Pollen-based quantitative reconstructions of Holocene regional vegetation cover (plant-functional types and land-cover types) in Europe suitable for climate modelling

We present quantitative reconstructions of regional vegetation cover in north-western Europe, western Europe north of the Alps, and eastern Europe for five time windows in the Holocene [around 6k, 3k, 0.5k, 0.2k, and 0.05k calendar years before present (bp)] at a 1 degrees x1 degrees spatial scale with the objective of producing vegetation descriptions suitable for climate modelling. The REVEALS model was applied on 636 pollen records from lakes and bogs to reconstruct the past cover of 25 plant taxa grouped into 10 plant-functional types and three land-cover types [evergreen trees, summer-green (deciduous) trees, and open land]. The model corrects for some of the biases in pollen percentages by using pollen productivity estimates and fall speeds of pollen, and by applying simple but robust models of pollen dispersal and deposition. The emerging patterns of tree migration and deforestation between 6k bp and modern time in the REVEALS estimates agree with our general understanding of the vegetation history of Europe based on pollen percentages. However, the degree of anthropogenic deforestation (i.e. cover of cultivated and grazing land) at 3k, 0.5k, and 0.2k bp is significantly higher than deduced from pollen percentages. This is also the case at 6k in some parts of Europe, in particular Britain and Ireland. Furthermore, the relationship between summer-green and evergreen trees, and between individual tree taxa, differs significantly when expressed as pollen percentages or as REVEALS estimates of tree cover. For instance, when Pinus is dominant over Picea as pollen percentages, Picea is dominant over Pinus as REVEALS estimates. These differences play a major role in the reconstruction of European landscapes and for the study of land cover-climate interactions, biodiversity and human resources.Peer reviewe

Erratum: SC83288 is a clinical development candidate for the treatment of severe malaria

No abstract available

Erratum: SC83288 is a clinical development candidate for the treatment of severe malaria

No abstract available

Europe's lost forests: a pollen-based synthesis for the last 11,000 years

8000 years ago, prior to Neolithic agriculture, Europe was mostly a wooded continent. Since then, its forest cover has been progressively fragmented, so that today it covers less than half of Europe’s land area, in many cases having been cleared to make way for fields and pasture-land. Establishing the origin of Europe’s current, more open land-cover mosaic requires a long-term perspective, for which pollen analysis offers a key tool. In this study we utilise and compare three numerical approaches to transforming pollen data into past forest cover, drawing on >1000 14C-dated site records. All reconstructions highlight the different histories of the mixed temperate and the northern boreal forests, with the former declining progressively since ~6000 years ago, linked to forest clearance for agriculture in later prehistory (especially in northwest Europe) and early historic times (e.g. in north central Europe). In contrast, extensive human impact on the needle-leaf forests of northern Europe only becomes detectable in the last two millennia and has left a larger area of forest in place. Forest loss has been a dominant feature of Europe’s landscape ecology in the second half of the current interglacial, with consequences for carbon cycling, ecosystem functioning and biodiversity

Inhibitory Effect of TNF-α on Malaria Pre-Erythrocytic Stage Development: Influence of Host Hepatocyte/Parasite Combinations

BACKGROUND: The liver stages of malaria parasites are inhibited by cytokines such as interferon-gamma or Interleukin (IL)-6. Binding of these cytokines to their receptors at the surface of the infected hepatocytes leads to the production of nitric oxide (NO) and radical oxygen intermediates (ROI), which kill hepatic parasites. However, conflicting results were obtained with TNF-alpha possibly because of differences in the models used. We have reassessed the role of TNF-alpha in the different cellular systems used to study the Plasmodium pre-erythrocytic stages. METHODS AND FINDINGS: Human or mouse TNF-alpha were tested against human and rodent malaria parasites grown in vitro in human or rodent primary hepatocytes, or in hepatoma cell lines. Our data demonstrated that TNF-alpha treatment prevents the development of malaria pre-erythrocytic stages. This inhibitory effect however varies with the infecting parasite species and with the nature and origin of the cytokine and hepatocytes. Inhibition was only observed for all parasite species tested when hepatocytes were pre-incubated 24 or 48 hrs before infection and activity was directed only against early hepatic parasite. We further showed that TNF-alpha inhibition was mediated by a soluble factor present in the supernatant of TNF-alpha stimulated hepatocytes but it was not related to NO or ROI. Treatment TNF-alpha prevents the development of human and rodent malaria pre-erythrocytic stages through the activity of a mediator that remains to be identified. CONCLUSIONS: Treatment TNF-alpha prevents the development of human and rodent malaria pre-erythrocytic stages through the activity of a mediator that remains to be identified. However, the nature of the cytokine-host cell-parasite combination must be carefully considered for extrapolation to the human infection

Gene Disruption of Plasmodium falciparum p52 Results in Attenuation of Malaria Liver Stage Development in Cultured Primary Human Hepatocytes

Difficulties with inducing sterile and long lasting protective immunity against malaria with subunit vaccines has renewed interest in vaccinations with attenuated Plasmodium parasites. Immunizations with sporozoites that are attenuated by radiation (RAS) can induce strong protective immunity both in humans and rodent models of malaria. Recently, in rodent parasites it has been shown that through the deletion of a single gene, sporozoites can also become attenuated in liver stage development and, importantly, immunization with these sporozoites results in immune responses identical to RAS. The promise of vaccination using these genetically attenuated sporozoites (GAS) depends on translating the results in rodent malaria models to human malaria. In this study, we perform the first essential step in this transition by disrupting, p52, in P. falciparum an ortholog of the rodent parasite gene, p36p, which we had previously shown can confer long lasting protective immunity in mice. These P. falciparum P52 deficient sporozoites demonstrate gliding motility, cell traversal and an invasion rate into primary human hepatocytes in vitro that is comparable to wild type sporozoites. However, inside the host hepatocyte development is arrested very soon after invasion. This study reveals, for the first time, that disrupting the equivalent gene in both P. falciparum and rodent malaria Plasmodium species generates parasites that become similarly arrested during liver stage development and these results pave the way for further development of GAS for human use

Discovery of potent, novel, non-toxic anti-malarial compounds via quantum modelling, virtual screening and in vitro experimental validation

<p>Abstract</p> <p>Background</p> <p>Developing resistance towards existing anti-malarial therapies emphasize the urgent need for new therapeutic options. Additionally, many malaria drugs in use today have high toxicity and low therapeutic indices. Gradient Biomodeling, LLC has developed a quantum-model search technology that uses quantum similarity and does not depend explicitly on chemical structure, as molecules are rigorously described in fundamental quantum attributes related to individual pharmacological properties. Therapeutic activity, as well as toxicity and other essential properties can be analysed and optimized simultaneously, independently of one another. Such methodology is suitable for a search of novel, non-toxic, active anti-malarial compounds.</p> <p>Methods</p> <p>A set of innovative algorithms is used for the fast calculation and interpretation of electron-density attributes of molecular structures at the quantum level for rapid discovery of prospective pharmaceuticals. Potency and efficacy, as well as additional physicochemical, metabolic, pharmacokinetic, safety, permeability and other properties were characterized by the procedure. Once quantum models are developed and experimentally validated, the methodology provides a straightforward implementation for lead discovery, compound optimizzation and <it>de novo </it>molecular design.</p> <p>Results</p> <p>Starting with a diverse training set of 26 well-known anti-malarial agents combined with 1730 moderately active and inactive molecules, novel compounds that have strong anti-malarial activity, low cytotoxicity and structural dissimilarity from the training set were discovered and experimentally validated. Twelve compounds were identified <it>in silico </it>and tested <it>in vitro</it>; eight of them showed anti-malarial activity (IC50 ≤ 10 μM), with six being very effective (IC50 ≤ 1 μM), and four exhibiting low nanomolar potency. The most active compounds were also tested for mammalian cytotoxicity and found to be non-toxic, with a therapeutic index of more than 6,900 for the most active compound.</p> <p>Conclusions</p> <p>Gradient's metric modelling approach and electron-density molecular representations can be powerful tools in the discovery and design of novel anti-malarial compounds. Since the quantum models are agnostic of the particular biological target, the technology can account for different mechanisms of action and be used for <it>de novo </it>design of small molecules with activity against not only the asexual phase of the malaria parasite, but also against the liver stage of the parasite development, which may lead to true causal prophylaxis.</p

Travelers With Cutaneous Leishmaniasis Cured Without Systemic Therapy

Guidelines recommend wound care and/or local therapy as first-line treatment for cutaneous leishmaniasis. An analysis of a referral treatment program in 135 travelers showed that this approach was feasible in 62% of patients, with positive outcome in 83% of evaluable patient

Long-term land-cover/use change in a traditional farming landscape in Romania inferred from pollen data, historical maps and satellite images

Traditional farming landscapes in the temperate zone that have persisted for millennia can be exceptionally species-rich and are therefore key conservation targets. In contrast to Europe’s West, Eastern Europe harbours widespread traditional farming landscapes, but drastic socio-economic and political changes in the twentieth century are likely to have impacted these landscapes profoundly. We reconstructed long-term land-use/cover and biodiversity changes over the last 150 years in a traditional farming landscape of outstanding species diversity in Transylvania. We used the Regional Estimates of Vegetation Abundance from Large Sites model applied to a pollen record from the Transylvanian Plain and a suite of historical and satellite-based maps. We documented widespread changes in the extent and location of grassland and cropland, a loss of wood pastures as well as a gradual increase in forest extent. Land management in the socialist period (1947–1989) led to grassland expansion, but grassland diversity decreased due to intensive production. Land-use intensity has declined since the collapse of socialism in 1989, resulting in widespread cropland abandonment and conversion to grassland. However, these trends may be temporary due to both ongoing woody encroachment as well as grassland management intensification in productive areas. Remarkably, only 8% of all grasslands existed throughout the entire time period (1860–2010), highlighting the importance of land-use history when identifying target areas for conservation, given that old-growth grasslands are most valuable in terms of biodiversity. Combining datasets from different disciplines can yield important additional insights into dynamic landscape and biodiversity changes, informing conservation actions to maintain these species-rich landscapes in the longer term