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89Zr−immunoPET is a hot topic as 89Zr cumulates the advantages of 64Cu and 124I without their drawbacks. We report the synthesis of a model ligand of a chiral bioconjugable tetrahydroxamic chelator combining the desferriferrioxamine B siderophore and 1‐hydroxy‐2‐piperidone ((PIPO)H), a chiral cyclic hydroxamic acid derivative, and the study by NMR spectroscopy of its zirconium complex. Nuclear Overhauser effect measurements (ROESY) indicated that the complex exists in the form of two diastereomers, in 77 : 23 ratio, resulting from the combination of the central chiralities at the 3‐C of the (PIPO)H component and at the Zr4+ cation. The 44 lowest energy structures out of more than 1000 configurations/conformations returned by calculations based on density functional theory were examined. Comparison of the ROESY data and the calculated interatomic H⋅⋅⋅H distances allowed us to select the most probable configuration and conformations of the major complex. [ABSTRACT FROM AUTHOR]

Acoucité¹, centre of expertise in environmental acoustics and observatory of the sound environment, has investigated the changes in sound environment and its perception during the French lockdown period. The approach adopted is multidimensional, since it combines long-term acoustic measurements, large area noise mapping, as well as the study of sound perception self-reported by population sample through an on-line structured questionnaire. Data from 21 continuous sound monitoring stations² were analysed for the entire lockdown period in five conurbations in the south of France and compared to typical values in the “normal” situation (before lockdown) in order to quantify the reduction in terms of sound levels. Reductions from 4 dB to 6 dB (Lden) were observed for monitoring stations with highly dominant road noise. These results were used to obtain new Strategic Noise Maps for road noise (corresponding to the lockdown situation) for the conurbations of Lyon and Grenoble. The impact of such reductions in terms of noise exposure of their inhabitants was thus assessed. An estimation of the impact on health effects in comparison with the “normal” situation (Strategic Noise Maps “Round 3 CE-DE-2002”) was also carried out. This estimation considers a scenario where the above level reductions (4 to 6 dB) would take place in the long-term. An on-line perception questionnaire was available during the lockdown period with the aim of gathering information on the way that the changes in sound environment were perceived by people all over France and ended up with more than 3000 respondents. This paper reports the main findings of the study in terms of acoustics and sound perception.

Microbial species utilize secreted-signaling molecules to coordinate their behavior. Our previous investigations demonstrated a key role for the Candida albicans-secreted quorum-sensing molecule farnesol in modulating Staphylococcus aureus response to antimicrobials in mixed biofilms. In this study, we aimed to provide mechanistic insights into the impact of farnesol on S. aureus within the context of inter-species interactions. To mimic biofilm dynamics, farnesol-sensitized S. aureus cells were generated via sequential farnesol exposure. The sensitized phenotype exhibited dramatic loss of the typical pigment, which we identified as staphyloxanthin, an important virulence factor synthesized by the Crt operon in S. aureus. Additionally, farnesol exposure exerted oxidative-stress as indicated by transcriptional analysis demonstrating alterations in redox-sensors and major virulence regulators. Paradoxically, the activated stress-response conferred S. aureus with enhanced tolerance to H2O2 and phagocytic killing. Since expression of enzymes in the staphyloxanthin biosynthesis pathway was not impacted by farnesol, we generated a theoretical-binding model which indicated that farnesol may block staphyloxanthin biosynthesis via competitive-binding to the CrtM enzyme crucial for staphyloxanthin synthesis, due to high structural similarity to the CrtM substrate. Finally, mixed growth with C. albicans was found to similarly induce S. aureus depigmentation, but not during growth with a farnesol-deficient C. albicans strain. Collectively, the findings demonstrate that a fungal molecule acts as a redox-cycler eliciting a bacterial stress response via activation of the thiol-based redox system under the control of global regulators. Therefore, farnesol-induced transcriptional modulations of key regulatory networks in S. aureus may modulate the pathogenesis of C. albicans-S. aureus co-infections.

The West Nile virus (WNV) is an emerging infection of biodefense concern and there are no available treatments or vaccines. Here we used a high-throughput method based on a novel gene expression analysis, RNA-Seq, to give a global picture of differential gene expression by primary human macrophages of 10 healthy donors infected in vitro with WNV. From a total of 28 million reads per sample, we identified 1,514 transcripts that were differentially expressed after infection. Both predicted and novel gene changes were detected, as were gene isoforms, and while many of the genes were expressed by all donors, some were unique. Knock-down of genes not previously known to be associated with WNV resistance identified their critical role in control of viral infection. Our study distinguishes both common gene pathways as well as novel cellular responses. Such analyses will be valuable for translational studies of susceptible and resistant individuals—and for targeting therapeutics—in multiple biological settings.

Alzheimer's disease is a neurodegenerative disorder characterized by the accumulation of amyloid peptides in the brain. While the production of Aβ is dependent on the cleavage of the β-amyloid precursor protein by the β-secretase BACE1, the α-secretase activity, mainly supported by ADAM10, counterbalances this pathway by both preventing Aβ production and triggering the release of the neuroprotective soluble APP alpha (sAPPα metabolite. For this reason, strategies aimed at promoting α-secretase and/or blocking β-secretase seem to be indicated for the purpose of containing the disease. Here we investigated the effects of ECa 233, a standardized extract of the plant Centella asiatica, on βAPP levels and sAPPα secretion as well as on the expression and catalytic activity of the α-secretases ADAM10 and ADAM17 and the β-secretase BACE1 in human cells. Our results interestingly demonstrate that the ECa 233 extract is able to significantly stimulate α-secretase activity and to inhibit β-secretase activity in a dose-dependent manner in the human SH-SY5Y neuroblastoma cell line. In conclusion, these results reveal an original doubly beneficial effect of ECa 233, which is both capable of promoting the non-amyloidogenic α-secretase activity and interfering with the amyloidogenic pathway and thereby stands as a promising candidate for the future development of mild, safe and preventive therapeutic treatment of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Acinetobacter baumannii is a common pathogen whose recent resistance to drugs has emerged as a major health problem. Ethanol has been found to increase the virulence of A. baumannii in Dictyostelium discoideum and Caenorhabditis elegans models of infection. To better understand the causes of this effect, we examined the transcriptional profile of A. baumannii grown in the presence or absence of ethanol using RNA-Seq. Using the Illumina/Solexa platform, a total of 43,453,960 reads (35 nt) were obtained, of which 3,596,474 mapped uniquely to the genome. Our analysis revealed that ethanol induces the expression of 49 genes that belong to different functional categories. A strong induction was observed for genes encoding metabolic enzymes, indicating that ethanol is efficiently assimilated. In addition, we detected the induction of genes encoding stress proteins, including upsA, hsp90, groEL and lon as well as permeases, efflux pumps and a secreted phospholipase C. In stationary phase, ethanol strongly induced several genes involved with iron assimilation and a high-affinity phosphate transport system, indicating that A. baumannii makes a better use of the iron and phosphate resources in the medium when ethanol is used as a carbon source. To evaluate the role of phospholipase C (Plc1) in virulence, we generated and analyzed a deletion mutant for plc1. This strain exhibits a modest, but reproducible, reduction in the cytotoxic effect caused by A. baumannii on epithelial cells, suggesting that phospholipase C is important for virulence. Overall, our results indicate the power of applying RNA-Seq to identify key modulators of bacterial pathogenesis. We suggest that the effect of ethanol on the virulence of A. baumannii is multifactorial and includes a general stress response and other specific components such as phospholipase C.

Alzheimer's and prion pathologies are often seen as distinct neurodegenerative diseases, particularly because the infectious character of some prion-associated pathology makes this stand apart from classical neurodegenerative, age-related syndromes. Are there specific common denominators that could link the two diseases? It appears that [beta]APP ([beta]-amyloid precursor protein) and Pr[P.sup.c] (cellular prion protein), the `guilty' proteins involved in these pathologies, undergo protein-kinase-C-regulated proteolysis by identical proteases of the disintegrin family. This cleavage occurs in an analogous way, in the middle of the `toxic' A[beta] and Pr[P.sup.c]106--126 domains of [beta]APP and Pr[P.sup.c], respectively. As these two sequences trigger similar caspase-dependent and -independent cascades, this proteolytic attack could be seen as an inactivating process aimed at clearing cells of these endogenous `toxins' and, thus, preventing the associated proteinaceous accumulation usually detected in affected brains. It is our opinion that targeting these disintegrins with specific `activators' could be a suitable strategy to slow down, or even arrest, [beta]APP and Pr[P.sup.c]-related aggregation and toxicity.