The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to

The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria

The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to

The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria

Regulatory (pan-)genome of an obligate intracellular pathogen in the PVC superphylum.

Like other obligate intracellular bacteria, the Chlamydiae feature a compact regulatory genome that remains uncharted owing to poor genetic tractability. Exploiting the reduced number of transcription factors (TFs) encoded in the chlamydial (pan-)genome as a model for TF control supporting the intracellular lifestyle, we determined the conserved landscape of TF specificities by ChIP-Seq (chromatin immunoprecipitation-sequencing) in the chlamydial pathogen Waddlia chondrophila. Among 10 conserved TFs, Euo emerged as a master TF targeting >100 promoters through conserved residues in a DNA excisionase-like winged helix-turn-helix-like (wHTH) fold. Minimal target (Euo) boxes were found in conserved developmentally-regulated genes governing vertical genome transmission (cytokinesis and DNA replication) and genome plasticity (transposases). Our ChIP-Seq analysis with intracellular bacteria not only reveals that global TF regulation is maintained in the reduced regulatory genomes of Chlamydiae, but also predicts that master TFs interpret genomic information in the obligate intracellular α-proteobacteria, including the rickettsiae, from which modern day mitochondria evolved

Modulation of anger control in suicide attempters by TPH-1

A genetic association between the tryptophan hydroxylase gene (TPH)-1 A218C polymorphism and suicidal behaviour is supported by numerous case-control studies as well as recent meta-analyses. Some data suggest that this polymorphism could also influence individual differences in anger-related personality traits, a phenotype partially under genetic control and known to increase the risk of suicide ideation and attempt. The aim of the present study was to investigate whether the TPH-1 A218C polymorphism affected anger-related personality traits in suicide attempters (n = 544). We hypothesized that suicide attempters carrying the AA genotype would display different scores on a scale measuring anger-related traits compared with suicide attempters carrying the CC genotype. Indeed, the dimension of Anger Control was significantly affected by the TPH-1 A218C polymorphism: suicide attempters carrying the AA genotype scored significantly lower on the Anger Control subscale than suicide attempters carrying the AC and CC genotypes. This polymorphism did not display any influence on the other State-Trait Anger Expression Inventory subscales. This result confirms our working hypothesis and suggests that the TPH-1 genotype could confer a vulnerability to suicidal behaviour through a reduced capacity to control anger, which in turn may represent a common psychopathological and behavioural pathway to suicidal behaviour in an important subgroup of clinical subjects

[Guidelines for good clinical practice: prevention and treatment of venous thromboembolism in medical patients].

International audienc

The Modeling of Time-Dependent Deformation and Fracturing of Brittle Rocks Under Varying Confining and Pore Pressures

International audienceA numerical hydro-mechanical model for brittle creep is proposed to describe the time-dependent deformation of heterogeneous brittle rock under constant confining and pore pressures. Material heterogeneity and a local material degradation law are incorporated into the model at the mesoscale which affects the mechanical behavior of rocks to capture the co-operative interaction between microcracks in the transition from distributed to localized damage. The model also describes the spatiotemporal acoustic emissions in the rock during the progressive damage process. The approach presented in this contribution differs from macroscopic approaches based on constitutive laws and microscopic approaches focused on fracture propagation. The model is first validated using experimental data for porous sandstone and is then used to simulate brittle creep tests under varying constant confining and pore pressures and applied differential stresses. We further explore the influence of sample homogeneity on brittle creep. The model accurately replicates the classic creep behavior observed in laboratory brittle creep experiments. In agreement with experimental observations, our model shows that decreasing effective pressure, increasing the applied differential stress, and decreasing sample homogeneity increase the creep strain rate and decrease the time-to-failure, respectively. The model shows that complex macroscopic time-dependent behavior can be explained by the microscale interaction of elements. The fact that the simulations are able to capture a similar hydro-mechanical time-dependent response to that of laboratory experiments implies that the model is an appropriate tool to investigate the complex time-dependent behavior of heterogeneous brittle rocks under coupled hydro-mechanical loading

Storage Reserve Accumulation in Arabidopsis: Metabolic and Developmental Control of Seed Filling

In the life cycle of higher plants, seed development is a key process connecting two distinct sporophytic generations. Seed development can be divided into embryo morphogenesis and seed maturation. An essential metabolic function of maturing seeds is the deposition of storage compounds that are mobilised to fuel post-germinative seedling growth. Given the importance of seeds for food and animal feed and considering the tremendous interest in using seed storage products as sustainable industrial feedstocks to replace diminishing fossil reserves, understanding the metabolic and developmental control of seed filling constitutes a major focus of plant research. Arabidopsis thaliana is an oilseed species closely related to the agronomically important Brassica oilseed crops. The main storage compounds accumulated in seeds of A. thaliana consist of oil stored as triacylglycerols (TAGs) and seed storage proteins (SSPs). Extensive tools developed for the molecular dissection of A. thaliana development and metabolism together with analytical and cytological procedures adapted for very small seeds have led to a good description of the biochemical pathways producing storage compounds. In recent years, studies using these tools have shed new light on the intricate regulatory network controlling the seed maturation process. This network involves sugar and hormone signalling together with a set of developmentally regulated transcription factors. Although much remains to be elucidated, the framework of the regulatory system controlling seed filling is coming into focus