Heterocyclic alpha-helix mimetics for targeting protein-protein interactions

The design and synthesis of alpha-helix peptidomimetics using inverse electron demand Diels-Alder reactions is described. The potency of the resulting pyridazine-based library to disrupt the Bak/Bcl-X(L) interaction was tested using an in vitro fluorescence polarization assay.     

Antibody response against saliva antigens of Anopheles gambiae and Aedes aegypti in travellers in tropical Africa

Exposure to vectors of infectious diseases has been associated with antibody responses against salivary antigens of arthropods among people living in endemic areas. This immune response has been proposed as a surrogate marker of exposure to vectors appropriate for evaluating the protective efficacy of antivectorial devices. The existence and potential use of such antibody responses in travellers transiently exposed to Plasmodium or arbovirus vectors in tropical areas has never been investigated. The IgM and IgG antibody responses of 88 French soldiers against the saliva of Anopheles gambiae and Aedes aegypti were evaluated before and after a 5-month journey in tropical Africa. Antibody responses against Anopheles and Aedes saliva increased significantly in 41% and 15% of the individuals, respectively, and appeared to be specific to the mosquito genus. A proteomic and immunoproteomic analysis of anopheles and Aedes saliva allowed for the identification of some antigens that were recognized by most of the exposed individuals. These results suggest that antibody responses to the saliva of mosquitoes could be considered as specific surrogate markers of exposure of travellers to mosquito vectors that transmit arthropod borne infections.     

Differentiating megakaryocytes in myelodysplastic syndromes succumb to mitochondrial derangement without caspase activation

Myelodysplastic syndromes (MDS) constitute a preneoplastic condition in which potentially malignant cancer stem cells continuously die during differentiation. This MDS-associated cell death often involves caspase-3 activation, yet can also occur without caspase activation, for instance in differentiating megakaryocytes (MK). We investigated, the mechanisms through which MK from MDS patients undergo premature cell death. While polyploid, mature MK from healthy subjects or MDS patients manifested caspase-3 activation during terminal differentiation, freshly isolated, immature MK from MDS died without caspase-3 activation. Similarly, purified bone marrow CD34⁺ cells from MDS patients that were driven into MK differentiation in vitro died without caspase-3 activation at an immature stage, before polyploidization. The premature death of MDS MK was accompanied by the mitochondrial release of cytochrome c, Smac/DIABLO and endonuclease G, a caspase-independent death effector, as well loss of the mitochondrial membrane potential and plasma membrane phosphatidylserine exposure before definitive loss of viability. Thus, a stereotyped pattern of mitochondrial alterations accompanies differentiation-associated MK death in MDS. T. Braun and G. Carvalho contributed equally to this paper.     

Persistence of long-term memory storage requires a late protein synthesis- and BDNF- dependent phase in the hippocampus

Persistence is the most characteristic attribute of long-term memory (LTM). To understand LTM, we must understand how memory traces persist over time despite the short-lived nature and rapid turnover of their molecular substrates. It is widely accepted that LTM formation is dependent upon hippocampal de novo protein synthesis and Brain-Derived Neurotrophic Factor (BDNF) signaling during or early after acquisition. Here we show that 12 hr after acquisition of a one-trial associative learning task, there is a novel protein synthesis and BDNF-dependent phase in the rat hippocampus that is critical for the persistence of LTM storage. Our findings indicate that a delayed stabilization phase is specifically required for maintenance, but not formation, of the memory trace. We propose that memory formation and memory persistence share some of the same molecular mechanisms and that recurrent rounds of consolidation-like events take place in the hippocampus for maintenance of the memory trace.     

Limiting processes for perennial plant reintroduction to restore dry grasslands

In restored grasslands of southern Europe, perennial plants remain highly underrepresented compared with the reference ecosystems. We tested various treatments to reintroduce common perennial plant species (Brachypodium retusum, Poaceae, and Thymus vulgaris, Lamiaceae), which are usually not or poorly reintroduced via soil and hay transfer. Treatments included microenvironmental manipulations (rock cover and plant interactions) and two grazing intensities. Target perennial species were transplanted in 2002 in the reference grassland ecosystem (intact grassland area used as a control) and in two abandoned fields. Survival was assessed in June 2003 and June 2004. Target species shoot and root biomass were measured in June 2004. Grazing greatly reduced the survival and biomass of both target species and its effects were reinforced by summer drought: plants that did not establish well enough during the autumn and spring did not survive summer. The restored rock cover had a mild positive effect, particularly on B. retusum. There were no negative or positive plant neighbor interactions in the steppe, while there was competition in both abandoned fields. Competition was particularly intense in the abandoned melon field, composed of a dense sward of annual grasses (Bromus sp.). In order to reintroduce perennial species to dry grasslands, the ideal combination of treatments is to exclude or reduce grazing during the first year to allow seedlings to establish and to recreate adequate microenvironmental conditions. Reducing competition from arable weeds may help but is not essential in such dry grasslands.     

Ensemble modelling of species distribution: the effects of geographical and environmental ranges

The aim of this study was to analyse the effects of species geographical and environmental ranges on the predictive performances of species distribution models (SDMs). We explored the usefulness of ensemble modelling approaches and tested whether species attributes influenced the outcomes of such approaches. Eight SDMs were used to model the current distribution of 35 fish species at 1110 stream sections in France. We first quantified the consensus among the resulting set of predictions for each fish species. Next, we created an average model by taking the average of the individual model predictions and tested whether the average model improved the predictive performances of single SDMs. Lastly, we described the ranges of fish species along four gradients: latitudinal, thermal, stream gradient (i.e. upstream‐downstream) and elevation. After accounting for the effects of phylogenetic relatedness and species prevalence, these four species attributes were related to the observed variations in both consensus among SDMs and predictive performances by using generalized estimation equations. Our results highlight the usefulness of ensemble approaches for identifying geographical areas of agreement among predictions. Although the geographical extent of species had no effect on the performances of SDMs, we demonstrated that more consensual and accurate predictions were obtained for species with low thermal and elevation ranges, validating the hypothesis that specialist species yield models with higher accuracy than generalist ones. We emphasized that significant improvements in the accuracy of SDMs can be achieved by using an average model. Furthermore, these improvements were higher for species with smaller ranges along the four gradients studied. The geographical extent and ranges of species along environmental gradients provide promising insights into our understanding of uncertainties in species distribution modelling.     

Rac1 drives melanoblast organization during mouse development by orchestrating pseudopod- driven motility and cell-cycle progression

1. Download : Download high-res image (218KB)
2. Download : Download full-size image

Highlights? Rac1 and the Scar/WAVE complex drive pseudopod-based motility of melanoblasts ? Rac1-depleted melanoblasts move using unique actin-based stubs and not blebs ? Rac1 controls pseudopod frequency but is dispensable for pseudopod formation ? Loss of Rac1 delays melanoblast cell-cycle progression and cytokinesis     

Skeletal ossification and sequence heterochrony in xenarthran evolution

Previous analyses of how mammals vary in their ossification sequences have focused on monotremes, marsupials, and boreoeutherian placentals. Here, we focus on the sequence of cranial and postcranial ossification events during growth in the xenarthran skull and skeleton, including armadillos, anteaters, and sloths. We use two different methods to quantify sequence heterochrony: sequence analysis of variance (ANOVA) and event‐paring/Parsimov. Our results indicate that Parsimov is conservative and does not detect clear heterochronic shifts between xenarthran and boreoeutherian placentals. Sequence‐ANOVA performs better, but both methods exhibit sensitivity to the artifactual accumulation of ties. By controlling for ties and taking into account results that the methods have in common, our analysis suggests that xenarthrans significantly differ from other placentals by a late ossification of the sternum and an early ossification of the phalanges and pubis. We interpret these differences as showing that heterochrony plays a role in the skeletal development of xenarthrans, a change from previous studies that have emphasized the developmental homogeneity of the skeleton across placental mammals.