Guanine specific binding at a DNA junction formed by d[CG(5-BrU)ACG]2 with a topoisomerase poison in the presence of Co2+Ions���,���

The structure of the duplex d[CG(5-BrU)ACG]2 bound to 9-bromophenazine-4-carboxamide has been solved through MAD phasing at 2.0 �� resolution. It shows an unexpected and previously unreported intercalation cavity stabilized by the drug and novel binding modes of Co2+ ions at certain guanine N7 sites. For the intercalation cavity the terminal cytosine is rotated to pair with the guanine of a symmetry-related duplex to create a pseudo-Holliday junction geometry, with two such cavities linked through the minor groove interactions of the N2/N3 guanine sites at an angle of 40��, creating a quadruplex-like structure. The mode of binding of the drug is shown to be disordered, with the major conformations showing the side chain bound to the N7 position of adjacent guanines. The other end of the duplex exhibits a terminal base fraying in the presence of Co2+ ions linking symmetry-related guanines, causing the helices to intertwine through the minor groove. The stabilization of the structure by the intercalating drug shows that this class of compound may bind to DNA junctions as well as duplex DNA or to strand-nicked DNA (���hemi-intercalated'), as in the cleavable complex. This suggests a structural basis for the dual poisoning of topoisomerase I and II enzymes by this family of drugs.

Time-resolved in situ X-ray scattering studies of aqueous hydroxypropylcellulose solutions

The evolution of the global orientation parameter for a series of aqueous hydroxypropylcellulose solutions both during and following the cessation of a steady-state shear flow is reported. Time-resolved orientation measurements were made in situ through a novel X-ray rheometer coupled with a two-dimensional electronic X-ray camera, and using an intense X-ray source at the LURE synchrotron. After the cessation of flow, the global orientation decreases from the steady-state orientation level to zero following shear flow at low shear rate or to a small but finite value after flow at a high shear rate. The decrease of orientation with time shows different behaviour, dependent upon the previously applied shear rate.

Commercial real estate return distributions: a review of literature and empirical evidence

This paper review the literature on the distribution of commercial real estate returns. There is growing evidence that the assumption of normality in returns is not safe. Distributions are found to be peaked, fat-tailed and, tentatively, skewed. There is some evidence of compound distributions and non-linearity. Public traded real estate assets (such as property company or REIT shares) behave in a fashion more similar to other common stocks. However, as in equity markets, it would be unwise to assume normality uncritically. Empirical evidence for UK real estate markets is obtained by applying distribution fitting routines to IPD Monthly Index data for the aggregate index and selected sub-sectors. It is clear that normality is rejected in most cases. It is often argued that observed differences in real estate returns are a measurement issue resulting from appraiser behaviour. However, unsmoothing the series does not assist in modelling returns. A large proportion of returns are close to zero. This would be characteristic of a thinly-traded market where new information arrives infrequently. Analysis of quarterly data suggests that, over longer trading periods, return distributions may conform more closely to those found in other asset markets. These results have implications for the formulation and implementation of a multi-asset portfolio allocation strategy.

On the numerical integration of a class of singular perturbation problems

A three-point difference scheme recently proposed in Ref. 1 for the numerical solution of a class of linear, singularly perturbed, two-point boundary-value problems is investigated. The scheme is derived from a first-order approximation to the original problem with a small deviating argument. It is shown here that, in the limit, as the deviating argument tends to zero, the difference scheme converges to a one-sided approximation to the original singularly perturbed equation in conservation form. The limiting scheme is shown to be stable on any uniform grid. Therefore, no advantage arises from using the deviating argument, and the most accurate and efficient results are obtained with the deviation at its zero limit.

Regularized logistic models for probabilistic forecasting and diagnostics

Logistic models are studied as a tool to convert dynamical forecast information (deterministic and ensemble) into probability forecasts. A logistic model is obtained by setting the logarithmic odds ratio equal to a linear combination of the inputs. As with any statistical model, logistic models will suffer from overfitting if the number of inputs is comparable to the number of forecast instances. Computational approaches to avoid overfitting by regularization are discussed, and efficient techniques for model assessment and selection are presented. A logit version of the lasso (originally a linear regression technique), is discussed. In lasso models, less important inputs are identified and the corresponding coefficient is set to zero, providing an efficient and automatic model reduction procedure. For the same reason, lasso models are particularly appealing for diagnostic purposes.

Physically consistent responses of the global atmospheric hydrological cycle in models and observations

Robust and physically understandable responses of the global atmospheric water cycle to a warming climate are presented. By considering interannual responses to changes in surface temperature (T), observations and AMIP5 simulations agree on an increase in column integrated water vapor at the rate 7 %/K (in line with the Clausius��Clapeyron equation) and of precipitation at the rate 2-��3 %/K (in line with energetic constraints). Using simple and complex climate models, we demonstrate that radiative forcing by greenhouse gases is currently suppressing global precipitation (P) at ~ -0.15 %/decade. Along with natural variability, this can explain why observed trends in global P over the period 1988-2008 are close to zero. Regional responses in the global water cycle are strongly constrained by changes in moisture fluxes. Model simulations show an increased moisture flux into the tropical wet region at 900 hPa and an enhanced outflow (of smaller magnitude) at around 600 hPa with warming. Moisture transport explains an increase in P in the wet tropical regions and small or negative changes in the dry regions of the subtropics in CMIP5 simulations of a warming climate. For AMIP5 simulations and satellite observations, the heaviest 5-day rainfall totals increase in intensity at ~15 %/K over the ocean with reductions at all percentiles over land. The climate change response in CMIP5 simulations shows consistent increases in P over ocean and land for the highest intensities, close to the Clausius-Clapeyron scaling of 7 %/K, while P declines for the lowest percentiles, indicating that interannual variability over land may not be a good proxy for climate change. The local changes in precipitation and its extremes are highly dependent upon small shifts in the large-scale atmospheric circulation and regional feedbacks.

Transport impacts on atmosphere and climate: shipping

Emissions of exhaust gases and particles from oceangoing ships are a significant and growing contributor to the total emissions from the transportation sector. We present an assessment of the contribution of gaseous and particulate emissions from oceangoing shipping to anthropogenic emissions and air quality. We also assess the degradation in human health and climate change created by these emissions. Regulating ship emissions requires comprehensive knowledge of current fuel consumption and emissions, understanding of their impact on atmospheric composition and climate, and projections of potential future evolutions and mitigation options. Nearly 70% of ship emissions occur within 400 km of coastlines, causing air quality problems through the formation of ground-level ozone, sulphur emissions and particulate matter in coastal areas and harbours with heavy traffic. Furthermore, ozone and aerosol precursor emissions as well as their derivative species from ships may be transported in the atmosphere over several hundreds of kilometres, and thus contribute to air quality problems further inland, even though they are emitted at sea. In addition, ship emissions impact climate. Recent studies indicate that the cooling due to altered clouds far outweighs the warming effects from greenhouse gases such as carbon dioxide (CO2) or ozone from shipping, overall causing a negative present-day radiative forcing (RF). Current efforts to reduce sulphur and other pollutants from shipping may modify this. However, given the short residence time of sulphate compared to CO2, the climate response from sulphate is of the order decades while that of CO2 is centuries. The climatic trade-off between positive and negative radiative forcing is still a topic of scientific research, but from what is currently known, a simple cancellation of global mean forcing components is potentially inappropriate and a more comprehensive assessment metric is required. The CO2 equivalent emissions using the global temperature change potential (GTP) metric indicate that after 50 years the net global mean effect of current emissions is close to zero through cancellation of warming by CO2 and cooling by sulphate and nitrogen oxides.

Rigid body trajectories in different 6D spaces

The objective of this paper is to show that the group SE(3) with an imposed Lie-Poisson structure can be used to determine the trajectory in a spatial frame of a rigid body in Euclidean space. Identical results for the trajectory are obtained in spherical and hyperbolic space by scaling the linear displacements appropriately since the influence of the moments of inertia on the trajectories tends to zero as the scaling factor increases. The semidirect product of the linear and rotational motions gives the trajectory from a body frame perspective. It is shown that this cannot be used to determine the trajectory in the spatial frame. The body frame trajectory is thus independent of the velocity coupling. In addition, it is shown that the analysis can be greatly simplified by aligning the axes of the spatial frame with the axis of symmetry which is unchanging for a natural system with no forces and rotation about an axis of symmetry.

Comments on 'Balance and the slow quasimanifold: some explicit results'

The concept of slow vortical dynamics and its role in theoretical understanding is central to geophysical fluid dynamics. It leads, for example, to ���potential vorticity thinking��� (Hoskins et al. 1985). Mathematically, one imagines an invariant manifold within the phase space of solutions, called the slow manifold (Leith 1980; Lorenz 1980), to which the dynamics are constrained. Whether this slow manifold truly exists has been a major subject of inquiry over the past 20 years. It has become clear that an exact slow manifold is an exceptional case, restricted to steady or perhaps temporally periodic flows (Warn 1997). Thus the concept of a ���fuzzy slow manifold��� (Warn and M��nard 1986) has been suggested. The idea is that nearly slow dynamics will occur in a stochastic layer about the putative slow manifold. The natural question then is, how thick is this layer? In a recent paper, Ford et al. (2000) argue that Lighthill emission���the spontaneous emission of freely propagating acoustic waves by unsteady vortical flows���is applicable to the problem of balance, with the Mach number Ma replaced by the Froude number F, and that it is a fundamental mechanism for this fuzziness. They consider the rotating shallow-water equations and find emission of inertia���gravity waves at O(F2). This is rather surprising at first sight, because several studies of balanced dynamics with the rotating shallow-water equations have gone beyond second order in F, and found only an exponentially small unbalanced component (Warn and M��nard 1986; Lorenz and Krishnamurthy 1987; Bokhove and Shepherd 1996; Wirosoetisno and Shepherd 2000). We have no technical objection to the analysis of Ford et al. (2000), but wish to point out that it depends crucially on R 1, where R is the Rossby number. This condition requires the ratio of the characteristic length scale of the flow L to the Rossby deformation radius LR to go to zero in the limit F ��� 0. This is the low Froude number scaling of Charney (1963), which, while originally designed for the Tropics, has been argued to be also relevant to mesoscale dynamics (Riley et al. 1981). If L/LR is fixed, however, then F ��� 0 implies R ��� 0, which is the standard quasigeostrophic scaling of Charney (1948; see, e.g., Pedlosky 1987). In this limit there is reason to expect the fuzziness of the slow manifold to be ���exponentially thin,��� and balance to be much more accurate than is consistent with (algebraic) Lighthill emission.

The reversibility of sea level rise

During the last century, global climate has been warming, and projections indicate that such a warming is likely to continue over coming decades. Most of the extra heat is stored in the ocean, resulting in thermal expansion of seawater and global mean sea level rise. Previous studies have shown that after CO2 emissions cease or CO2 concentration is stabilized, global mean surface air temperature stabilizes or decreases slowly, but sea level continues to rise. Using idealized CO2 scenario simulations with a hierarchy of models including an AOGCM and a step-response model, the authors show how the evolution of thermal expansion can be interpreted in terms of the climate energy balance and the vertical profile of ocean warming. Whereas surface temperature depends on cumulative CO2 emissions, sea level rise due to thermal expansion depends on the time profile of emissions. Sea level rise is smaller for later emissions, implying that targets to limit sea level rise would need to refer to the rate of emissions, not only to the time integral. Thermal expansion is in principle reversible, but to halt or reverse it quickly requires the radiative forcing to be reduced substantially, which is possible on centennial time scales only by geoengineering. If it could be done, the results indicate that heat would leave the ocean more readily than it entered, but even if thermal expansion were returned to zero, the geographical pattern of sea level would be altered. Therefore, despite any aggressive CO2 mitigation, regional sea level change is inevitable.

Analysis of the seasonal cycle within the first international urban land-surface model comparison

A number of urban land-surface models have been developed in recent years to satisfy the growing requirements for urban weather and climate interactions and prediction. These models vary considerably in their complexity and the processes that they represent. Although the models have been evaluated, the observational datasets have typically been of short duration and so are not suitable to assess the performance over the seasonal cycle. The First International Urban Land-Surface Model comparison used an observational dataset that spanned a period greater than a year, which enables an analysis over the seasonal cycle, whilst the variety of models that took part in the comparison allows the analysis to include a full range of model complexity. The results show that, in general, urban models do capture the seasonal cycle for each of the surface fluxes, but have larger errors in the summer months than in the winter. The net all-wave radiation has the smallest errors at all times of the year but with a negative bias. The latent heat flux and the net storage heat flux are also underestimated, whereas the sensible heat flux generally has a positive bias throughout the seasonal cycle. A representation of vegetation is a necessary, but not sufficient, condition for modelling the latent heat flux and associated sensible heat flux at all times of the year. Models that include a temporal variation in anthropogenic heat flux show some increased skill in the sensible heat flux at night during the winter, although their daytime values are consistently overestimated at all times of the year. Models that use the net all-wave radiation to determine the net storage heat flux have the best agreement with observed values of this flux during the daytime in summer, but perform worse during the winter months. The latter could result from a bias of summer periods in the observational datasets used to derive the relations with net all-wave radiation. Apart from these models, all of the other model categories considered in the analysis result in a mean net storage heat flux that is close to zero throughout the seasonal cycle, which is not seen in the observations. Models with a simple treatment of the physical processes generally perform at least as well as models with greater complexity.

Eigenvalues of a one-dimensional Dirac operator pencil

We study the spectrum of a one-dimensional Dirac operator pencil, with a coupling constant in front of the potential considered as the spectral parameter. Motivated by recent investigations of graphene waveguides, we focus on the values of the coupling constant for which the kernel of the Dirac operator contains a square integrable function. In physics literature such a function is called a confined zero mode. Several results on the asymptotic distribution of coupling constants giving rise to zero modes are obtained. In particular, we show that this distribution depends in a subtle way on the sign variation and the presence of gaps in the potential. Surprisingly, it also depends on the arithmetic properties of certain quantities determined by the potential. We further observe that variable sign potentials may produce complex eigenvalues of the operator pencil. Some examples and numerical calculations illustrating these phenomena are presented.

Predictability of the western North Pacific summer climate associated with different ENSO phases by ENSEMBLES multi-model seasonal forecasts

Predictability of the western North Pacific (WNP) summer climate associated with different El Ni��o���Southern Oscillation (ENSO) phases is investigated in this study based on the 1-month lead retrospective forecasts of five state-of-the-art coupled models from ENSEMBLES. During the period from 1960 to 2005, the models well capture the WNP summer climate anomalies during most of years in different ENSO phases except the La Ni��a decaying summers. In the El Ni��o developing, El Ni��o decaying and La Ni��a developing summers, the prediction skills are high for the WNP summer monsoon index (WNPMI), with the prediction correlation larger than 0.7. The high prediction skills of the lower-tropospheric circulation during these phases are found mainly over the tropical western Pacific Ocean, South China Sea and subtropical WNP. These good predictions correspond well to their close teleconnection with ENSO and the high prediction skills of tropical SSTs. By contrast, for the La Ni��a decaying summers, the prediction skills are considerably low with the prediction correlation for the WNPMI near to zero and low prediction skills around the Philippines and subtropical WNP. These poor predictions relate to the weak summer anomalies of the WNPMI during the La Ni��a decaying years and no significant connections between the WNP lower-tropospheric circulation anomalies and the SSTs over the tropical central and eastern Pacific Ocean in observations. However, the models tend to predict an apparent anomalous cyclone over the WNP during the La Ni��a decaying years, indicating a linearity of the circulation response over WNP in the models prediction in comparison with that during the El Ni��o decaying years which differs from observations. In addition, the models show considerable capability in describing the WNP summer anomalies during the ENSO neutral summers. These anomalies are related to the positive feedback between the WNP lower-tropospheric circulation and the local SSTs. The models can capture this positive feedback but with some uncertainties from different ensemble members during the ENSO neutral summers.

Use of simulated intestinal fluids with Caco-2 cells and rat ileum

In most in vitro studies of oral drug permeability, little attempt is made to reproduce the gastrointestinal lumenal environment. The aim of this study was to evaluate the compatibility of simulated intestinal fluid (SIF) solutions with Caco-2 cell monolayers and Ussing chamber-mounted rat ileum under standard permeability experiment protocols. In preliminary experiments, fasted-state simulated intestinal fluid (FaSSIF) and fed-state simulated intestinal fluid (FeSSIF) solutions based on the dissolution medium formulae of Dressman and co-workers (1998) were modified for compatibility with Caco-2 cells to produce FaS-SIF and FeSSIF "transport" solutions for use with in vitro permeability models. For Caco-2 cells exposed to FaSSIF and FESSIF transport solutions, the transepithelial electrical resistance was maintained for over 4 h and mannitol permeability was equivalent to that in control (Hank's Balanced Salt Solution-treated) cell layers. Scanning electron microscopy revealed that microvilli generally maintained a normal distribution, although some shortening of microvilli and occasional small areas of denudation were observed. For rat ileum in the Ussing chambers, the potential difference (PD) collapsed to zero over 120 min when exposed to the FaSSIF transport solution and an even faster collapse of the PD was observed when the FeSSIF transport solution was used. Electron micrographs revealed erosion of the villi tips and substantial denudation of the microvilli after exposure of ileal tissue to FaSSIF and FeSSIF solutions, and permeability to mannitol was increased by almost two-fold. This study indicated that FaSSIF and FeSSIF transport solutions can be used with Caco-2 monolayers to evaluate drug permeability, but rat ileum in Ussing chambers is adversely affected by these solutions. Metoprolol permeability in Caco-2 experiments was reduced by 33% using the FaSSIF and 75% using the FeSSIF compared to permeability measured using HBSS. This illustrates that using physiological solutions can influence permeability measurements.

Formulation and implementation of a residual-mean ocean circulation model

A parameterization of mesoscale eddies in coarse-resolution ocean general circulation models (GCM) is formulated and implemented using a residual-mean formalism. In that framework, mean buoyancy is advected by the residual velocity (the sum of the Eulerian and eddy-induced velocities) and modified by a residual flux which accounts for the diabatic effects of mesoscale eddies. The residual velocity is obtained by stepping forward a residual-mean momentum equation in which eddy stresses appear as forcing terms. Study of the spatial distribution of eddy stresses, derived by using them as control parameters to ������fit������ the residual-mean model to observations, supports the idea that eddy stresses can be likened to a vertical down-gradient flux of momentum with a coefficient which is constant in the vertical. The residual eddy flux is set to zero in the ocean interior, where mesoscale eddies are assumed to be quasi-adiabatic, but is parameterized by a horizontal down-gradient diffusivity near the surface where eddies develop a diabatic component as they stir properties horizontally across steep isopycnals. The residual-mean model is implemented and tested in the MIT general circulation model. It is shown that the resulting model (1) has a climatology that is superior to that obtained using the Gent and McWilliams parameterization scheme with a spatially uniform diffusivity and (2) allows one to significantly reduce the (spurious) horizontal viscosity used in coarse resolution GCMs.