DOGS: Reaction-Driven de novo Design of Bioactive Compounds

We present a computational method for the reaction-based de novo design of drug-like molecules. The software DOGS (Design of Genuine Structures) features a ligand-based strategy for automated ‘in silico’ assembly of potentially novel bioactive compounds. The quality of the designed compounds is assessed by a graph kernel method measuring their similarity to known bioactive reference ligands in terms of structural and pharmacophoric features. We implemented a deterministic compound construction procedure that explicitly considers compound synthesizability, based on a compilation of 25'144 readily available synthetic building blocks and 58 established reaction principles. This enables the software to suggest a synthesis route for each designed compound. Two prospective case studies are presented together with details on the algorithm and its implementation. De novo designed ligand candidates for the human histamine H4 receptor and γ-secretase were synthesized as suggested by the software. The computational approach proved to be suitable for scaffold-hopping from known ligands to novel chemotypes, and for generating bioactive molecules with drug-like properties

Abrolhos Bank Reef Health Evaluated by Means of Water Quality, Microbial Diversity, Benthic Cover, and Fish Biomass Data

The health of the coral reefs of the Abrolhos Bank (southwestern Atlantic) was characterized with a holistic approach using measurements of four ecosystem components: (i) inorganic and organic nutrient concentrations, [1] fish biomass, [1] macroalgal and coral cover and (iv) microbial community composition and abundance. The possible benefits of protection from fishing were particularly evaluated by comparing sites with varying levels of protection. Two reefs within the well-enforced no-take area of the National Marine Park of Abrolhos (Parcel dos Abrolhos and California) were compared with two unprotected coastal reefs (Sebastião Gomes and Pedra de Leste) and one legally protected but poorly enforced coastal reef (the “paper park” of Timbebas Reef). The fish biomass was lower and the fleshy macroalgal cover was higher in the unprotected reefs compared with the protected areas. The unprotected and protected reefs had similar seawater chemistry. Lower vibrio CFU counts were observed in the fully protected area of California Reef. Metagenome analysis showed that the unprotected reefs had a higher abundance of archaeal and viral sequences and more bacterial pathogens, while the protected reefs had a higher abundance of genes related to photosynthesis. Similar to other reef systems in the world, there was evidence that reductions in the biomass of herbivorous fishes and the consequent increase in macroalgal cover in the Abrolhos Bank may be affecting microbial diversity and abundance. Through the integration of different types of ecological data, the present study showed that protection from fishing may lead to greater reef health. The data presented herein suggest that protected coral reefs have higher microbial diversity, with the most degraded reef (Sebastião Gomes) showing a marked reduction in microbial species richness. It is concluded that ecological conditions in unprotected reefs may promote the growth and rapid evolution of opportunistic microbial pathogens

The buccinator during mastication: A functional and anatomical evaluation in minipigs

Objective: The buccinator muscle forms the lateral wall of the oral cavity. It is presumed to aid mastication by maintaining bolus position. Such a function would involve thickening the cheek, possibly compressing the alveolar bone and contributing to malocclusions. However, neither buccinator deformation nor its effect on pressure has been demonstrated. Our objective was to evaluate buccinator EMG during feeding, its changes in length and thickness, and the pressure exerted on its alveolar attachment, using miniature pigs as an animal model. Methods: EMG of the buccinator and other oral muscles was recorded with fine-wire electrodes. Anteroposterior length and mediolateral thickness of the buccinator were evaluated with implanted sonomicrometry crystals, and pressure was measured by flat transducers placed beneath the mandibular origin of the buccinator. Recordings were made during feeding and muscle stimulation. Tissues were collected postmortem for histology. Results: During mastication, buccinator EMG showed regular peaks that preceded those of the jaw closers. Pattern differences clearly distinguished working and balancing sides. The buccinator shortened and thickened when it contracted. Positive pressures were observed at the mandibular attachment of the buccinator, increasing when the muscle was active. Histological evaluation showed a complex interweaving of fibres closely associated with salivary tissue. Conclusions: Buccinator contraction does thicken the cheek, and during mastication this activity takes place just as the closing stroke begins. In addition to controlling the bolus, there may be an effect on salivation. Despite the fact that the muscle pulls on its attachment, the local mechanical environment at the alveolar bone is one of positive pressure. (C) 2010 Elsevier Ltd. All rights reserved.559627638NIDCR [DE08513]National Council for Scientific and Technological Development-BrazilNIDCR [DE08513