Biology subjects

Girard, N.

Publications and source records attributed to Girard, N..

12 recordsLinked to original sources

bioRxiv2026

Characterization of Fetal Cortical Development Using Spectral Analysis of Gyrification (SPANGY)

The prenatal period of human brain development is critical for mental health and cognition across the entire lifespan. During this period, the cortex undergoes a dramatic transformation from a smooth lissencephalic surface into an elaborately folded structure, a process whose precise characterization is essential for understanding neurodevelopmental trajectories. This study represents the first application of Spectral Analysis of Gyrification (SPANGY) to a large multi-centric fetal brain MRI dataset (635 subjects, 20-38 weeks gestational age). SPANGY characterizes geometric variations on a surface based on the wavelength of folds, hence, providing a quantitative local description of gyrification at the individual level. Using rigorous normative modeling (GAMLSS) and statistical harmonization (ComBat-GAM), we established age-specific reference trajectories for multi-scale gyrification features (spectral frequency bands). We provide the first ever quantification of the temporally-ordered emergence of cortical folding in successive waves: the earliest-emerging low frequency, deep fissures are progressively superseded by the accelerating expansion of higher frequency folds. The normative curves provide the first step in taking prenatal neurodevelopmental assessment from qualitative inspection into a rigorous statistical inference, creating an objective reference against which deviations from healthy brain growth can be caught earlier, and with greater precision.

neuroscience↗

bioRxiv2026

Specific dendritic cells spatial organization is associated to ICB Response in Non Small Cell Lung Cancer (NSCLC)

Dendritic cells (DCs) are central orchestrators of antitumor immunity. Several DC subsets--including conventional type 1 (cDC1), conventional type 2 (cDC2), plasmacytoid DCs (pDCs), and mature DC populations--play distinct roles in immune surveillance, tumor control, immunotherapy response and prognosis. Recent findings suggest that cDC1 are spatially closed to CD8 T-cell and contribute to tertiary lymphoid structure formation in lung cancer. However, how other DC subsets interact with cDC1 to shape the tumor microenvironment (TME) remains largely unknown. Here, we analyzed the spatial distribution of major DC subsets, including cDC1, cDC2, mature DC and pDC, together with CD8 T cells in a cohort of anti-PD1-treated NSCLC patients and we deciphered the corresponding immune microenvironment behavior by paired transcriptomic analysis. We found that, while other DC subsets populated the stroma, cDC2 were localized both in the stroma and in tumor nests. Moreover, unlike other DC subsets, cDC2 abundancy did not affect ICB response both at transcriptomic and in situ analysis. We described spatial organization of DCs in megaclusters characterized by distinct proportions of DC subsets. Patients enriched in megaclusters involving variable proportion of pDC, cDC1 and mature DC, exhibited pro-inflammatory transcriptomic programs while those enriched in cDC2-based megaclusters showed limited immune activation features. Globally, DC in lung cancer were structured around three distinct DC spatial patterns, namely cDC1-driven, cDC2-driven and DC-Scattered, each defined by unique compositions of DC megaclusters, immune features and pathways activation profiles. Among them, the cDC1-driven pattern was associated to prolonged anti-PD1 response in two independent cohorts.

cancer biology↗

bioRxiv2026

Data quality biases normative models derived from fetal brain MRI

Normative modeling is increasingly used to characterize typical growth trajectories and identify atypical neurodevelopment, including early brain development using magnetic resonance imaging (MRI) acquired before birth. Recent work has emphasized the importance of large sample sizes for accurate and robust centile estimation. In this study, we investigate how image quality influences fetal brain normative models, a critical factor in this context where MRI is acquired on a moving fetus in utero. Using a multi-centric cohort of 635 fetal MRI scans, we applied a standardized visual quality control (QC) protocol with continuous quality ratings. We fit normative models for multiple brain structures under progressively relaxed QC stringency, and quantified the deviations in centile estimates relative to a high-quality reference subgroup. Our results showed that including lower-quality data systematically biased normative centiles, with the strongest effects observed in the outer centiles, particularly the lower tail (1st-10th). Bias increased progressively as QC stringency was relaxed and could not be attributed solely to the number of subjects used to fit the models. Quality-induced bias was structure-dependent, and often not visually apparent at the segmentation level. These findings highlight that image quality is an important source of bias in normative fetal brain modeling, and that increasing sample size at the expense of quality may systematically affect centile estimates, potentially jeopardizing the utility of the model.

neuroscience↗

bioRxiv2025

Common origin for effector and regulatory Follicular and Tissue-Adapted CD4+ T cells in Non-Small Cell Lung Cancer

Tumor-invaded lymph nodes (LNs) serve as critical hubs for anti-tumor immunity, yet their role in orchestrating immune responses remains poorly understood. Using integrated single-cell RNA sequencing, T cell receptor sequencing, and chromatin accessibility profiling, we analyzed CD4+ T cells from matched blood, tumor-invaded LNs, and tumors of treatment-naive non-small cell lung cancer patients. We identified distinct immunological landscapes across these compartments. Compared to blood, tumor-invaded LNs and tumors were enriched for follicular regulatory T cells (Treg-Tfr), conventional T cell subsets with Tfh-like characteristics (Tconv-Tfh and Tconv-CXCL13), and tissue-resident memory Tregs (Treg-Trm). These populations share a BATF-dependent transcriptional program that governs T-cell activation and tissue adaptation, while simultaneously engaging distinct, subset-specific regulatory networks. Integrative TCR-RNA analysis revealed that tumor-reactive, neoantigen-specific T cell clones were enriched within these subsets and demonstrated extensive LN-tumor clonal sharing, indicating active recirculation between compartments. Through clonal coupling analysis and trajectory inference, we uncovered that Treg-Tfr cells function as multipotent progenitors that bifurcate into tissue-resident Treg-Trm or into ex-Tregs adopting a Tfh-like CXCL13+ ewector phenotype. Remarkably, follicular CD4+ T subsets from LNs and tumor were transcriptionally and epigenetically similar and localized to analogous germinal center niches. These findings establish tumor-invaded LNs as functional extensions of the tumor microenvironment that generate and maintain tumor-reactive CD4+ lineages. The identification of tissue-resident Treg-Tfr plasticity reveals a critical developmental checkpoint that could be therapeutically targeted to redirect immunosuppressive programs toward anti-tumor ewector responses.

immunology↗

bioRxiv2024

Radiotherapy triggers pro-angiogenic signaling in human lung

Radiotherapy is one of the main therapeutic options for the treatment of lung cancer. Although highly efficient, radiation cause severe damages to normal tissue and radio-induced toxicities vary from mild pneumonitis to pulmonary fibrosis. The mechanism leading to these toxicities remain unclear. To investigate the molecular responses of human lung to radiotherapy, we analyzed, by single cell RNAseq, lung tissue resected in the vicinity of the tumor (i.e. treated with radiation) and compared the transcriptional profiles of the distinct lung populations from the same patient removed at distance from the tumor (i.e. non-treated with radiation). Analysis of six lung samples from patients suffering from Pancoast tumor, a rare lung malignancy that requires neo-adjuvant radiotherapy before surgery, revealed a strong induction of VEGF signaling after radiotherapy. Expression of VEGFA, one of the canonical pro-angiogenic ligands, was found upregulated in multiple cell populations in lung exposed to high doses of radiation. Irradiated capillaries, particularly gCap cells, expressing KDR/VEGFR2, present transcriptional profile similar to tip cells, characterized by sprouting and motility capacities. In addition, we identified a sub-population of alveolar macrophages expressing FLT1/VEGFR1, a receptor for VEGFA, in lung tissues treated by radiotherapy. Cell-Cell communication analysis revealed that FLT1/VEGFR1 positive macrophages interact with tip cells after radiotherapy through IL1B-IL1R signaling. Lastly, analysis of mouse single cell dataset confirmed the increase in the proportion of gCap cells presenting a tip-like phenotype after radiation injury. Altogether, this study describes, at the single cell level, the pro-angiogenic responses of human lung after radiotherapy. These results will lead to a better understanding of the physiopathology of lung radiation injury and may pave the way to optimize treatments to improve patients quality of life.

cancer biology↗

bioRxiv2024

Deep learning uncovers histological patterns of YAP1/TEAD activity related to disease aggressiveness in cancer patients.

Over the last decade, Hippo signaling has emerged as a major tumor-suppressing pathway. Its dysregulation is associated with abnormal expression of YAP1 and TEAD-family genes. Recent works have highlighted the role of YAP1/TEAD activity in several cancers and its potential therapeutic implications. Therefore, identifying patients with a dysregulated Hippo pathway is key to enhancing treatment impact. Although recent studies have derived RNAseq-based signatures, there remains a need for a reproducible and cost-effective method to measure the pathway activation. In recent years, deep learning applied to histology slides have emerged as an effective way to predict molecular information from a data modality available in clinical routine. Here, we trained models to predict YAP1/TEAD activity from H&E-stained histology slides in multiple cancers. The robustness of our approach was assessed in seven independent validation cohorts. Finally, we showed that histological markers of disease aggressiveness were associated with dysfunctional Hippo signaling.

bioinformatics↗

bioRxiv2024

Normative models combining fetal and postnatal MRI data to characterize neurodevelopmental trajectories during the transition from in- to ex-utero

The perinatal period involves transitioning from an intra- to an extrauterine environment, which requires a complex adaptation of the brain. This period is marked with dynamic and multifaceted cortical changes in both structure and function. Most studies to date have focused either on the fetal or postnatal period, independently. To the best of our knowledge, this is the first neurodevelopmental study targeting the cortical trajectory of typically developing perinatal subjects, combining MRIs from both fetal and postnatal participants. Prior to analysis, preprocessing and segmentation parameters were harmonized across all subjects in order to overcome methodological limitations that arise when studying such different populations. We conducted a normative modeling analysis on a sample of 607 subjects, age ranged 24 to 45 weeks post-conception, to observe changes that arise as participants traverse the birth barrier. We observed that the trajectories of global surface area and several volumetric features, including total gray matter, white matter, brainstem, cerebellum and hippocampi, follow distinct but continuous patterns during this transition. We further report three features presenting a discontinuity in their neurodevelopmental trajectories as participants traverse from a fetal to a postnatal environment: the extra-cerebrospinal fluid volume, the ventricular volume and global gyrification. The current study demonstrates the presence of unique neurodevelopmental patterns for several structural features during the perinatal period, and confirms that not all features are affected in the same way as they cross the birth barrier. SIGNIFICANCE STATEMENTThe perinatal phase comprises the fetal and immediate postnatal period, and is generally described as the time surrounding birth. Comprehensively understanding this period is crucial due to the presence of dynamic and multifaceted brain changes. What makes this investigation unique is that it is the first neurodevelopmental study, to the best of our knowledge, focused on the cortical trajectory of typically developing perinatal subjects through the combination of both fetal and postnatal participants into one analysis. We report that certain brain feature trajectories change drastically as fetuses become newborns, while other features remain continuous. These observations are relevant in both the isolation of biomarkers for later cognitive and physiological disorders and in the understanding of typical cerebral development.

neuroscience↗

bioRxiv2021

Unravelling the puzzle of anthranoids metabolism in living plant cells using spectral imaging coupled to mass spectrometry

Vismione H (VH) is a fluorescent prenylated anthranoid produced by plants from the Hypericaceae family, with antiprotozoal activities against malaria and leishmaniosis. Little is known about its biosynthesis and metabolism in plants or its mode of action against parasites. When VH is isolated from Psorospermum glaberrimum, it is rapidly converted into madagascine anthrone and anthraquinone, which are characterized by markedly different fluorescent properties. To locate the fluorescence of VH in living plant cells and discriminate it from that of the other metabolites, an original strategy combining spectral imaging (SImaging), confocal microscopy and non-targeted metabolomics using mass spectrometry, was developed. Besides VH, structurally related molecules including madagascine, emodin, quinizarin as well as lapachol and fraxetin were analyzed. This strategy readily allowed a spatiotemporal characterization and discrimination of spectral fingerprints from anthranoids-derived metabolites and related complexes with cations and proteins. In addition, our study validates the capability of plant cells to metabolize VH into madagascine anthrone, anthraquinones and unexpected metabolites, leading to new hypotheses on the metabolism of anthranoids in plants.

plant biology↗

bioRxiv2020

Contribution of resident and circulating precursors to tumor-infiltrating CD8+ T cell populations in non-small cell lung cancer patients

Tumor-infiltrating lymphocytes (TILs) in general, and CD8+ TILs in particular, represent a favorable prognostic factor in non-small cell lung cancer (NSCLC). The tissue origin, regenerative capacities, and differentiation pathways of TIL subpopulations, however, remain poorly understood. Using a combination of single cell RNA and T cell receptor (TCR) sequencing, we investigate the functional organization of TIL populations in primary NSCLC. We identify two CD8+ TIL subpopulations expressing memory-like gene modules: one is also present in blood (circulating precursors) and the other one in juxta-tumor tissue (tissue resident precursors). In tumors, these two precursor populations converge through a unique transitional state into terminally differentiated cells, often referred to as dysfunctional or exhausted. Differentiation is associated with TCR expansion, and transition from precursor to late differentiated states correlates with intratumor T cell cycling. These results provide a coherent working model for TIL origin, filiation and functional organization in primary NSCLC.

immunology↗

bioRxiv2018

Redefining mesothelioma types as a continuum uncovers the immune and vascular systems as key players in the diagnosis and prognosis of this disease

Malignant Pleural Mesothelioma (MPM) is an aggressive disease related to asbestos exposure, which incidence is expected to increase in the future, and with no effective therapeutic options. We have performed unsupervised analyses of publicly available RNAseq data for 297 MPM. We found that the molecular profile and the prognosis of this disease is better explained by a continuous model rather than by the current WHO classification into the epitheloid, biphasic and sarcomatoid histological types. The main source of variation of this continuum was explained by the immune and vascular pathways, with strong differences in the expression of pro-angiogenic genes and immune checkpoint inhibitors across samples. These data may inform future classifications of MPM and may also guide personalised therapeutic approaches for this disease.\n\nSignificanceMalignant Pleural Mesothelioma (MPM) is an aggressive disease with no effective therapeutic options. Unsupervised transcriptomic analyses of 297 MPM unveiled the vascular and the immune systems as key players in the prognosis of this disease, and identified potential therapeutic approaches for this disease targeting these pathways.

cancer biology↗

bioRxiv2018

Activation of the mTOR/ Akt pathway in thymic epithelial cells derived from thymomas

The pathogenesis of thymic epithelial tumors remains poorly elucidated. The PI3K/Akt/mTOR pathway plays a key role in various cancers; interestingly, several phase I/II study reported a positive effect of mTOR inhibitors in disease control in thymoma patients. A major limit for deciphering cellular and molecular events leading to the transformation of thymic epithelial cells or for testing drug candidates is the lack of reliable in vitro cell system\n\nWe analyzed protein expression and activation of key players of the Akt/mTOR pathway namely Akt, mTOR, and P70S6K in thirteen A, B and AB thymomas as well as in normal thymuses. While only Akt and the phospho-Akt were expressed in normal thymuses, both Akt and mTOR were activated, with B2 thymomas expressing higher level of activated phospho-Akt than A or AB subtypes. Phospho-P70S6K was expressed in all thymic tumors whatever their subtypes, and absent in normal thymus. Interestingly, in primary thymic epithelial cells maintained for short period of time after their derivation from seven AB and B thymomas, we report the activation of Akt; mTOR and P70S6. Finally, we analyzed the effect of mTOR inhibitor on thymoma derived epithelial cells and showed that rapamycin (100 nM/ ml) significantly reduced cell proliferation.\n\nOur results suggest that the activation of the Akt/ mTOR pathway might participate to the cell proliferation associated with tumor growth. Ultimately, our data enhance the potential role of thymic epithelial cells derived from tissue specimens for in vitro exploration of molecular abnormalities specific to rare thymic tumors.

cancer biology↗

bioRxiv2017

SPANOL (SPectral ANalysis Of Lobes): A spectral clustering framework for individual and group parcellation of cortical surfaces in lobes

Understanding the link between structure, function and development in the brain is a key topic in neuroimaging that benefits from the tremendous progress of multi-modal MRI and its computational analysis. It implies, inter alia, to be able to parcellate the brain volume or cortical surface into biologically relevant regions. These parcellations may be inferred from existing atlases (e.g. Desikan) or sets of rules, as would do a neuroanatomist for lobes, but also directly driven from the data (e.g. functional or structural connectivity) with minimum a priori. In the present work, we aimed at using the intrinsic geometric information contained in the eigenfunctions of Laplace-Beltrami Operator to obtain parcellations of the cortical surface based only on its description by triangular meshes. We proposed a framework adapted from spectral clustering, general in scope and suitable for the co-parcellation of a group of subjects. We applied it to a dataset of 62 adults, optimized it and revealed a striking agreement between parcels produced by this unsupervised clustering and Freesurfer lobes (Desikan atlas), which cannot be explained by chance. Already suitable by itself, this spectral analysis of lobes (Spanol) could conveniently be fitted into a multimodal pipeline for optimized and fast lobar segmentation. Eventually, we showed promising results of Spanol on smoother brains and notably on a dataset of 15 fetuses, with an interest for both the understanding of cortical ontogeny and the applicative field of perinatal computational neuroanatomy.

neuroscience↗