Artemisinin-dipeptidyl vinyl sulfone hybrid molecules: Design,synthesis and preliminary SAR for antiplasmodial activity and falcipain-2 inhibition

A series of artemisinin–vinyl sulfone hybrid molecules with the potential to act in the parasite food vacuole via endoperoxide activation and falcipain inhibition was synthesized and screened for antiplasmodial activity and falcipain-2 inhibition. All conjugates were active against the Plasmodium falciparum W2 strain in the low nanomolar range and those containing the Leu-hPhe core inhibited falcipain-2 in low micromolar range.     

Anti-tumoral activity of imidazoquines,a new class of antimalarials derived from primaquine

The growth inhibitory activity of imidazoquines, antimalarial imidazolidin-4-ones derived from primaquine, on human cancer cell lines HT-29, Caco-2, and MCF-7 has been evaluated. Primaquine, N-dipeptidyl-primaquine derivatives, and other quinolines have been included in the study for comparison purposes. Primaquine and some of its derivatives were significantly active against the MCF-7 human breast cancer cell line, so these compounds might represent useful leads targeted at the development of novel specific agents against breast cancer. Conversely, all compounds were generally inactive against HT-29, with only one of the imidazoquines having IC₅₀ below 50 μM. Activities against the Caco-2 cell line were modest and did not follow any defined trend.     

Toucans (Ramphastos ambiguus) facilitate resilience against seed dispersal limitation to a large‐seeded tree (Virola surinamensis) in a human‐modified landscape

Large‐seeded plants may suffer seed dispersal limitation in human‐modified landscapes if seed dispersers are absent or unable to disperse their seeds. We investigated dispersal limitation for the large‐seeded tree Virola surinamensis in a human‐modified landscape in southern Costa Rica. During two fruiting seasons, we monitored crop size, seed removal rates, the number of fruiting conspecifics within 100 m, and feeding visitation rates by frugivores at trees located in high and low forest disturbance conditions. Seed removal rates and the total number of seeds removed were high regardless of the disturbance level, but these parameters increased with tree crop size and decreased with the number of fruiting V. surinamensis trees within a 100 m radius. Trees at low disturbance levels were more likely to be visited by seed dispersers. Black mandibled toucans (Ramphastos ambiguus) and spider monkeys (Ateles geoffroyi) were the most important seed dispersers, based on visitation patterns and seed removal rates. Spider monkey feeding visits were more frequent at high disturbance levels, but the monkeys preferentially visited isolated trees with large yields and surrounded by a low number of fruiting Virola trees within 100 m. Toucan visitation patterns were not constrained by any of the predictors and they visited trees equally across the landscape. We suggest that isolated and highly fecund Virola trees are an important food resource for spider monkeys in human‐modified landscapes and that toucans can provide resilience against seed dispersal limitations for large‐seeded plants in human‐modified landscapes in the absence of hunting.     

A density functional theory investigation of the interaction of the tetraaqua calcium cation with bidentate carbonyl ligands

Calcium complexes with bidentate carbonyl ligands are important in biological systems, medicine and industry, where the concentration of Ca²⁺ is controlled using chelating ligands. The exchange of two water molecules of [Ca(H₂O)₆]²⁺ for one bidentate monosubstituted and homo disubstituted dicarbonyl ligand was investigated using the B3LYP/6-311++G(d,p) method. The ligand substituents NH₂, OCH₃, OH, CH₃, H, F, Cl, CN and NO₂ are functional groups with distinct electron-donating and -withdrawing effects that bond directly to the sp² C atom of the carbonyl group. The geometry, charge and energy characteristics of the complexes were analyzed to help understand the effects of substituents, spacer length and chelation. Coordination strength was quantified in terms of the enthalpy and free energy of the exchange reaction. The most negative enthalpies were calculated for the coordination of bidentate ligands containing three to five methylene group spacers between carbonyls. The chelate effect contribution was analyzed based on the thermochemistry. The electronic character of the substituent modulates the strength of binding to the metal cation, as ligands containing electron-donor substituents coordinate stronger than those with electron-acceptor substituents. This is reflected in the geometric (bond length and chelating angle), electronic (atomic charges) and energetic (components of the total interacting energy) characteristics of the complexes. Energy decomposition analysis (EDA)—an approach for partitioning of the energy into its chemical origins—shows that the electrostatic component of the coordination is predominant, and yields relevant contribution of the covalent term, especially for the electron-withdrawing substituted ligands. The chelate effect of the bidentate ligands was noticeable when compared with substitution by two monodentate ligands.

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Graphical abstract The affinity of 18 bidentate carbonyl ligands toward the [Ca(H₂O)₄]²⁺ cation is evaluated in terms of energetic, geometric and electronic parameters of the isolated ligands and the substituted aqua complexes. The electronic effects—inductive and mesomeric—intrinsic to the molecular structure of each ligand are found to modulate the strength of the metal-ligand interaction. The effects of polysubstitution, chelation and the length of the alkyl spacers between the anchor points of the ligand are also analyzed.

     

Combined effects of landscape composition and heterogeneity on farmland avian diversity

Conserving biodiversity on farmland is an essential element of worldwide efforts for reversing the global biodiversity decline. Common approaches involve improving the natural component of the landscape by increasing the amount of natural and seminatural habitats (e.g., hedgerows, woodlots, and ponds) or improving the production component of the landscape by increasing the amount of biodiversity‐friendly crops. Because these approaches may negatively impact on economic output, it was suggested that an alternative might be to enhance the diversity (compositional heterogeneity) or the spatial complexity (configurational heterogeneity) of land cover types, without necessarily changing composition. Here, we develop a case study to evaluate these ideas, examining whether managing landscape composition or heterogeneity, or both, would be required to achieve conservation benefits on avian diversity in open Mediterranean farmland. We surveyed birds in farmland landscapes of southern Portugal, before (1995–1997) and after (2010–2012) the European Union's Common Agricultural Policy (CAP) reform of 2003, and related spatial and temporal variation in bird species richness to variables describing the composition, and the compositional and configurational heterogeneity, of the natural and production components of the landscape. We found that the composition of the production component had the strongest effects on avian diversity, with a particularly marked effect on the richness of farmland and steppe bird species. Composition of the natural component was also influential, mainly affecting the richness of woodland/shrubland species. Although there were some effects of compositional and configurational heterogeneity, these were much weaker and inconsistent than those of landscape composition. Overall, we suggest that conservation efforts in our area should focus primarily on the composition of the production component, by striving to maximize the prevalence of biodiversity‐friendly crops. This recommendation probably applies to other areas such as ours, where a range of species of conservation concern is strongly associated with crop habitats.     

Landscape determinants of European roller foraging habitat: implications for the definition of agri-environmental measures for species conservation

Across much of Europe, farmland birds are declining more than those in other habitats. From a conservation perspective, identifying the primary preferred habitats could help improve the foraging conditions of target species and, consequently, enhance their breeding success and survival. Here, we investigated the ranging behaviour and foraging habitat selection of the European roller (Coracias garrulus) during the breeding season in an agricultural landscape of South Iberia. The occurrence of foraging rollers was predicted to gradually increase with decreasing distance from the nest and increasing availability of perches, such as fences and electric wires. Traditional olive groves and stubble fields were positively and negatively associated with the occurrence of rollers, respectively. Additionally, analysis of hunting strikes showed that rollers highly prefer foraging in fallows rather than cereal or stubble fields. Prey surveys revealed that fallows had the highest abundance of grasshoppers, rollers’ preferred prey during chick-rearing. Pair home-ranges, obtained from 95% fixed Kernel estimators averaged 70.9 ha (range = 34–118 ha) and most foraging trips (80%) occurred in the close vicinity of the nest (<500 m). Number of chicks fledged was not affected by mean foraging distances travelled during the chick-rearing period. Overall, our results suggest that traditional extensive practices of cereal cultivation, with large areas of low-intensity grazed fallows, represent a high-quality foraging habitat for rollers and should be promoted through agri-environmental schemes within at least 1-km radius from the nest. These recommendations are targeted at the roller, but have been shown to apply broadly to several other steppe-bird species.     

Morphological and Genetic Diversity of Opisthosporidia: New Aphelid Paraphelidium tribonemae gen. et sp. nov.

Aphelids are a poorly known group of parasitoids of algae that have raised considerable interest due to their pivotal phylogenetic position. Together with Cryptomycota and the highly derived Microsporidia, they have been recently re‐classified as the Opisthosporidia, which constitute the sister group to the fungi within the Holomycota. Despite their huge diversity, as revealed by molecular environmental studies, and their phylogenetic interest, only three genera have been described (Aphelidium, Amoeboaphelidium, and Pseudaphelidium), from which 18S rRNA gene sequences exist only for Amoeboaphelidium and Aphelidium species. Here, we describe the life cycle and ultrastructure of a new representative of Aphelida, Paraphelidium tribonemae gen. et sp. nov., and provide the first 18S rRNA gene sequence obtained for this genus. Molecular phylogenetic analysis indicates that Paraphelidium is distantly related to both Aphelidium and Amoebaphelidium, highlighting the wide genetic diversity of aphelids. Paraphelidium tribonemae has amoeboflagellate zoospores containing a lipid‐microbody complex, dictyosomes, and mitochondria with rhomboid cristae, which are also present in trophonts and plasmodia. The amoeboid trophont uses pseudopodia to feed from the host cytoplasm. Although genetically distinct, the genus Paraphelidium is morphologically indistinguishable from other aphelid genera and has zoospores able to produce lamellipodia with subfilopodia like those of Amoeboaphelidium.     

Functional responses of contrasting seed predator guilds to masting in two Mediterranean oak species

The predator satiation hypothesis poses that synchronous and variable seed production during masting events increases seed escape through seed predator satiation. The success of this strategy depends upon the type of consumer functional response, in this case defined as the change in seed consumption rate by a predator as a function of change in seed density. Type II (where the proportion of seed consumed is highest at low levels of seed availability) and type III (where the proportion of seed consumed is highest at some intermediate level of seed availability and then declines towards zero) functional responses describe negative density‐dependence and indicate predator satiation. The type of function response should be contingent upon herbivore traits: type II responses are predicted for dietary specialist predators with low mobility, and type III responses are predicted for highly mobile, dietary generalist predators. Surprisingly, most studies have not evaluated whether functional responses vary among seed predator guilds. Here we describe the functional responses at population and individual tree level of highly mobile generalist (birds and rodents) and less mobile specialist (insects) pre‐dispersal seed predators attacking acorns of two sympatric oaks (Quercus suber and Q. canariensis) over a 10‐year period. Our results showed that in most cases specialist seed predators exhibited the predicted type II functional response at both the individual tree and population level for both oak species. However, generalist seed predators did not exhibit the predicted type III response; instead, they also exhibited a type II response at the individual tree and population level for both oak species. By independently assessing the effects of multiple seed predators associated with the same host tree species, our work highlights the influence of herbivore traits on the outcome of plant–seed predator interactions in masting species, and thus furthers our understanding of the ecological and evolutionary mechanisms underlying masting behaviour.     

Antioxidant treatment reverses mitochondrial dysfunction in a sepsis animal model

Evidence from the literature has demonstrated that reactive oxygen species (ROS) play an important role in the development of multiple organ failure and septic shock. In addition, mitochondrial dysfunction has been implicated in the pathogenesis of multiple organ dysfunction syndrome (MODS). The hypothesis of cytopathic hypoxia postulates that impairment in mitochondrial oxidative phosphorylation reduces aerobic adenosine triphosphate (ATP) production and potentially induces MODS. In this work, our aim was to evaluate the effects of antioxidants on oxidative damage and energy metabolism parameters in liver of rats submitted to a cecal ligation puncture (CLP) model of sepsis. We speculate that CLP induces a sequence of events that culminate with liver cells death. We propose that mitochondrial superoxide production induces mitochondrial oxidative damage, leading to mitochondrial dysfunction, swelling and release of cytochrome c. These events occur in early sepsis development, as reported in the present work. Liver cells necrosis only occurs 24 h after CLP, but all other events occur earlier (6-12 h). Moreover, we showed that antioxidants may prevent oxidative damage and mitochondrial dysfunction in liver of rats after CLP. In another set of experiments, we verified that L-NAME administration did not reverse increase of superoxide anion production, TBARS formation, protein carbonylation, mitochondrial swelling, increased serum AST or inhibition on complex IV activity caused by CLP. Considering that this drug inhibits nitric oxide synthase and that no parameter was reversed by its administration, we suggest that all the events reported in this study are not mediated by nitric oxide. In conclusion, although it is difficult to extrapolate our findings to human, it is tempting to speculate that antioxidants may be used in the future in the treatment of this disease.     

ChromaPipe: a pipeline for analysis, quality control and management for a DNA sequencing facility

Optimizing and monitoring the data flow in high-throughput sequencing facilities is important for data input and output, for tracking the status of results for the users of the facility, and to guarantee a good, high-quality service. In a multi-user system environment with different throughputs, each user wants to access his/her data easily, track his/her sequencing history, analyze sequences and their quality, and apply some basic post-sequencing analysis, without the necessity of installing further software. Recently, Fiocruz established such a core facility as a "technological platform". Infrastructure includes a 48-capillary 3730 DNA Sequence Analyzer (Applied Biosystems) and supporting equipment. The service includes running samples for large-scale users, performing DNA sequencing reactions and runs for medium and small users, and participation in partial or full genome projects. We implemented a workflow that fulfills these requirements for small and high throughput users. Our implementation also includes the monitoring of data for continuous quality improvement (reports by plate, month and user) by the sequencing staff. For the user, different analyses of the chromatograms, such as visualization of good quality regions, as well as processing, such as comparisons or assemblies, are available. So far, 180 users have made use of the service, generating 155,000 sequences, 35% of which were produced for the BCG Moreau-RJ genome project. The pipeline (named ChromaPipe for Chromatogram Pipeline) is available for download by the scientific community at the url http://bioinfo.pdtis.fiocruz.br/ChromaPipe/. The support for assembly is also configured as a web service: http://bioinfo.pdtis.fiocruz.br/Assembly/.