Anthelmintic activities against Haemonchus contortus or Trichostrongylus colubriformis from small ruminants are influenced by structural features of condensed tannins

Plants containing condensed tannins (CTs) may hold promise as alternatives to synthetic anthelmintic (AH) drugs for controlling gastrointestinal nematodes (GINs). However, the structural features that contribute to the AH activities of CTs remain elusive. This study probed the relationships between CT structures and their AH activities. Eighteen plant resources were selected based on their diverse CT structures. From each plant resource, two CT fractions were isolated and their in vitro AH activities were measured with the Larval Exsheathment Inhibition Assay, which was applied to Haemonchus contortus and Trichostrongylus colubriformis. Calculation of mean EC50 values indicated that H. contortus was more susceptible than T colubriformis to the different fractions and that the F1 fractions were less efficient than the F2 ones, as indicated by the respective mean values for H.contortus F1 = 136.9 ± 74.1 µg/ml; and for H.contortus F2 = 108.1 ± 53.2 µg/ml and for T colubriformis F1 = 233 ± 54.3 µg/ml and F2=166 ± 39.9 µg/ml. The results showed that the AH activity against H. contortus was associated with the monomeric subunits that give rise to prodelphinidins (P < 0.05) and with CT polymer size (P < 0.10). However, for T. colubriformis AH activity was correlated only with prodelphinidins (P < 0.05). These results suggest that CTs have different modes of action against different parasite species.

The potential of flood forecasting using a variable-resolution global Digital Terrain Model and flood extents from Synthetic Aperture Radar images

A basic data requirement of a river flood inundation model is a Digital Terrain Model (DTM) of the reach being studied. The scale at which modeling is required determines the accuracy required of the DTM. For modeling floods in urban areas, a high resolution DTM such as that produced by airborne LiDAR (Light Detection And Ranging) is most useful, and large parts of many developed countries have now been mapped using LiDAR. In remoter areas, it is possible to model flooding on a larger scale using a lower resolution DTM, and in the near future the DTM of choice is likely to be that derived from the TanDEM-X Digital Elevation Model (DEM). A variable-resolution global DTM obtained by combining existing high and low resolution data sets would be useful for modeling flood water dynamics globally, at high resolution wherever possible and at lower resolution over larger rivers in remote areas. A further important data resource used in flood modeling is the flood extent, commonly derived from Synthetic Aperture Radar (SAR) images. Flood extents become more useful if they are intersected with the DTM, when water level observations (WLOs) at the flood boundary can be estimated at various points along the river reach. To illustrate the utility of such a global DTM, two examples of recent research involving WLOs at opposite ends of the spatial scale are discussed. The first requires high resolution spatial data, and involves the assimilation of WLOs from a real sequence of high resolution SAR images into a flood model to update the model state with observations over time, and to estimate river discharge and model parameters, including river bathymetry and friction. The results indicate the feasibility of such an Earth Observation-based flood forecasting system. The second example is at a larger scale, and uses SAR-derived WLOs to improve the lower-resolution TanDEM-X DEM in the area covered by the flood extents. The resulting reduction in random height error is significant.

Phosphorothioate backbone modifications of nucleotide-based drugs are potent platelet activators

Nucleotide-based drug candidates such as antisense oligonucleotides, aptamers, immunoreceptor-activating nucleotides, or (anti)microRNAs hold great therapeutic promise for many human diseases. Phosphorothioate (PS) backbone modification of nucleotide-based drugs is common practice to protect these promising drug candidates from rapid degradation by plasma and intracellular nucleases. Effects of the changes in physicochemical properties associated with PS modification on platelets have not been elucidated so far. Here we report the unexpected binding of PS-modified oligonucleotides to platelets eliciting strong platelet activation, signaling, reactive oxygen species generation, adhesion, spreading, aggregation, and thrombus formation in vitro and in vivo. Mechanistically, the platelet-specific receptor glycoprotein VI (GPVI) mediates these platelet-activating effects. Notably, platelets from GPVI function-deficient patients do not exhibit binding of PS-modified oligonucleotides, and platelet activation is fully abolished. Our data demonstrate a novel, unexpected, PS backbone-dependent, platelet-activating effect of nucleotide-based drug candidates mediated by GPVI. This unforeseen effect should be considered in the ongoing development programs for the broad range of upcoming and promising DNA/RNA therapeutics.

Improving the TanDEM-X Digital Elevation Model for flood modelling using flood extents from Synthetic Aperture Radar images

The topography of many floodplains in the developed world has now been surveyed with high resolution sensors such as airborne LiDAR (Light Detection and Ranging), giving accurate Digital Elevation Models (DEMs) that facilitate accurate flood inundation modelling. This is not always the case for remote rivers in developing countries. However, the accuracy of DEMs produced for modelling studies on such rivers should be enhanced in the near future by the high resolution TanDEM-X WorldDEM. In a parallel development, increasing use is now being made of flood extents derived from high resolution Synthetic Aperture Radar (SAR) images for calibrating, validating and assimilating observations into flood inundation models in order to improve these. This paper discusses an additional use of SAR flood extents, namely to improve the accuracy of the TanDEM-X DEM in the floodplain covered by the flood extents, thereby permanently improving this DEM for future flood modelling and other studies. The method is based on the fact that for larger rivers the water elevation generally changes only slowly along a reach, so that the boundary of the flood extent (the waterline) can be regarded locally as a quasi-contour. As a result, heights of adjacent pixels along a small section of waterline can be regarded as samples with a common population mean. The height of the central pixel in the section can be replaced with the average of these heights, leading to a more accurate estimate. While this will result in a reduction in the height errors along a waterline, the waterline is a linear feature in a two-dimensional space. However, improvements to the DEM heights between adjacent pairs of waterlines can also be made, because DEM heights enclosed by the higher waterline of a pair must be at least no higher than the corrected heights along the higher waterline, whereas DEM heights not enclosed by the lower waterline must in general be no lower than the corrected heights along the lower waterline. In addition, DEM heights between the higher and lower waterlines can also be assigned smaller errors because of the reduced errors on the corrected waterline heights. The method was tested on a section of the TanDEM-X Intermediate DEM (IDEM) covering an 11km reach of the Warwickshire Avon, England. Flood extents from four COSMO-SKyMed images were available at various stages of a flood in November 2012, and a LiDAR DEM was available for validation. In the area covered by the flood extents, the original IDEM heights had a mean difference from the corresponding LiDAR heights of 0.5 m with a standard deviation of 2.0 m, while the corrected heights had a mean difference of 0.3 m with standard deviation 1.2 m. These figures show that significant reductions in IDEM height bias and error can be made using the method, with the corrected error being only 60% of the original. Even if only a single SAR image obtained near the peak of the flood was used, the corrected error was only 66% of the original. The method should also be capable of improving the final TanDEM-X DEM and other DEMs, and may also be of use with data from the SWOT (Surface Water and Ocean Topography) satellite.

The Cold War and its aftermath in the Americas: the search for a synthetic interpretation of U.S. policy

More than two decades have passed since the fall of the Berlin Wall and the transfer of the Cold War file from a daily preoccupation of policy makers to a more detached assessment by historians. Scholars of U.S.-Latin American relations are beginning to take advantage both of the distance in time and of newly opened archives to reflect on the four decades that, from the 1940s to the 1980s, divided the Americas, as they did much of the world. Others are seeking to understand U.S. policy and inter-American relations in the post-Cold War era, a period that not only lacks a clear definition but also still has no name. Still others have turned their gaze forward to offer policies in regard to the region for the new Obama administration. Numerous books and review essays have addressed these three subjects—the Cold War, the post-Cold War era, and current and future issues on the inter-American agenda. Few of these studies attempt, however, to connect the three subjects or to offer new and comprehensive theories to explain the course of U.S. policies from the beginning of the twentieth century until the present. Indeed, some works and policy makers continue to use the mind-sets of the Cold War as though that conflict were still being fought. With the benefit of newly opened archives, some scholars have nevertheless drawn insights from the depths of the Cold War that improve our understanding of U.S. policies and inter-American relations, but they do not address the question as to whether the United States has escaped the longer cycle of intervention followed by neglect that has characterized its relations with Latin America. Another question is whether U.S. policies differ markedly before, during, and after the Cold War. In what follows, we ask whether the books reviewed here provide any insights in this regard and whether they offer a compass for the future of inter-American relations. We also offer our own thoughts as to how their various perspectives could be synthesized to address these questions more comprehensively.

Proanthocyanidins inhibit Ascaris suum glutathione-S-transferase activity and increase susceptibility of larvae to levamisole and ivermectin in vitro

Proanthocyanidins (PAC) are a class of plant secondary metabolites commonly found in the diet that have shown potential to control gastrointestinal nematode infections. The anti-parasitic mechanism(s) of PAC remain obscure, however the protein-binding properties of PAC suggest that disturbance of key enzyme functions may be a potential mode of action. Glutathione-S-transferases (GSTs) are essential for parasite detoxification and have been investigated as drug and vaccine targets. Here, we show that purified PAC strongly inhibit the activity of both recombinant and native GSTs from the parasitic nematode Ascaris suum. As GSTs are involved in detoxifying xenobiotic substances within the parasite, we hypothesised that this inhibition may render parasites hyper-susceptible to anthelmintic drugs. Migration inhibition assays with A. suum larvae demonstrated that the potency of levamisole (LEV) and ivermectin (IVM) were significantly increased in the presence of PAC purified from pine bark (4.6-fold and 3.2-fold reduction in IC50 value for LEV and IVM, respectively). Synergy analysis revealed that the relationship between PAC and LEV appeared to be synergistic in nature, suggesting a specific enhancement of LEV activity, whilst the relationship between PAC and IVM was additive rather than synergistic, suggesting independent actions. Our results demonstrate that these common dietary compounds may increase the efficacy of synthetic anthelmintic drugs in vitro, and also suggest one possible mechanism for their well-known anti-parasitic activity.