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Decoding Cerebrospinal Fluid: Integrative Metabolomics Across Multiple Platforms
No full textInternational audienceCerebrospinal fluid (CSF) is a key biological matrix that reflects the physiological and pathological states of the central nervous system (CNS). It supports brain function by regulating ionic balance, facilitating molecular transport, and clearing metabolic waste. In this article, we present a standardized protocol for CSF collection along with an integrative multiplatform metabolomic workflow that combines proton nuclear magnetic resonance spectroscopy (1 H-NMRS) and high-performance liquid chromatography coupled to mass spectrometry (HPLC-MS). Integrating these complementary analytical modalities enhances metabolite coverage and improves analytical robustness, enabling a more comprehensive and reliable characterization of the CSF metabolome. This workflow supports the discovery of potential biomarkers and advances our understanding of neurochemical alterations within the CNS
A Functional Intronic Variant of LILRB1 Associated with Clinical Malaria in the Senegalese Population
No full textInternational audienceBackgroundMalaria remains a major health challenge in sub-Saharan Africa despite extensive control measures. Host genetic variation influences susceptibility, but the role of inhibitory receptors such as LILRB1—targeted by Plasmodium falciparum RIFINs—remains unclear. We investigated whether regulatory variants in LILRB1 modulate malaria risk.MethodsRegulatory variants were prioritized from African expression quantitative trait locus (eQTL) datasets by integrating linkage disequilibrium, chromatin accessibility, transcription factor binding, and immune cell–specific expression. Three non-coding variants (rs10416697, rs10423364, rs7246537) and one coding variant (rs1061680) were selected. Genotyping was performed in 267 Senegalese individuals (116 severe malaria, 74 mild malaria, 77 healthy controls). Logistic regression adjusted for age assessed genetic associations. The effect of rs7246537 on promoter activity was tested using luciferase assays.ResultsAmong 10,110 candidate eQTLs, 49 were associated with LILRB1 expression in African populations; three overlapped open chromatin near the distal promoter. Only rs7246537 showed significant association with malaria: allele A carriers had lower risk of clinical malaria (OR = 0.50, 95% CI: 0.28-0.88, p = 0.0165) and cerebral malaria (OR = 0.44, 95% CI: 0.22-0.86, p = 0.0176). rs7246537 colocalized with a YY1-binding site, and luciferase assays confirmed allele-specific effects, with the A allele driving twofold lower promoter activity compared with the G allele.Conclusionsrs7246537 is a functional regulatory variant that reduces malaria susceptibility in Senegalese populations by modulating LILRB1 expression. These findings underscore the importance of non-coding variants and inhibitory immune pathways in malaria pathogenesis
Checking methodology and statistics when reading an observational study
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The DIGIT-HF trial and the Mihai Gheorghiade legacy: time to reconsider cardiac glycosides as effective therapy in HFrEF
No full textInternational audienceCardiac glycosides have been used for more than two centuries in patients with heart failure with reduced ejection fraction (HFrEF), but their use has steadily declined in recent decades, largely due to safety concerns raised by observational studies and the availability of outcomemodifying therapies with more favorable safety profiles. Evidence from earlier randomized trials suggested that digoxin improves symptoms and reduces heart-failure hospitalizations without affecting survival, but these studies were conducted before the widespread adoption of contemporary guideline-directed medical therapy (GDMT).Digitoxin is a cardiac glycoside that differs from digoxin through its hepatic clearance and more stable pharmacokinetics, diminishing the impact of renal dysfunction and serum concentration fluctuations, thereby improving safety and facilitating long-term use in routine care. Here, we critically discuss in the context of available evidence the findings of the recently published DIGIT-HF (Digitoxin to Improve Outcomes in Patients with Advanced Chronic Heart Failure) trial, which for the first time evaluated the efficacy and safety of digitoxin in contemporary patients with HFrEF.</div
Supramolecular rotaxanes and polyrotaxanes as potential MRI contrast agents: a comprehensive 17O NMR and relaxometric study
No full textInternational audienceRotaxanes and polyrotaxanes made of substituted cyclodextrins (CDs) were designed as potential MRI contrast agents or bimodal optical and MRI probes. After characterization of the threading kinetics and the exact composition of the polyrotaxanes, their MRI properties have been investigated by 1 H relaxometry and 17 O NMR. We demonstrated that the relaxivity of these systems is increasing with increasing size (modified CDs, rotaxanes, and polyrotaxanes). 17 O NMR studies show that the various systems have similar water exchange rates, in the same range as that of Gd-DOTA-monoamide complexes. Interestingly, NMRD data of the smaller systems can be only analyzed by considering both local and global motions via Lipari-Szabo approach, underlining the importance of internal flexibility. On the other hand, the disubsituted rotaxane and the polyrotaxanes are highly rigid and can be characterized with a single rotational correlation time. Their relaxivity is considerably enhanced by a second sphere contribution which is strongly dependent on the structure. It increases from the rotaxane to the mono-and the disubstituted polyrotaxanes, and as expected, it diminishes with decreasing coverage of the axle. The fundamental understanding provided by this comprehensive study will help the design of versatile and more efficient supramolecular interlocked systems such as rotaxanes and polyrotaxanes for MRI applications.</div
Contrastive learning and physics oriented evaluation for advanced segmentation in electron tomography
No full textInternational audienceDeep learning methods are now achieving strong results for segmentation tasks, and the standard metric for evaluating methods is the Intersection over Union (IOU). However, we show in this paper that IOU is not efficient in evaluating the quality of segmentation for electron tomography (ET) images of zeolites. We perform a physics-oriented evaluation to ensure that the segmentation results yield coherent physical measures. We also formalize Mixed Supervised / Self-Supervised Contrastive Learning Segmentation (M3S-CLS), a semi-supervised approach using a contrastive learning approach that uses expert annotations to train the neural network model. A detailed comparison of this method with a standard cross-entropy-based model is provided. In addition, we publish a database of five fully segmented ET volumes along with corresponding baseline results. The code and the database is available at http://gitlab.univ-st-etienne.fr/labhc-iscv/M3S-CLS
Evaluation of dual-function molecules containing both Zn-Ionophore and aggregation inhibition moieties for mutant p53 protein reactivation
No full textInternational audienceThe p53 protein plays an important role in preventing cancer and is critical in inducing an antiproliferative response. Unfortunately, the p53 pathway is compromised in almost all cancers, and mutations to p53 lead to loss of function due to protein unfolding, compromised Zn2+ binding, aggregation and amyloid formation. Herein, two new multidentate N,O donor ligands LI-A and LH-A were tested to potentially restore Zn2+ binding to mutant p53, while also inhibiting protein aggregation. The design of these ligands centered on combining an iminodiacetate (IDA) metal binding moiety which was previously determined to exhibit favourable Zn2+ binding affinity and Cu2+/Zn2+ selectivity ratio, with a benzothiazole unit that has been demonstrated to limit mutant p53 protein aggregation. The new ligands were shown to exhibit Zn2+ Kd values in the low nM range based on a fluorophore competition assay, while also inhibiting mutant p53 aggregation via a Thioflavin-T (ThT) assay. In cell-based assays and NCI-60 screening, neither of the new ligands displayed significant cytotoxicity. A reactive oxygen species (ROS) assay showed that neither of the new ligands increased intracellular ROS, however, the previously studied LI compound did show an increase in ROS, providing further information on the mechanism of action of this class of compounds. The current results highlight that the dipicolylamine (DPA) unit is important for anticancer activity, and that phenolate substitution has an important role in dictating the mechanism of cytotoxicity
Sweetness exposure modulates brain networks in children responding to sucrose solutions: a functional MRI study
No full textInternational audienceContextChildhood obesity is a pervasive health issue, with sugar consumption implicated not only in its development but also in adverse effects on brain health. While extensive research has explored adult brain processes in response to sweet taste, there is limited understanding of how children's brains activate in similar, contexts.MethodIn this study, 34 children aged 8-12 undent food frequency and sweetness liking assessments before participating in a functional magnetic resonance imaging (fMRI) scan during a gustatory paradigm involving varying sweetness levels. Utilizing independent component analysis (ICA), we examined functional networks engaged during sweet taste perception and after swallowing.ResultsOur study identified distinct brain networks for tasting, swallowing, and a transitional stage linking the two. Children with lower BMI and higher sugar intake showed greater activation in the transition network, suggesting enhanced interoceptive sensitivity.ConclusionThis novel investigation provides a foundational understanding of how sweetness exposure modulates brain networks in children responding to sucrose solutions, offering valuable insights into the interplay between sugar consumption, childhood obesity, and neural responses
Large-scale meta-analysis and precision functional assays identify FANCM regions in which PTVs confer different risks for ER-negative and triple-negative breast cancer
No full textInternational audienceThe breast cancer risk conferred by germline protein truncating variants (PTVs) in known and putative breast cancer genes has been extensively investigated. However, the effect of FANCM PTVs on breast cancer risk remains unclear. Our previous clinical, genetic and functional results on the N-terminal p.Arg658∗ and the two C-terminal p.Gln1701∗ and p.Gly1906Alafs∗12 variants suggested that FANCM PTVs may confer different risks for ER-negative (ER-neg) and triple-negative (TN) breast cancer subtypes. Here, we performed meta-analyses of seven studies totaling 144 681 breast cancer cases and 123 632 controls. FANCM PTVs were tested for association with breast cancer risk overall and the disease clinical subtypes by single variant and burden analyses. Two CRISPR-Cas9-based functional assays were also conducted to test the fitness of cells after knock-in of the p.Arg658∗, p.Gln1701∗ and p.Gly1906Alafs∗12 PTVs and the sensitivity of different FANCM regions to genome editing. Our results suggest that the N-terminal FANCM region upstream of p.Tyr725 harbors essential functions, whereas downstream regions appear dispensable. This is supported by our genetic data which indicate that all FANCM PTVs, excluding the two C-terminal p.Gln1701∗ and p.Gly1906Alafs∗12, are associated with an increased risk of ER-neg (OR = 1.41, P = 0.023) and TN (OR = 1.64, P = 0.0023). Notably, PTVs upstream of AA position 670 are associated with a moderate risk of developing TN breast cancer, and that even when the p.Arg658∗ carriers were excluded from the analysis. Importantly, our results confirm previous data indicating that p.Arg658∗ carriers are at moderate risk of developing ER-neg (OR = 2.08, P = 0.030) and TN (OR = 3.26; P = 0.0034), whereas carriers of p.Gln1701∗ and p.Gly1906Alafs∗12 should not be considered at increased risk. Our data are useful for counseling carriers of FANCM PTVs, but further analyses are warranted to obtain more precise risk estimates
Design and synthesis of first-in-class stapled peptides targeting the E3 ligase MuRF1 to potentially prevent muscle wasting
No full textInternational audienceThis study focuses on developing stapled peptides that target the E3 ubiquitin ligase MuRF1 (TRIM63), a key player in muscle protein degradation and muscle wasting. MuRF1 is so far the only E3 involved in the degradation of contractile proteins in muscle tissue, making it a potential therapeutic target for conditions like cachexia, sarcopenia, and chronic disease-related muscle atrophy. We designed two stapled decapeptides mimicking a helical segment of MuRF1's coiled-coil domain, aiming at perturbating its structural organization. To enhance their α-helical structure, these peptides were stabilized using hydrocarbon stapling and were prepared using solid-phase peptide synthesis. Their binding affinities to MuRF1 were assessed using spectral shift and microscale thermophoresis (MST) assays. Stapled peptides bound efficiently to MuRF1 with equilibrium dissociation constants KD in the range 1.5–1.8 μM, whereas their unstapled counterparts showed little or no binding. This work represents an early promising step in targeting MuRF1, thus offering a potential therapeutic approach to prevent or reduce muscle wasting