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Evidence for the absence of a relationship between inflammation and cognition in a cohort of 1565 individuals with bipolar spectrum disorders: a Bayesian analysis of network
No full textInternational audiencePrevious studies have reported variable associations between peripheral inflammatory markers and cognitive functioning in individuals with bipolar spectrum disorders (BSD), with some identifying significant links and others finding no relationship. Such inconsistencies raise important questions about the role of inflammation in cognitive impairment among individuals with BSD. This study aims to investigate the relationship between peripheral inflammatory markers and cognitive function in a clinical sample of individuals with BSD using a Bayesian network analysis framework. We analyzed data from a large cohort (n = 1565) focusing on hsCRP and a subsample (n = 249) that included concurrent assessments of additional cytokines including Interleukin-6 and Tumor Necrosis Factor-alpha. A Bayesian approach was utilized to quantify uncertainty regarding the presence or absence of associations between inflammation and cognitive function. Our findings revealed no significant associations between inflammatory markers and cognitive performance in both samples. Strong evidence was found supporting the absence of association, with network analysis indicating distinct clusters for cognitive and inflammatory variables, suggesting they function as independent constructs with limited interactions. In our clinical sample of individuals with BSD, our findings do not support a direct association between some inflammatory markers and cognition, aligning with studies that found minimal or no associations. Our study emphasizes the importance of utilizing Bayesian methods to assess these relationships rigorously and suggests further exploration of individual differences and subgroup effects in future research
Neurological and psychiatric issues in 187 adults with early-treated PKU: The ECOPHEN study
No full textInternational audienceIntroduction: Phenylketonuria (PKU) is an autosomal recessive disorder caused by mutations in the PAH gene leading to phenylalanine hydroxylase deficiency. This results in the accumulation of phenylalanine (Phe) in blood and brain, causing neurological and psychiatric impairments if untreated. Newborn screening (NBS) introduced in the 1960s enables early PKU diagnosis, allowing prompt dietary or sapropterin treatment. The long-term outcomes in adults with early-treated PKU, however, may include subtle neurocognitive deficits alongside somatic neurological and psychiatric complications, which remain incompletely characterized. Patients and methods: The ECOPHEN study was a French 5-year multicenter prospective cohort assessing neuropsychiatric disorders in adults with early-treated PKU. Results: Here are presented the data at inclusion. The study recruited 187 patients who were classified by PKU severity-classic, mild, or mild persistent hyperphenylalaninemia-and diet adherence status. Neurological history revealed symptoms in 11.2 % of patients, exclusively in classic PKU, including tremor, migraines, and balance disorders, without significant differences between diet groups. Neurological examination abnormalities predominantly included abnormal deep tendon reflexes in classic PKU patients. Psychiatric issues affected 25.7 % of patients across severity groups, mainly depressive episodes and anxiety, with no clear influence of diet adherence. Discussion/conclusion: The present study highlights neurological complications persisting despite early treatment, particularly in classic PKU. Diet adherence and current plasma Phe levels did not correlate significantly with neurological or psychiatric outcomes, possibly due to suboptimal metabolic control. Limitations included the cross-sectional design, absence of control group, and retrospective data collection. Overall, adults with early-treated PKU show a generally favorable outcome but remain at risk for neuropsychiatric manifestations, supporting the need for lifelong follow-up including neurologic and psychiatric evaluation
Chemical inhibition of SUMOylation activates the FSHD locus
No full textInternational audienceFacioscapulohumeral muscular dystrophy (FSHD) is a progressive and debilitating muscle disease for which no cure currently exists. In the majority of cases, FSHD is associated with the contraction of the D4Z4 macrosatellite repeat array at the 4q35 locus, leading to the inappropriate activation of DUX4 , normally expressed during early embryogenesis. In FSHD, the genetic contraction is accompanied by hypomethylation of the D4Z4 array. Although a connection between DNA hypomethylation and DUX4 expression has been suggested, the precise mechanisms that regulate DUX4 transcription remain incompletely defined. The post-translational modification by SUMO was shown previously to repress the expression of Dux , the DUX4 homolog, in mouse embryonic stem cells. Based on these findings, we explored here the contribution of SUMOylation in the regulation of DUX4 in human muscle cells. We demonstrate that TAK‑981 (subasumstat), a selective SUMOylation inhibitor, promotes transcriptional reprogramming of the 4q35 locus and induces DUX4 expression. Importantly, this activation occurs independently of changes in DNA methylation or SMCHD1 ATPase activity. Our findings identify SUMOylation inhibition as a novel regulatory process driving DUX4 expression. This work uncovers the importance of SUMOylation in the epigenetic control of the 4q35 locus and DUX4 transcription, providing a potential therapeutic strategy to modulate DUX4 expression in FSHD
Spectral colour changes: a promising parameter for smart flax dew retting monitoring solutions
No full textInternational audienceNatural fibres from plants such as flax (Linum usitatissimum) are gaining interest as possible green replacements of synthetic fibres to reduce textile pollution footprints. However, the extraction-facilitating process of bast fibres from the flax stem, i.e. dew retting, is still empirically evaluated, resulting in either over or under retted fibre, both of which decrease the resulting fibre quality and introduce batch variability. There is currently no in-the-field device available to help farmers to monitor and manage flax dew retting. Flax growers generally use a ‘Fried-test’ or ‘organoleptic’ evaluations to define dew retting progression. In this study, we have measured this stem surface colour change using a spectrophotometer. Spectra in 400 to 700 nm range were acquired during 3 retting periods, carried out in different retting years, involving 4 fields in total. Cluster analysis of spectra revealed four distinct stages of retting which we termed: beginning, early, middle and advanced. Moreover, by the use of a statistical pipeline including PCA and PLS-DA we established that measurements of only four selected wavelengths (480, 490, 600, and 610 nm) are sufficient to predict the retting stage with a high degree of confidence. This work paves the way for the future development of colour sensors, which could be mounted on drones. Such onboard sensors would provide farmers with a practical tool to identify the optimal moment to end retting
Context-aware anomaly detection by community detection in the Internet of Things
No full textInternational audienceThis paper introduces a novel context-aware anomaly detection framework for the Internet of Things, leveraging community detection in multi-edge graphs with a heterogeneous Graph Neural Network (HeteroGNN) architecture to enhance network security. The proposed framework detects anomalies such as unexpected communication patterns among devices that rarely interact, unusual traffic spikes during off-hours, or deviations in the contextual and knowledge-based interactions of devices. For example, in an industrial IoT environment, unauthorized access or malicious activity can be inferred from unexpected communication within a device community after working hours. Our detection approach uses multi-edge graphs to model diverse interactions (network communication, context, knowledge) and applies community detection to capture stable graph structures. By incorporating these insights into a HeteroGNN, the framework effectively distinguishes anomalous edges while maintaining scalability and adaptability to dynamic network conditions. Experimental evaluation on the CIC-ToN-IoT and CIC-IDS2017 dataset demonstrates the framework’s superior accuracy, precision, and robustness, establishing it as a practical and effective solution for securing IoT networks against both known and emerging threats
Case report and literature review of neurodevelopmental syndrome linked to DOT1L variants
No full textInternational audienceIntroduction: The DOT1L gene encodes a histone lysine methyltransferase that has the distinctive characteristic of being composed of a DOT1 catalytic domain that targets lysine 79 of the core globular domain of histone H3. DOT1L missense variants have recently been implicated in an autosomal dominant inheritance syndrome with developmental delay and congenital anomalies in postnatal cohorts. We report the twenty-sixth patient with this disorder.Methods: Trio genome sequencing (GS) was performed in a patient with developmental delay.Results: Clinical examination showed a predominant global developmental delay affecting language, with cerebral abnormalities visible on magnetic resonance imaging, hypotonia, and ophthalmological and musculoskeletal abnormalities. GS revealed a de novo heterozygous missense variant in exon 3 of DOT1L (c.161C > T; p.(Ala54Val)), which is reported for the first time as the cause of developmental delay and congenital anomalies.Discussion: Among the 26 reported patients, 23 have missense variants, two have truncating variants, and one has an in-frame deletion. The mode of transmission is predominantly de novo. Current studies indicate multiple pathogenic mechanisms underlying DOT1L-related disorder, including both gain-of-function and loss-of-function effects, underscoring the complexity of the disease etiology. Although the gene exhibits intolerance to loss-of-function variants, a considerable number of truncating variants are observed in control populations, suggesting incomplete penetrance and heterogeneity in the phenotypic expression of DOT1L-associated disorder. No phenotype-genotype correlation could be established. Among reported patients, including ours, the most consistent clinical manifestations are global developmental delay, predominantly affecting language and behavior, and possibly distinctive facial features
Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk
No full textInternational audienceABSTRACT Background Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We used data from the Ovarian Cancer Association Consortium (OCAC), Consortium of Investigators of Modifiers of BRCA1 / BRCA2 (CIMBA), UK Biobank (UKBB), and FinnGen to identify novel HGSOC susceptibility loci and develop polygenic scores (PGS). Methods We analyzed >22 million variants for 398,238 women. Associations were assessed separately by consortium and meta-analysed. OCAC and CIMBA data were used to develop PGS which were trained on FinnGen data and validated in UKBB and BioBank Japan Results Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was finding that TP53 3’-UTR SNP rs78378222 was associated with HGSOC (per T allele relative risk (RR)=1.44, 95%CI:1.28-1.62, P=1.76×10 -9 ). The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95%CI:1.37-1.54) per standard deviation in the UKBB validation (AUROC curve=0.61, 95%CI:0.59-0.62). Conclusions This study represents the largest GWAS for HGSOC to date. The results highlight that improvements in imputation reference panels and increased sample sizes can identify HGSOC associated variants that previously went undetected, resulting in improved PGS. The use of updated PGS in cancer risk prediction algorithms will then improve personalized risk prediction for HGSOC
Self-assembled nanodomains of semi-fluorinated alkanes on phospholipid monolayers
No full textInternational audienceHypothesis: The incorporation of semi-fluorinated alkanes into phospholipid monolayers modulates their interfacial behavior and structural organization through fluorocarbon-hydrocarbon interactions. While prior studies demonstrated hierarchical self-assembly of a semi-fluorinated tetrablock in dipalmitoylphosphatidylcholine (DPPC) monolayers, it remains unclear how variations in the hydrocarbon chain length and molecular architecture of the semi-fluorinated alkane influence phase behavior and multilayer formation. We hypothesize that comparing diblocks and tetrablocks will reveal key structural determinants governing nanodomain formation and vertical stacking.Experiments: We studied Langmuir monolayers composed of DPPC mixed with semi-fluorinated diblocks C10F21CmH2m+1 (F10Hm, m = 16 and 20) and tetrablocks ((C10F21CH2)(CmH2m+1)CH-CH(C10F21CH2)(CmH2m+1) (di(F10Hm), m = 16 and 20). Surface pressure-area and surface potential-area isotherms were recorded, and fluorescence and atomic force microscopies were employed to examine domain morphology. Additionally, compression-expansion cycles were performed to assess the stability of the observed assemblies.Findings: All (F-alkyl)alkanes formed nanodomains at low surface pressures, which reorganized into vertically stacked multilayers upon compression. However, while di(F10H16) forms flower-like hierarchical structures at the phase boundary of DPPC, driven by chain-length compatibility and dipolar interactions, di(F10H20) shows more diffuse assemblies. We analyze the difference in assembling behavior between the two derivatives and highlight the critical role of hydrocarbon segments' length and symmetry in governing vertical segregation and domain morphology, thus offering new insight into the design of responsive interfacial materials
Cerebral diffusion of posaconazole in an experimental model of disseminated scedosporiosis
No full textInternational audienceBackground: Posaconazole, a broad spectrum antifungal, may be used in salvage therapy for cerebral infections caused by Scedosporium species. In this study, its pharmacokinetics was investigated in a rat model of scedosporiosis to evaluate the effect of the infection on cerebral diffusion.Methods: Posaconazole was administered to two groups of rats randomized according to the infection status. Drug levels in plasma, cerebrospinal fluid, and brain tissue were measured up to 168 h after administration, and data were analyzed using a non-compartmental approach. In addition, interleukins (IL) (IL-1β and IL-10) were quantified by ELISA, and cerebral expression of genes encoding some efflux pumps was assessed by reverse transcription-quantitative PCR.Results: Cerebral diffusion of posaconazole and, to a lesser extent, cerebrospinal fluid exposure were significantly affected by infection. A ten-fold increase in the area under the curve and a delayed time (Tmax) to reach the maximum concentration (Cmax) were observed in the brain, along with a time lag to reach Cmax and Tmax between plasma and the brain. Infection was associated with changes in plasma pharmacokinetics, particularly at late sampling times.Conclusions: These findings suggest increased permeability of the blood-brain-barrier, possibly related to changes in IL or gene expression levels in the brain. Infection and the resulting inflammation should therefore be considered for therapeutic drug monitoring, especially in cases of cerebral infection
Liver X receptors and the hallmarks of aging: From molecular mechanisms to therapeutic opportunities
No full textInternational audienceAging is the primary risk factor for cardiovascular disease, cancer, neurodegeneration, and other chronic disorders. Therefore, targeting the hallmarks of aging has emerged as a promising strategy to extend healthspan. Liver X receptors (LXRs) are ligand-dependent nuclear receptors that are activated by specific oxysterols and cholesterol derivatives. They are traditionally known as key regulators of cholesterol homeostasis. However, recent evidence reveals that LXRs also influence autophagy, mitochondrial function, epigenetics, senescence, stem cell dynamics, and intercellular communication. This positions LXRs at the crossroads of multiple hallmarks of aging. This review synthesizes current knowledge on endogenous and synthetic LXR ligands, their transcriptional mechanisms, and their effects on the aforementioned hallmarks and age-related pathophysiology. The clinical development of pan-LXR agonists for atherosclerosis has been hindered by side effects, notably hepatic steatosis. Emerging strategies, including LXRβ-selective ligands, selective LXR modulators (SLiMs), and biased agonists such as dendrogenin A, offer ways to separate the protective vascular, metabolic, and neuroprotective effects from adverse outcomes. Additionally, we explore how LXR signaling intersects with the hallmarks of aging and how it can be leveraged to intervene in atherosclerosis, diabetes, cancer, osteoporosis, age-related macular degeneration, and neurodegenerative diseases. Positioning LXRs within the geroscience framework suggests that LXRs may serve as pharmacological hubs to delay aging and its comorbidities. Future work should prioritize isoform-and tissue-selective approaches, metabolite-inspired ligand design, and integration with the hallmarks of aging to unlock the full therapeutic potential of LXRs.</div