Discovery of potent furan piperazine sodium channel blockers for treatment of neuropathic pain

The synthesis and pharmacological characterization of a novel furan-based class of voltage-gated sodium channel blockers is reported. Compounds were evaluated for their ability to block the tetrodotoxin-resistant sodium channel Na(v)1.8 (PN3) as well as the Na(v)1.2 and Na(v)1.5 subtypes. Benchmark compounds from this series possessed enhanced potency, oral bioavailability, and robust efficacy in a rodent model of neuropathic pain, together with improved CNS and cardiovascular safety profiles compared to the clinically used sodium channel blockers mexiletine and lamotrigine.     

Genetic variation of stomatal traits and carbon isotope discrimination in two hybrid poplar families (Populus deltoides 'S9-2' x P. nigra 'Ghoy' and P. deltoides 'S9-2' x P. trichocarpa 'V24')

Background and Aims

Stomata play an important role in both the CO₂ assimilation and water relations of trees. Therefore, stomatal traits have been suggested as criteria for selection of clones or genotypes which are more productive and have larger water-use efficiency (WUE) than others. However, the relationships between plant growth, WUE and stomatal traits are still unclear depending on plant material (genus, species, families, genotypes) and, more precisely, on the strength of the relationships between the plants. In this study, the correlations between these three traits categories, i.e. plant growth, WUE and stomatal traits, were compared in two related poplar families.

Methods

Stomatal traits (stomatal density, length and ratio adaxial : abaxial stomatal densities) of a selection of F₁ genotypes and the parents of two hybrid poplar families Populus deltoides ‘S9-2’ × P. nigra ‘Ghoy’ (D × N family, 50 F₁) and P. deltoides ‘S9-2’ × P. trichocarpa ‘V24’ (D × T family, 50 F₁) were measured, together with stem height and circumference. Carbon isotope discrimination (Δ) was determined and used as an indicator of leaf-level intrinsic WUE.

Key Results

Leaves of hybrids and parents were amphistomatous, except for the P. trichocarpa parent. Both families displayed high values of heritability for stomatal traits and Δ. In the progeny, the relationship between stem circumference and Δ was weak for the D × N family, while abaxial and total stomatal density were positively associated with stem dimensions for the D × T family only.

Conclusions

Genetic variation in stomatal traits and Δ was large within as well as between the different poplar species and their hybrids, but there were no direct relationships between stomatal traits and plant growth or Δ. As already noticed in various poplar hybrids, the absence of, or the weak, relationship between Δ and plant growth allows the possibility of selecting poplar genotypes combining high productivity and high WUE. In this study, stomatal traits are of limited value as criteria for selection of genotypes with good growth and large WUE.Key words: Adaxial and abaxial stomatal density, stomatal length, heritability, water-use efficiency (WUE), F₁ hybrids, breeding, Populus deltoides, Populus nigra, Populus trichocarpa     

Mycotoxigenic infestation in samples of cereal straw from Bihar, India

A survey of different types of cereal straw samples viz. paddy, maize and wheat, from Bihar State, India, was conducted in order to examine the mould flora and mycotoxin contamination. Out of 170 samples examined for mould flora,Aspergillus flavus group of fungi had highest level of incidence followed byA niger. Isolates ofA flavus, A ochraceus, Fusarium verticillioides andPenicillium citrinum were screened for their mycotoxins producing abilities. Out of 75, 63 and 68 isolates ofA flavus group obtained from stored straw of paddy, maize and wheat samples, respectively, 27 (36%), 14 (22%) and 24 (35%) were found to be toxigenic which produced different combinations of aflatoxins in different concentrations. The percentage toxigenicity was comparatively lower in the isolates of other mycotoxigenic fungi from all types of samples. Out of 222 samples of straw analysed for natural occurrence of different mycotoxins, besides the aflatoxins present, zearalenone, ochratoxin A and citrinin were also recorded alone or as co-contaminants. A conducive climate together with the socioeconomic conditions of this region are important determinants for the high incidence of mycotoxins in cereal straw samples.     

Homologies of the adductor mandibulae muscles in Tetraodontiformes as indicated by nerve branching patterns

Homologies of the adductor mandibulae muscles in eight families of Tetraodontiformes were hypothesized from the branching patterns of ramus mandibularis trigeminus. Insertions of the muscles to the upper or lower jaw were weak indicators of homology, migrations of the sites occurring frequently in A1, A2, A2, and A3. In monacanthids, tetraodontids, and diodontids, A1 tended to be split into numerous subsections, whereas in aracanids and ostraciids, A3 was highly developed, comprising three or four subsections. In tetraodontids, A2 was found to be a composite of A1 subsection and A2. The methods of and limits to applying nerve branching patterns to muscle homology are discussed. A new naming system that reflects both muscle homologies and insertions is proposed.     

A family of diatom-like silicon transporters in the siliceous loricate choanoflagellates

Biosilicification is widespread across the eukaryotes and requires concentration of silicon in intracellular vesicles. Knowledge of the molecular mechanisms underlying this process remains limited, with unrelated silicon-transporting proteins found in the eukaryotic clades previously studied. Here, we report the identification of silicon transporter (SIT)-type genes from the siliceous loricate choanoflagellates Stephanoeca diplocostata and Diaphanoeca grandis. Until now, the SIT gene family has been identified only in diatoms and other siliceous stramenopiles, which are distantly related to choanoflagellates among the eukaryotes. This is the first evidence of similarity between SITs from different eukaryotic supergroups. Phylogenetic analysis indicates that choanoflagellate and stramenopile SITs form distinct monophyletic groups. The absence of putative SIT genes in any other eukaryotic groups, including non-siliceous choanoflagellates, leads us to propose that SIT genes underwent a lateral gene transfer event between stramenopiles and loricate choanoflagellates. We suggest that the incorporation of a foreign SIT gene into the stramenopile or choanoflagellate genome resulted in a major metabolic change: the acquisition of biomineralized silica structures. This hypothesis implies that biosilicification has evolved multiple times independently in the eukaryotes, and paves the way for a better understanding of the biochemical basis of silicon transport through identification of conserved sequence motifs.     

Productivity, leaf traits and carbon isotope discrimination in 29 Populus deltoides x P. nigra clones

Here we tested whether some leaf traits could be used as predictors for productivity in a range of Populus deltoides x P. nigra clones. These traits were assessed in 3-yr-old rooted cuttings from 29 clones growing in an open field trial, in a five randomized complete block design, under optimal irrigation. Variables were assigned to four groups describing productivity (above-ground biomass, total leaf area), leaf growth (total number of leaves increment rate), leaf structure (area of the largest leaf, specific leaf area, carbon and nitrogen contents), and carbon isotope discrimination in the leaves (Delta). High-yielding clones displayed larger total leaf area and individual leaf area, while no correlation could be detected between productivity and either leaf structure or Delta. By contrast, Delta was negatively correlated with number of leaves increment rate and leaf N content. Our study shows that there is a potential to improve water-use efficiency in poplar without necessarily reducing the overall productivity.     

Multiple angiopoietin recombinant proteins activate the Tie1 receptor tyrosine kinase and promote its interaction with Tie2

The Tie1 receptor tyrosine kinase was isolated over a decade ago, but so far no ligand has been found to activate this receptor. Here, we have examined the potential of angiopoietins, ligands for the related Tie2 receptor, to mediate Tie1 activation. We show that a soluble Ang1 chimeric protein, COMP-Ang1, stimulates Tie1 phosphorylation in endothelial cells with similar kinetics and angiopoietin dose dependence when compared with Tie2. The phosphorylation of overexpressed Tie1 was weakly induced by COMP-Ang1 also in transfected cells that do not express Tie2. When cotransfected, Tie2 formed heteromeric complexes with Tie1, enhanced Tie1 activation, and induced phosphorylation of a kinase-inactive Tie1 in a ligand-dependent manner. Tie1 phosphorylation was also induced by native Ang1 and Ang4, although less efficiently than with COMP-Ang1. In conclusion, we show that Tie1 phosphorylation is induced by multiple angiopoietin proteins and that the activation is amplified via Tie2. These results should be important in dissecting the signal transduction pathways and biological functions of Tie1.     

Design, synthesis and structure-activity relationships of 6-O-arylpropargyl diazalides with potent activity against multidrug-resistant Streptococcus pneumoniae

A novel series of 6-O-arylpropargyl diazalides was synthesized and evaluated for their antibacterial activity. Members of this series exhibited potent activity against erythromycin-resistant respiratory tract pathogens.