overturning and gyre transports are assessed with overturning freshwater transports southward at all latitudes. At 26°N eddy transports are negligible, overturning transport is 0.67 ± 0.19 Sv southward and gyre transport is 0.44 ± 0.17 Sv northward, with divergence between 26°N and the Bering Strait of 0.13 ± 0.23 Sv over 2004–2010.

Influence of UV radiation on chlorophyll, and antioxidant enzymes of wetland plants in different types of constructed wetland

A surface- and vertical subsurface-flow-constructed wetland were designed to study the response of chlorophyll and antioxidant enzymes to elevated UV radiation in three types of wetland plants (Canna indica, Phragmites austrail, and Typha augustifolia). Results showed that (1) chlorophyll content of C. indica, P. austrail, and T. augustifolia in the constructed wetland was significantly lower where UV radiation was increased by 10 and 20 % above ambient solar level than in treatment with ambient solar UV radiation (p < 0.05). (2) The malondialdehyde (MDA) content, guaiacol peroxidase (POD), superoxide dismutase (SOD), and catalase (CAT) activities of wetland plants increased with elevated UV radiation intensity. (3) The increased rate of MDA, SOD, POD, and CAT activities of C. indica, P. australis, and T. angustifolia by elevated UV radiation of 10 % was higher in vertical subsurface-flow-constructed wetland than in surface-flow-constructed wetland. The sensitivity of MDA, SOD, POD, and CAT activities of C. indica, P. austrail, and T. augustifolia to the elevated UV radiation was lower in surface-flow-constructed wetland than in the vertical subsurface-flow-constructed wetland, which was related to a reduction in UV radiation intensity through the dissolved organic carbon and suspended matter in the water. C. indica had the highest SOD and POD activities, which implied it is more sensitive to enhanced UV radiation. Therefore, different wetland plants had different antioxidant enzymes by elevated UV radiation, which were more sensitive in vertical subsurface-flow-constructed wetland than in surface-flow-constructed wetland.