Biology subjects

Vallee, M.

Publications and source records attributed to Vallee, M..

4 recordsLinked to original sources

bioRxiv2025

Stress-induced plasminogen activator inhibitor-1 (PAI-1) as a blood biomarker and brain risk factor for PTSD

Post-traumatic stress disorder (PTSD) is a severe stress-related psychiatric condition triggered by traumatic life-threatening events, characterized notably by an altered memory profile. Although clinically well-documented, no specific biomarker exists. This translational study identifies plasminogen activator inhibitor-1 (PAI-1) as a brain risk factor for PTSD, thereby supporting its potential as a blood-derived biomarker. Mice with genetically ablated PAI-1 were protected from developing a PTSD-like memory profile. Conversely, mice exhibiting PTSD-like cognitive impairment showed increased blood PAI-1 levels, correlating with their profile severity. In the brain, PAI-1 levels were specifically increased in the dorsal hippocampus, a key region for cognitive functions and in the etiology of PTSD. Finally, a longitudinal study of soldiers revealed that those developing PTSD symptoms exhibit rising blood PAI-1 levels over a 12-month period. Its significant association with various indicators of PTSD-related psychological distress attests to PAI-1s potential as a blood biomarker and brain therapeutic target for PTSD.

neuroscience↗

bioRxiv2025

Pregnenolone and AEF0117 block cannabinoid-induced hyperlocomotion through GSK3β signaling at striatopallidal neurons

Administration of {Delta}9-tetrahydrocannabinol (THC), the main psychoactive component of the plant Cannabis sativa, can induce psychotic symptomatology in humans and a large spectrum of acute psychotic-like behaviors in mice, including hyperlocomotion observed at low dose of THC (0.3 mg/kg). The cellular and molecular substrates of this effect have not been fully identified yet. Here we demonstrate that THC-induced hyperlocomotion depends on plasma membrane CB1R, which regulate the {beta}-arrestin 1/Akt/GSK3{beta} signaling pathway in D2R-positive neurons of the dorsal striatum forming the striatopallidal pathway of the basal ganglia. Pregnenolone (PREG) and its clinically developed analog, AEF0117, which are signaling specific inhibitors of CB1R (CB1-SSi), prevented GSK3{beta}-dependent psychomotor stimulation induced by THC. Overall, this work highlights a novel intracellular mechanism of CB1R, thereby revealing a neuronal pathway underlying an important but still underexplored effect of THC and cannabis consumption, which could help the development of innovative therapeutic concepts against psychotic conditions.

neuroscience↗

bioRxiv2022

Exploring the in-situ evolution of Nitrofurantoin resistance in clinically derived Uropathogenic Escherichia coli isolates.

BACKGROUNDNitrofurantoin has been re-introduced as a first-choice antibiotic to treat uncomplicated acute urinary tract infections in England and Wales. Its mode of action involves initial reduction by nitroreductases, to generate electrophilic intermediates that inhibit protein and nucleic acid synthesis. Highly effective against common uropathogens such as Escherichia coli, its use is accompanied by a low incidence (<10%) of antimicrobial resistance. Resistance to Nitrofurantoin is predominantly via the acquisition of loss-of-function, step-wise mutations in the nitroreductase genes nfsA and nfsB. OBJECTIVETo explore the in situ evolution of NitR, longitudinal uropathogenic E. coli isolates recovered from two rUTI patients. RESULTSGrowth rate analysis identified a 2-10% slower doubling time for Nitrofurantoin resistant strains, but statistically, these data suggested there was no fitness advantage of evolved strains over their sensitive predecessor (ANOVA P-value = 0.13). Genetic manipulation of E. coli to mimic nitrofurantoin resistance evolution, again confirmed no fitness advantages (ANOVA P-value = 0.22). Rather, further analysis argued that a first-step mutant gained a selective advantage, at sub-MIC (4-8 mg/L) nitrofurantoin concentrations. CONCLUSIONCorrelation of these findings to Nitrofurantoin pharmacokinetic data suggests that the low incidence of E. coli NitR, within the community, is driven by urine-based nitrofurantoin concentrations that selectively inhibit the growth of E. coli strains carrying the key first-step loss-of-function mutation.

microbiology↗

bioRxiv2019

Needlestack: an ultra-sensitive variant caller for multi-sample next generation sequencing data

The emergence of Next-Generation Sequencing (NGS) has revolutionized the way of reaching a genome sequence, with the promise of potentially providing a comprehensive characterization of DNA variations. Nevertheless, detecting somatic mutations is still a difficult problem, in particular when trying to identify low abundance mutations such as subclonal mutations, tumour-derived alterations in body fluids or somatic mutations from histological normal tissue. The main challenge is to precisely distinguish between sequencing artefacts and true mutations, particularly when the latter are so rare they reach similar abundance levels as artefacts. Here, we present needlestack, a highly sensitive variant caller, which directly learns from the data the level of systematic sequencing errors to accurately call mutations. Needlestack is based on the idea that the sequencing error rate can be dynamically estimated from analyzing multiple samples together. We show that the sequencing error rate varies across alterations, illustrating the need to precisely estimate it. We evaluate the performance of needlestack for various types of variations, and we show that needlestack is robust among positions and outperforms existing state-of-the-art method for low abundance mutations. Needlestack, along with its source code is freely available on the GitHub plateform: https://github.com/IARCbioinfo/needlestack.

bioinformatics↗