A Geospatial Modelling Approach Integrating Archaeobotany and Genetics to Trace the Origin and Dispersal of Domesticated Plants

Background: The study of the prehistoric origins and dispersal routes of domesticated plants is often based on the analysis of either archaeobotanical or genetic data. As more data become available, spatially explicit models of crop dispersal can be used to combine different types of evidence. Methodology/Principal Findings: We present a model in which a crop disperses through a landscape that is represented by a conductance matrix. From this matrix, we derive least-cost distances from the geographical origin of the crop and use these to predict the age of archaeological crop remains and the heterozygosity of crop populations. We use measures of the overlap and divergence of dispersal trajectories to predict genetic similarity between crop populations. The conductance matrix is constructed from environmental variables using a number of parameters. Model parameters are determined with multiple-criteria optimization, simultaneously fitting the archaeobotanical and genetic data. The consilience reached by the model is the extent to which it converges around solutions optimal for both archaeobotanical and genetic data. We apply the modelling approach to the dispersal of maize in the Americas. Conclusions/Significance: The approach makes possible the integrative inference of crop dispersal processes, whil

Discovery of short-course antiwolbachial quinazolines for elimination of filarial worm infections

Parasitic filarial nematodes cause debilitating infections in people in resource-limited countries. A clinically validated approach to eliminating worms uses a 4- to 6-week course of doxycycline that targets Wolbachia, a bacterial endosymbiont required for worm viability and reproduction. However, the prolonged length of therapy and contraindication in children and pregnant women have slowed adoption of this treatment. Here, we describe discovery and optimization of quinazolines CBR417 and CBR490 that, with a single dose, achieve &gt;99% elimination of Wolbachia in the in vivo Litomosoides sigmodontis filarial infection model. The efficacious quinazoline series was identified by pairing a primary cell-based high-content imaging screen with an orthogonal ex vivo validation assay to rapidly quantify Wolbachia elimination in Brugia pahangi filarial ovaries. We screened 300,368 small molecules in the primary assay and identified 288 potent and selective hits. Of 134 primary hits tested, only 23.9% were active in the worm-based validation assay, 8 of which contained a quinazoline heterocycle core. Medicinal chemistry optimization generated quinazolines with excellent pharmacokinetic profiles in mice. Potent antiwolbachial activity was confirmed in L. sigmodontis, Brugia malayi, and Onchocerca ochengi in vivo preclinical models of filarial disease and in vitro selectivity against Loa loa (a safety concern in endemic areas). The favorable efficacy and in vitro safety profiles of CBR490 and CBR417 further support these as clinical candidates for treatment of filarial infections.</p

Discovery of short-course antiwolbachial quinazolines for elimination of filarial worm infections

Parasitic filarial nematodes cause debilitating infections in people in resource-limited countries. A clinically validated approach to eliminating worms uses a 4- to 6-week course of doxycycline that targetsandnbsp;Wolbachia, a bacterial endosymbiont required for worm viability and reproduction. However, the prolonged length of therapy and contraindication in children and pregnant women have slowed adoption of this treatment. Here, we describe discovery and optimization of quinazolines CBR417 and CBR490 that, with a single dose, achieve andgt;99% elimination ofandnbsp;Wolbachiaandnbsp;in the in vivoandnbsp;Litomosoides sigmodontisandnbsp;filarial infection model. The efficacious quinazoline series was identified by pairing a primary cell-based high-content imaging screen with an orthogonal ex vivo validation assay to rapidly quantifyandnbsp;Wolbachiaandnbsp;elimination inandnbsp;Brugia pahangiandnbsp;filarial ovaries. We screened 300,368 small molecules in the primary assay and identified 288 potent and selective hits. Of 134 primary hits tested, only 23.9% were active in the worm-based validation assay, 8 of which contained a quinazoline heterocycle core. Medicinal chemistry optimization generated quinazolines with excellent pharmacokinetic profiles in mice. Potent antiwolbachial activity was confirmed inandnbsp;L. sigmodontis,andnbsp;Brugia malayi, andandnbsp;Onchocerca ochengiandnbsp;in vivo preclinical models of filarial disease and in vitro selectivity againstandnbsp;Loa loaandnbsp;(a safety concern in endemic areas). The favorable efficacy and in vitro safety profiles of CBR490 and CBR417 further support these as clinical candidates for treatment of filarial infections.</p

Transformações da terra: para uma perspectiva agroecológica na história Transformation of the land: towards an agroecological perspective in history

O artigo discute a constituição do campo da história ambiental, que se deu nos anos 70 em meio aos debates sobre a crise ecológica e a eclosão do movimento ambientalista. Esta história não aceita a noção de que as sociedades humanas não produzem alterações ambientais significativas, e interpela as condições específicas dessa interação recorrente. O sistema agroecológico representa um dos casos mais típicos de rearranjo da atividade humana sobre os ecossistemas naturais, em uma relação complexa de interação entre plantas nativas, vegetação forasteira, fertilidade dos solos e diversas práticas agrícolas. O itinerário dessas mudanças é essencial para se compreender a história do ponto de vista ambiental<br>This article discusses the formation of the field of environmental history which originated in the 1970s in the middle of the debates on the ecologic crisis and the emergence of the environmental movement. This history rejects the notion that human societies do not cause significant environmental alterations and analyzes the specific conditions of that recurring interaction. The agroecologic system is one of the most typical cases of the intervention of human activity on natural ecosystems in a complex interaction between indigenous plants, exotic vegetation, fertility of the soil and diverse agricultural practices. The roadmap of these changes is essential to understand history from the view point of the environment