Preparation and pharmacological profile of 7-(alpha-azolylbenzyl)-1H-indoles and indolines as new aromatase inhibitors

Aromatase (P450 arom) is a target of pharmacological interest for the treatment of breast cancer. New series of 7-(alpha-azolylbenzyl)-1H-indoles and indolines were synthesized as non-steroidal inhibitors of P450 arom. Selectivity was studied towards P450 17alpha enzyme. The most active compound, 1-ethyl-7-[(imidazol-1-yl)(4-chlorophenyl)methyl]-1H-indole 12c exhibited promising relative potency (rp) of 336 (rp of aminoglutethimide=1) and most of the described azoles were active and selective towards P450 arom.     

Distinct and common developmental expression patterns of the murine Pkd2 and Pkd1 genes

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most commonly inherited renal diseases. At least two genes, PKD2 and PKD1 are implicated in the development of this disease. Our pathogenetic studies showed that the human and murine polycystic kidney disease (PKD) involves failure to switch out of a renal developmental program. We have thus undertaken a detailed comparative expression analysis of Pkd2 and Pkd1 from the morula stage to adulthood. Pkd2 expression was detected as early as the morula and blastocyst stages as observed for Pkd1. Strong Pkd2 expression, similar to Pkd1, was displayed in all mesenchymal and cartilaginous tissues during mouse development. However major differences in Pkd2 expression in comparison to Pkd1 were identified. First, in contrast to Pkd1, the neural crest cell-derived tissues displayed a low to undetectable Pkd2 expression at all ages. Second, no increase in Pkd2 expression was detected during mesenchymal condensation. Third, high Pkd2 expression in the kidneys was localized mainly to the tubular epithelium of the cortical region from murine development to adulthood.     

Relationships between root density of the African grass Hyparrhenia diplandra and nitrification at the decimetric scale: an inhibition-stimulation balance hypothesis

Previous studies have shown that Lamto savannah exhibits two different types of nitrogen cycle with high and low nitrification sites and suggested that the perennial grass Hyparrhenia diplandra is responsible for this duality at a subpopulation level, with one ecotype being thought to be able to inhibit nitrification. The present work aimed to investigate the relationships between nitrification and the roots of H. diplandra at two scales. (i) Site-scale experiments gave new insight into the hypothesized control of nitrification by H. diplandra tussocks: the two ecotypes exhibited opposite influences, inhibition in a low nitrification site (A) and stimulation in a high nitrification site (B). (ii) Decimetric-scale experiments demonstrated close negative or positive relationships (in sites A or B, respectively) between the roots and nitrification (in the 0-10 cm soil layer), showing an unexpectedly high sensitivity of the nitrification process to root density. In both soils, the correlation between the roots and nitrification decreased with depth and practically disappeared in the 20-30 cm soil layer (where the nitrification potential was found to be very low). Therefore, the impact of H. diplandra on nitrification may be viewed as an inhibition-stimulation balance.     

Systemic administration of cationic phosphonolipids/DNA complexes and the relationship between formulation and lung transfection efficiency

Performances of cationic lipid formulations for intravenous gene delivery to mouse lungs have been previously reported. We report in this study that cationic phosphonolipids, when appropriately formulated, can be good synthetic vectors for gene delivery to lung after intravenous administration. One of our reagents, GLB43, was capable of mediating a 500-fold higher expression in the lungs of mice than could be obtained with free pDNA alone (P=0.018). We demonstrate that the most important parameters for cationic phosphonolipid transfection activity after systemic administration are the chemical structure of the cationic phosphonolipid, the lipid to DNA charge ratio and the inclusion of co-lipid in the formulation. We report using a luciferase reporter gene that transfection activity in vivo 24 h after cationic phosphonolipid systemic administration could not be predicted from in vitro analysis. In contrast to in vitro studies, cationic phosphonolipids including the oleyl acyl chains (GLB43) were more effective than its analogue with the myristyl acyl chains (GLB73). Using pathological analysis of animal livers, we demonstrate that the toxicity level was correlated with the lipoplex formulation and the lipid to DNA ratio.     

Multiple Phosphorylation Sites and Quaternary Organization of Guanine-Nucleotide Exchange Complex of Elongation Factor-1 (EF-1βγδ/ValRS) Control the Various Functions of EF-1α

The eukaryotic guanine-nucleotide exchange factor commonly called elongation factor-1 (EF-1), comprises four different subunits including valyl-tRNA synthetase (EF-1/ValRS). The factor is multiply-phosphorylated by three different protein kinases, protein kinase C, casein kinase II and cyclin dependent kinase 1 (CDK1). EF-1/ValRS is organized as a macromolecular complex for which we propose a new structural model. Evidence that EF-1/ValRS is a sophisticated supramolecular complex containing many phosphorylation sites, makes it a potential regulator of any of the functions of its partner EF-1, not only involved in protein synthesis elongation, but also in many other cellular functions.     

Ultrafast excited-state dynamics of phenyleneethynylene oligomers in solution.

The excited-state dynamics of oligomeric phenyleneethynylenes (OPEs) of various length and substitution has been investigated by femtosecond time-resolved spectroscopy. The fluorescence lifetime of the OPEs decreases with the number of phenyleneethynylene units up to about 9. This effect is due to an increase of the oscillator strength for the S(1)-S(0) transition. Dynamic features occurring within a few tens of picoseconds and ascribed to structural relaxation directly after population of the S(1) state can be observed in non-viscous solvents. The effect of torsional disorder on the fluorescence intensity is shown to depend strongly on the nature of the substituent on the phenyl groups. All these effects are qualitatively discussed with a simple exciton model.     

Behavioural Ecology and Group Cohesion of Juvenile Western Lowland Gorillas (Gorilla g. gorilla) during Rehabilitation in the Batéké Plateaux National Park,Gabon

Rehabilitation of animals followed by reintroduction into the wild can benefit conservation by supplementing depleted wild populations or reintroducing a species in an area where it has been extirpated or become extinct. The western lowland gorilla (WLG, Gorilla g. gorilla) is persistently poached; infants are often illegally traded and used as pets. Some are confiscated and rehabilitated, then kept in sanctuaries or reintroduced into the wild. Prior to reintroduction, the ability of the orphans to survive independently in their environment needs to be assessed. Here, we performed a multivariate analysis, including diet composition, activity-budget, and pattern of strata using of a group of five juvenile WLG in the process of rehabilitation and distinguished three sub-periods of ecological significance: the high furgivory period, the Dialium fruits consumption period, and the high folivory period. The consequences of these variations on their well-being (play behaviour) and the group cohesion (spatial proximity and social interactions) were examined. Like wild WLGs, diets shifted seasonally from frugivorous to folivorous, while the same staple foods were consumed and large amounts of Dialium fruits were seasonally gathered high in trees. When succulent fruit intake was the highest, thus providing high energy from sugar, juveniles spent less time feeding, more time playing and group cohesion was the highest. Conversely, the cohesion decreased with increasing folivory, individuals spent more time feeding and less time playing together. Nonetheless, the group cohesion also decreased after the death of one highly social, wild-born orphan. This may underscore the importance of skilled individuals in the cohesion and well-being of the entire group and, ultimately, to rehabilitation success. This study evaluates the rehabilitation success with regards to the methods used and highlights the need to consider a set of individual and environmental factors for enhancing rehabilitation while preserving the local biodiversity and individual well-being.     

The Spread of Aedes albopictus in Metropolitan France: Contribution of Environmental Drivers and Human Activities and Predictions for a Near Future

Invasion of new territories by insect vector species that can transmit pathogens is one of the most important threats for human health. The spread of the mosquito Aedes albopictus in Europe is emblematic, because of its major role in the emergence and transmission of arboviruses such as dengue or chikungunya. Here, we modeled the spread of this mosquito species in France through a statistical framework taking advantage of a long-term surveillance dataset going back to the first observation of Ae. albopictus in the Metropolitan area. After validating the model, we show that human activities are especially important for mosquito dispersion while land use is a major factor for mosquito establishment. More importantly, we show that Ae. albopictus invasion is accelerating through time in this area, resulting in a geographic range extending further and further year after year. We also show that sporadic “jump” of Ae. albopictus in a new location far from the colonized area did not succeed in starting a new invasion front so far. Finally, we discuss on a potential adaptation to cooler climate and the risk of invasion into Northern latitudes.