Novel benzimidazole derivatives as selective CB2 agonists

The preparation and evaluation of a novel class of CB2 agonists based on a benzimidazole moiety are reported. They showed binding affinities up to 1nM towards the CB2 receptor with partial to full agonist potencies. They also demonstrated good to excellent selectivity (>1000-fold) over the CB1 receptor.     

Ca regulation of connexin 43 hemichannels in C6 glioma and glial cells

Connexin hemichannels have a low open probability under normal conditions but open in response to various stimuli, forming a release pathway for small paracrine messengers. We investigated hemichannel-mediated ATP responses triggered by changes of intracellular Ca²⁺ ([Ca²⁺]_i) in Cx43 expressing glioma cells and primary glial cells. The involvement of hemichannels was confirmed with gja1 gene-silencing and exclusion of other release mechanisms. Hemichannel responses were triggered when [Ca²⁺]_i was in the 500 nM range but the responses disappeared with larger [Ca²⁺]_i transients. Ca²⁺-triggered responses induced by A23187 and glutamate activated a signaling cascade that involved calmodulin (CaM), CaM-dependent kinase II, p38 mitogen activated kinase, phospholipase A2, arachidonic acid (AA), lipoxygenases, cyclo-oxygenases, reactive oxygen species, nitric oxide and depolarization. Hemichannel responses were also triggered by activation of CaM with a Ca²⁺-like peptide or exogenous application of AA, and the cascade was furthermore operational in primary glial cells isolated from rat cortex. In addition, several positive feed-back loops contributed to amplify the responses. We conclude that an elevation of [Ca²⁺]_i triggers hemichannel opening, not by a direct action of Ca²⁺ on hemichannels but via multiple intermediate signaling steps that are adjoined by distinct signaling mechanisms activated by high [Ca²⁺]_i and acting to restrain cellular ATP loss.     

Cadmium uptake and distribution in Arabidopsis thaliana exposed to low chronic concentrations depends on plant growth

This study tested the hypothesis that Cd uptake is correlated with the shoot or root growth of Arabidopsis thaliana ecotype Columbia cultivated hydroponically at environmentally relevant Cd concentrations: 20, 100 and 350 nmol L^?1. Growth of both roots and shoots were delayed at 350 nmol L^?1. The rate of Cd uptake determined by spiking the nutrient solution with ¹⁰⁹Cd for 24 h, was significantly correlated with the root growth rate. The fraction of Cd absorbed that was allocated to shoots was constant with time but decreased with increasing exposure to Cd. Autoradiography and gamma counting showed that Cd was preferentially allocated to developing leaves. Hence, the quantity of Cd in shoots depended both on the root growth, which probably governed the uptake, and on the maturity of the leaves, which may have determined the Cd allocated to shoots through changes in the transpiration stream.     

Soil decomposition of wheat internodes of different maturity stages: relative impact of the soluble and structural fractions

The aim of this study was to clarify the importance of the soluble fraction on cell wall decomposition. Wheat plant was chosen as a model and was harvested at three stages of maturity: anthesis (A stage), 20 days after anthesis (B stage) and physiological maturity (PM stage). Wheat third internode (numbered down from the ear) were selected for this study. Internode age influenced the cumulative CO(2) kinetics with internodes from wheat stem harvested at anthesis mineralizing 62.1%+/-2.2 of added residue C whereas those harvested at the B and PM stages mineralized 58.8%+/-1.4 and 51.6%+/-1.7, respectively of the added C. Chemical analyses revealed that maturation of the selected internodes mainly altered residue quality by modifying the proportion of soluble to cell wall fractions rather than the quality of these fractions. The hexose to pentose ratios were good biomarkers of microbial sugars for both soluble and cell wall fractions, as were the uronic acids, which are not commonly determined in soil decomposition studies. This study clearly demonstrated that the contents of the internode soluble fraction did not affect the extent of cell wall C mineralization. Therefore, the soluble content of crop residues would not regulate the soil microbial populations able to mineralize cell wall C. However, this needs to be validated on a broader range of residue types with different nature of cell wall C or soluble compounds.     

Towards calixarene-based prodrugs: Drug release and antibacterial behaviour of a water-soluble nalidixic acid/calix[4]arene ester adduct

A water-soluble calixarene-based heterocyclic podand incorporating a quinolone antibiotic subunit, the nalidixic acid, was synthesised and fully characterised. Its prodrug behaviour was assessed in vitro by HPLC, demonstrating the release of the tethered quinolone in model biological conditions. Microbiological studies performed on various Gram-positive and Gram-negative reference strains showed very interesting antibacterial activities.     

Synthesis and biological evaluation of new heterocyclic quinolinones as anti-parasite and anti-HIV drug candidates

We have synthesized quinolinones with potential antiparasitic and anti-HIV activities by an original two-step method involving microwave irradiation and have evaluated their activities against Plasmodium falciparum, Leishmania donovani, Trichomonas vaginalis, and HIV. None of the tested compounds had been previously described using this method of synthesis. One of the compounds had interesting antiparasitic and anti-HIV activity, which could be improved by substitution with different radicals.     

Getting a Grip on Complexes

We are witnessing tremendous advances in our understanding of the organization of life. Complete genomes are being deciphered with ever increasing speed and accuracy, thereby setting the stage for addressing the entire gene product repertoire of cells, towards understanding whole biological systems. Advances in bioinformatics and mass spectrometric techniques have revealed the multitude of interactions present in the proteome. Multiprotein complexes are emerging as a paramount cornerstone of biological activity, as many proteins appear to participate, stably or transiently, in large multisubunit assemblies. Analysis of the architecture of these assemblies and their manifold interactions is imperative for understanding their function at the molecular level. Structural genomics efforts have fostered the development of many technologies towards achieving the throughput required for studying system-wide single proteins and small interaction motifs at high resolution. The present shift in focus towards large multiprotein complexes, in particular in eukaryotes, now calls for a likewise concerted effort to develop and provide new technologies that are urgently required to produce in quality and quantity the plethora of multiprotein assemblies that form the complexome, and to routinely study their structure and function at the molecular level. Current efforts towards this objective are summarized and reviewed in this contribution.Key Words: Proteome, interactome, multiprotein assemblies, structural genomics, robotics, multigene expression, multiBac, BEVS, ACEMBL, complexomics.     

The caudal regeneration blastema is an accumulation of rapidly proliferating stem cells in the flatworm Macrostomum lignano

Background  

Macrostomum lignano is a small free-living flatworm capable of regenerating all body parts posterior of the pharynx and anterior to the brain. We quantified the cellular composition of the caudal-most body region, the tail plate, and investigated regeneration of the tail plate in vivo and in semithin sections labeled with bromodeoxyuridine, a marker for stem cells (neoblasts) in S-phase.