Biology subjects

Danet, L.

Publications and source records attributed to Danet, L..

8 recordsLinked to original sources

bioRxiv2026

Molecular and spatial profiling identifies immune endotypes for the stratification of OA patients

Osteoarthritis (OA) is a prevalent and heterogeneous joint disease in which synovial inflammation drives structural progression and pain. Despite the recognized heterogeneity of OA, the cellular and molecular organization of synovial tissue remains poorly characterized and defining distinct histological and immune endotypes could guide precision medicine and therapeutic targeting. We show that histologically defined synovial pathotypes are conserved across independent cohorts and correspond to distinct molecular immune endotypes. Integration of bulk and spatial transcriptomics with proteomics revealed niche-specific gene and protein signatures, reflecting the anatomical and functional diversity of OA synovium. The lympho-myeloid pathotype was characterized by mature ectopic lymphoid structures containing CD21+CD23+ follicular dendritic cells, spatially organized T and B cell zones, and clonally expanded T and B cells with shared immune cell receptor motifs, consistent with local adaptive immune activity correlating with radiological joint damage. These findings highlight how immune organization and cellular composition shape OA pathogenesis and provide a framework for endotype-guided stratification and therapeutic targeting.

immunology↗

bioRxiv2025

Transcriptomic and functional comparison of cells isolated from healthy and degenerated ovine intervertebral discs

Structured abstractO_ST_ABSBackgroundC_ST_ABSIntervertebral disc degeneration (IVDD) is a leading cause of chronic low back pain and disability. Understanding the cellular and molecular mechanisms underlying disc degeneration is crucial for developing effective therapies. Sheep have emerged as a promising large-animal model for IVDD research due to their similarities with humans. They exhibit resembling spine anatomy and biomechanics, and they develop spontaneous age-associated degeneration of the disc. However, the specific cellular alterations occurring in annulus fibrosus (AF) and nucleus pulposus (NP) ovine cells during degeneration remain poorly characterized. In vitro, the benefits of using cells from aged sheep over young ones to mimic degenerative processes remain to be tested. MethodsAF and NP cells from young and aged sheep were analysed using bulk RNA sequencing, with a focus on two hallmarks of IVDD: cellular senescence and metabolic alterations. Functional assays completed this focus by assessing cells response under basal conditions and after pro-degenerative stimuli (IL-1{beta}, senescence induction). In addition, bulk transcriptomic data were deconvoluted using a reference single-cell RNA-seq dataset from healthy and degenerated human discs, and gene co-expression modules were compared across species. ResultsMRI and histological analyses revealed homogeneous mild degeneration across all lumbar discs in aged sheep, while lamb discs were uniformly healthy. Cells transcriptomic profiling identified robust age- and tissue-specific signatures, with aged NP and AF cells showing upregulation of inflammatory mediators, ECM-remodelling enzymes, and senescence-associated pathways. Cross-species analysis revealed shared transcriptional modules between aged sheep cells and human degenerated disc cells, supporting the translational relevance of the ovine model. Remarkably, young and aged cells shared a similar functional behaviour when exposed to stress-related stimuli. ConclusionsThis work confirms the compatibility of sheep cells with in vitro testing and their relevance to model human IVDD. Cross-validation with human single-cell data further highlights common pathogenic pathways, reinforcing the translational potential of the model. However, no added benefits were found in using older animals compared to younger ones as cell sources in functional assays. HighlightsO_LITranscriptomic profiling of AF and NP cells from young and aged sheep C_LIO_LIAged cells show inflammatory, ECM-remodelling and senescence signatures C_LIO_LIDeconvolution with human scRNA-seq links aged ovine and degenerated discs C_LIO_LISheep cells retain in vitro responsiveness to pro-degenerative stimuli C_LIO_LISupports the ovine model as a translational tool for IVDD research C_LI

cell biology↗

bioRxiv2025

Multimodal analysis of osteoarthritic chondrocytes reveals mitochondrial alterations and patient-specific OxPhos response to bezafibrate

BackgroundOsteoarthritis (OA) is the most common joint disease and is characterized by bone remodeling, cartilage degradation and synovial inflammation. To date, no effective treatment is available for this debilitating condition. Recent evidence suggests that mitochondrial dysfunction, including oxidative phosphorylation (OxPhos) failure, accumulates within OA chondrocytes and may contribute to pathogenesis. In this context, mitochondrial dysfunction may be associated with observable changes in mitochondrial number, size and shape. However, a comprehensive characterization of mitochondria-related features during OA, from tissue-to-cell level, is still lacking. Addressing these gaps could inform therapeutic strategies, such as the partial restoration of OxPhos, which has been proposed as a therapeutic approach. MethodsHere, we employed a multimodal approach that included Fourier-transform infrared spectroscopy (FTIR), scanning transmission electron microscopy (STEM) and real-time cellular metabolic assays (Seahorse technology) to better characterize mitochondrial parameters in cartilage during OA. Two types of experimental models were used using human cartilage: (1) undamaged versus damaged OA zones, and (2) non-OA versus OA samples. In addition, we investigated the potential of repurposing bezafibrate, an approved peroxisome proliferator-activated receptor (PPAR) agonist, as a mitochondria-based therapy to restore OxPhos in OA chondrocytes. ResultsWe identified that OA chondrocytes exhibit a decrease in glycogen deposits surface, and an increased number of mitochondria alongside an OxPhos dysfunction compared to non-OA chondrocytes. A similar trend toward glycogen storage deficiency and increased mitochondria number was observed in OA chondrocytes from damaged cartilage areas. Furthermore, multivariate analyses revealed that the clinical profiles of OA patients allowed OA chondrocytes to be separated into responders and non-responders to bezafibrate. ConclusionWe provide evidence that OA chondrocytes display decreased glycogen deposits surface, increased mitochondrial number and OxPhos dysfunction. Additionally, we identified that bezafibrate, a PPAR agonist, improved OxPhos function in a subgroup of OA chondrocytes derived from patients.

pathology↗

bioRxiv2025

A Reappraisal of the Role of the Mammillothalamic Tract in Memory Deficits Following Stroke in the Thalamus

The thalamus, traditionally viewed as a sensory relay station, is now recognized for its critical role in higher-order cognitive functions, including memory. While most research has focused on its distinct nuclei, the thalamus also contains crucial white matter tracts, such as the mammillothalamic tract (MTT), part of the Papez circuit. Despite its established role in memory, the MTT remains underappreciated in studies on the cognitive role of the thalamus, increasing the risk of misattributing memory functions to nearby thalamic nuclei. This study investigates the memory impact of thalamic strokes by considering disruption to the MTT. We examined 40 patients with chronic ischemic thalamic lesions and 45 healthy controls using neuropsychological assessments, focusing on the Free and Cued Selective Reminding Test (FCSRT) and high-resolution structural neuroimaging. Advanced imaging techniques, such as symptom mapping and disconnectome analyses, were employed to analyze the relationships between lesion sites, tract disconnections and cognitive outcomes. Additionally, the expression of calbindin-rich matrix cells and parvalbumin-rich core cells was examined to assess how the connectivity property of thalamic cells, and its disruption, can relate to cognitive deficits following a thalamic stroke. Patients with left-sided thalamic lesions, especially those involving the MTT, showed significant memory impairments. Symptom mapping identified a specific cluster of lesioned voxels in the left anterior-lateral thalamus, including the MTT, as being strongly associated with poorer memory performance. Disconnectome analysis confirmed that verbal memory deficits were associated with disruption of the MTT. Furthermore, a striking overlap was observed between the critical regions linked to memory deficits and calbindin-rich thalamic areas. However, this calbindin-rich region was also disrupted in patients without memory impairment, revealing that MTT disruption, and not lesions to this region, induced memory deficits in these patients. The identified FCSRT deficit cluster overlapped with brain regions consistently linked to memory processes following fMRI meta-analytic mapping of memory-related keywords. These findings challenge the traditional focus on thalamic nuclei and connector hubs, indicating a need to reappraise the importance of the MTT in memory impairment after a thalamic stroke. This study advocates for a shift in thalamic research, emphasizing the need to investigate tract-specific contributions and disruptions of the MTT but also of other tracts such as the interthalamic adhesion or amygdalo-fugal pathway, rather than holding only to a "nuclei-centric" view of the thalamus.

neuroscience↗

bioRxiv2024

A large cohort study (n = 591) on the impact of the presence or absence of the interthalamic adhesion: cognitive, neuroimaging, and genetic results

Both thalami can be connected by an Interthalamic Adhesion (IA). The extent of its presence varies among individuals and remains poorly understood. This study examines the IAs prevalence, anatomical variations, genetic determinants, and cognitive associations. Data from 591 healthy subjects (25-35 years) from the Human Connectome Project were analyzed and grouped as monozygotic (MZ) twins, dizygotic (DZ) twins, non-twin siblings, and unrelated individuals. MRI was used to characterize the IA, while neuropsychological assessments and Freesurfer parcellations were used to assess cognition and anatomical differences between subjects with or without an IA. The IA was absent in 12.7% of subjects, more commonly in males (20.0%) than females (6.3%), with no significant differences in age, education, or cognition between those with and without an IA. IA absence was associated with increased cerebrospinal fluid volumes, enlarged third ventricles, and thinning in several cortical areas. Genetic analysis revealed a higher concordance of IA presence among MZ twins (96%) than in other groups, indicating a strong genetic influence. The remaining 4% discrepancy was observed in male pairs only. This study underscores the genetic basis of IA, highlighting sexual dimorphism and neuroanatomical differences associated with its absence, though it does not affect cognition in healthy individuals.

neuroscience↗

bioRxiv2024

Factors behind poor cognitive outcome following a thalamic stroke

ObjectiveThalamic strokes produce a range of neurological, cognitive, and behavioral symptoms depending on the thalamic nuclei involved. While thalamic strokes are traditionally associated with severe cognitive deficits, recent studies suggest more modest impairments. This study aims to identify the factors that influence the severity of cognitive impairment following thalamic stroke. MethodsWe recruited 40 patients (median age 51) with chronic isolated thalamic stroke and 45 healthy subjects. All subjects underwent neuroimaging and neuropsychological testing. Cluster and principal component analyses were used to discriminate patients from healthy subjects based on cognitive performance. Disconnectome maps and cortical thickness were analyzed to understand the distant impact of thalamic strokes. ResultsTwo cognitive profiles emerged. Cluster 1 included mostly healthy subjects (n = 43) and patients with no or minor deficits (n = 20); Cluster 2 included patients (n = 19) and 2 healthy subjects with severe deficits of verbal memory, executive functions, and attention. Cluster 1 included all patients with right thalamic stroke. Cluster 2 included all patients with bilateral stroke or mammillothalamic tract disruption. Patients with left-sided stroke were equally divided between Cluster 1 and 2. Other significant differences included age, education, interthalamic adhesion disruption, lesion volume, and location. Disconnectome maps showed larger disruptions of the anterior thalamic projection in patients with left-sided stroke of Cluster 2. InterpretationContrary to common expectations, our findings indicate that many patients with thalamic stroke have relatively good cognitive outcomes. In contrast, we identified some of the factors behind poor outcomes that may help clinicians.

neuroscience↗

bioRxiv2024

Exploring the impact of interthalamic adhesion on human cognition: insights from healthy subjects and thalamic stroke patients

Background and ObjectivesInterthalamic adhesion (IA), also known as the massa intermedia, is a structure that connects the median borders of both thalami across the third ventricle. Given it is difficult to identify on routine neuroimaging, its anatomical variants and function remain poorly studied. The main objective of this study was to clarify the role of IA on cognition. Our main hypothesis was that thalamus stroke patients with an IA would show better performance on neuropsychological tests than individuals without an IA through possible compensatory mechanisms. MethodsThe study comprised a group of healthy subjects and a cohort of patients with isolated thalamic strokes at the chronic stage. All participants underwent 3T research T1w and FLAIR MRI as well as a neuropsychological assessment. The presence or absence of an IA and type of IA anatomical variant were evaluated by two independent reviewers. Results42 healthy subjects (mean age= 49) and 40 patients (mean age= 51) were finally included. 76% of participants had an IA, with a higher prevalence among women (92%) than men (61%). The presence or absence of an IA did not effect the neuropsychological performance of healthy subjects nor did the type of IA variant. Across all the tests, patients with an IA (n = 18) showed the lowest BF10 (157) while those without an IA (n = 10) exhibited the highest BF10 (10648) when compared to healthy subjects using a Bayesian rmANOVA. More specifically, patients without an IA performed more poorly in the verbal memory or Stroop task versus healthy subjects than patients with an IA. This effect was not explained by age, laterality of the infarct, volume or, localization of the lesion. Patients with an IA and lesions extending into the IA presented a similar trend to non-IA subjects which could however be explained by a greater volume of lesions. DiscussionIA does not appear to have a major role in cognition for healthy subjects but could play a compensatory part in patients with thalamic lesions.

neuroscience↗

bioRxiv2019

Midgut barriers prevent the replication and dissemination of the yellow fever vaccine in Aedes aegypti

BackgroundTo be transmitted to vertebrate hosts via the saliva of their vectors, arthropod-borne viruses have to cross several barriers in the mosquito body, including the midgut infection and escape barriers. Yellow fever virus (YFV) belongs to the genus Flavivirus, which includes human viruses transmitted by Aedes mosquitoes, such as Dengue and Zika viruses. The live-attenuated YFV-17D vaccine has been used safely and efficiently on a large scale since the end of World War II. Early studies have shown, using viral titration from salivary glands of infected mosquitoes, that YFV-17D can infect Aedes aegypti midgut, but does not disseminate to other tissues.\n\nMethodology/Principal FindingsHere, we re-visited this issue using a panel of techniques, such as RT-qPCR, Western blot, immunofluorescence and titration assays. We showed that YFV-17D replication was not efficient in Aedes aegypti midgut, as compared to the clinical isolate YFV-Dakar. Viruses that replicated in the midgut failed to disseminate to secondary organs. When injected into the thorax of mosquitoes, viruses succeeded in replicating into midgut-associated tissues, suggesting that, during natural infection, the block for YFV-17D replication occurs at the basal membrane of the midgut. Our NGS analysis revealed that YFV-Dakar genome exhibited a greater diversity than the vaccine strain; a trait that may contribute to its ability to infect and disseminate efficiently in Ae. aegypti.\n\nConclusions/SignificanceThe two barriers associated with Ae. aegypti midgut prevent YFV-17D replication. Our study contributes to our basic understanding of vector-pathogen interactions and may also aid in the development of non-transmissible live virus vaccines.\n\nAuthor summaryMost flaviviruses, including yellow fever virus (YFV), are transmitted between hosts by mosquito bites. The yellow fever vaccine (YFV-17D) is one of the safest and most effective live virus vaccine ever developed. It is also used as a platform for engineering vaccines against other health-threatening flaviviruses, such as Japanese encephalitis, West Nile, Dengue and Zika viruses. We studied here the replication and dissemination of YFV-17D in mosquitoes. Our data showed that YFV-17D replicates poorly in mosquito midgut and is unable to disseminate to secondary organs, as compare to a YFV clinical isolate. Our study contributes to our basic understanding of the interactions between viruses and their vectors, which is key for conceiving new approaches in inhibiting virus transmission and designing non-transmissible live virus vaccines.

microbiology↗