Novel non-nucleobase inhibitors of Staphylococcus aureus DNA polymerase IIIC

The preparation and biological evaluation of 5-substituted-6-hydroxy-2-(anilino)pyrimidinones as a new class of DNA polymerase IIIC inhibitors, required for the replication of chromosomal DNA in Gram-positive bacteria, are described. These new dGTP competitive inhibitors displayed good levels of in vitro inhibition and antibacterial activity against Staphylococcus aureus. A new class of dATP competitive inhibitors, 6-substituted-2-amino-5-alkyl-pyrimidin-4-ones, whose antibacterial activity was unaffected by serum, were identified.     

Triaminotriazine DNA helicase inhibitors with antibacterial activity

Screening of a chemical library in a DNA helicase assay involving the Pseudomonas aeruginosa DnaB helicase provided a triaminotriazine inhibitor with good antibacterial activity but associated cytotoxicity toward mammalian cells. Synthesis of analogs provided a few inhibitors that retained antibacterial activity and demonstrated a significant reduction in cytotoxicity. The impact of serum and initial investigations toward a mode of action highlight several features of this class of compounds as antibacterials.     

Energy-efficient indoor search by swarms of simulated flying robots without global information

Swarms of flying robots are a promising alternative to ground-based robots for search in indoor environments with advantages such as increased speed and the ability to fly above obstacles. However, there are numerous problems that must be surmounted including limitations in available sensory and on-board processing capabilities, and low flight endurance. This paper introduces a novel strategy to coordinate a swarm of flying robots for indoor exploration that significantly increases energy efficiency. The presented algorithm is fully distributed and scalable. It relies solely on local sensing and low-bandwidth communication, and does not require absolute positioning, localisation, or explicit world-models. It assumes that flying robots can temporarily attach to the ceiling, or land on the ground for efficient surveillance over extended periods of time. To further reduce energy consumption, the swarm is incrementally deployed by launching one robot at a time. Extensive simulation experiments demonstrate that increasing the time between consecutive robot launches significantly lowers energy consumption by reducing total swarm flight time, while also decreasing collision probability. As a trade-off, however, the search time increases with increased inter-launch periods. These effects are stronger in more complex environments. The proposed localisation-free strategy provides an energy efficient search behaviour adaptable to different environments or timing constraints.     

Motor Axon Pathfinding

Motor neurons are functionally related, but represent a diverse collection of cells that show strict preferences for specific axon pathways during embryonic development. In this article, we describe the ligands and receptors that guide motor axons as they extend toward their peripheral muscle targets. Motor neurons share similar guidance molecules with many other neuronal types, thus one challenge in the field of axon guidance has been to understand how the vast complexity of brain connections can be established with a relatively small number of factors. In the context of motor guidance, we highlight some of the temporal and spatial mechanisms used to optimize the fidelity of pathfinding and increase the functional diversity of the signaling proteins.Motor neurons residing in the brain stem and spinal cord extend axons into the periphery and are the final relay cells for locomotor commands. These cells are among the longest projection neurons in the body and their axons follow stereotypical pathways during embryogenesis to synapse with muscle and sympathetic/parasympathetic targets. Cellular studies of motor axon navigation in developing chick and zebrafish embryos have shown that motor neurons located at different rostrocaudal positions show specific preferences for axonal pathways (see Landmesser 2001; Lewis and Eisen 2003 for reviews). This early cellular research laid the foundation for molecular studies of motor axon guidance by establishing the concept that motor neurons are in fact a diverse cell population. The molecular studies covered in this article have sought to identify genetic differences between motor neurons and to characterize the signaling pathways that underlie the specificity of motor axon targeting.     

Methods for the identification of vascular markers in health and disease: From the bench to the clinic

Several diseases are characterized by changes in the molecular composition of vascular structures, thus offering the opportunity to use specific ligands (e.g., monoclonal antibodies) for imaging and therapy application. This novel pharmaceutical strategy, often referred to as “vascular targeting”, promises to facilitate the discovery and development of selective biopharmaceuticals for the management of angiogenesis-related diseases. This article reviews novel biomedical applications based on vascular targeting strategies, as well as methodologies which have been used for the discovery of vascular markers of pathology.     

A method for generation of bone marrow-derived macrophages from cryopreserved mouse bone marrow cells

The broad use of transgenic and gene-targeted mice has established bone marrow-derived macrophages (BMDM) as important mammalian host cells for investigation of the macrophages biology. Over the last decade, extensive research has been done to determine how to freeze and store viable hematopoietic human cells; however, there is no information regarding generation of BMDM from frozen murine bone marrow (BM) cells. Here, we establish a highly efficient protocol to freeze murine BM cells and further generate BMDM. Cryopreserved murine BM cells maintain their potential for BMDM differentiation for more than 6 years. We compared BMDM obtained from fresh and frozen BM cells and found that both are similarly able to trigger the expression of CD80 and CD86 in response to LPS or infection with the intracellular bacteria Legionella pneumophila. Additionally, BMDM obtained from fresh or frozen BM cells equally restrict or support the intracellular multiplication of pathogens such as L. pneumophila and the protozoan parasite Leishmania (L.) amazonensis. Although further investigation are required to support the use of the method for generation of dendritic cells, preliminary experiments indicate that bone marrow-derived dendritic cells can also be generated from cryopreserved BM cells. Overall, the method described and validated herein represents a technical advance as it allows ready and easy generation of BMDM from a stock of frozen BM cells.     

Comparison of chito-oligosaccharide production from three different colloidal chitosans using the endochitonsanolytic system of Bacillus thuringiensis

Bacillus thuringiensis is a nonhuman pathogen bacterium that is used as a fungal and insect biocontrol agent. Because of its environmental interaction, it possesses several extracellular enzymes that are able to degrade chitin and chitosan, two of the most important polymers because of their application in numerous fields. However, in recent years, it has been observed that oligosaccharides from the enzymatic degradation of chitosan have important benefits for human health. Comparison and exploration of the production of chito-oligosaccharides from different sources of chitosan will improve the process parameters and expand the biotechnology based in these molecules. This study shows the production of chito-oligosaccharides from three different sources of colloidal chitosan and conducts a qualitative–quantitative comparison between them, using the extracellular enzyme of B. thuringiensis. We found that in the three substrates, it is possible to get a mixture of chito-oligosaccharides from dimer to hexamer in a concentration range from 0.72 to 8.09?mg?·?g^?1 of original substrate. The best substrate to obtain these molecules was commercial chitosan as it has the highest production yields.     

Influence of multiple global change drivers on terrestrial carbon storage: additive effects are common

The interactive effects of multiple global change drivers on terrestrial carbon (C) storage remain poorly understood. Here, we synthesise data from 633 published studies to show how the interactive effects of multiple drivers are generally additive (i.e. not differing from the sum of their individual effects) rather than synergistic or antagonistic. We further show that (1) elevated CO₂, warming, N addition, P addition and increased rainfall, all exerted positive individual effects on plant C pools at both single‐plant and plant‐community levels; (2) plant C pool responses to individual or combined effects of multiple drivers are seldom scale‐dependent (i.e. not differing from single‐plant to plant‐community levels) and (3) soil and microbial biomass C pools are significantly less sensitive than plant C pools to individual or combined effects. We provide a quantitative basis for integrating additive effects of multiple global change drivers into future assessments of the C storage ability of terrestrial ecosystems.