Biology subjects

Fabre, M.

Publications and source records attributed to Fabre, M..

5 recordsLinked to original sources

bioRxiv2025

Population-scale sequencing resolves correlates and determinants of latent Epstein-Barr Virus infection

Epstein-Barr Virus (EBV) is an endemic herpesvirus implicated in autoimmunity, cancer, and neurological disorders. Though primary infection typically resolves with subclinical symptoms, long-term complications can arise due to immune dysregulation or viral latency, in which EBV DNA is detectable in blood for decades. Despite the ubiquity of this virus, we have an incomplete understanding of the highly variable responses to EBV that range from asymptomatic infection to a trigger for severe disease. Here, we demonstrate that existing whole genome sequencing (WGS) data contains ample non-human DNA sequences to reconstruct a molecular biomarker of latent EBV infection consistent with orthogonal phenotypes, including viral serology. Using the UK Biobank (n = 490,560) and All of Us (n = 245,394), we uncover reproducible complex trait associations that nominate latent blood-derived EBV DNA as a respiratory, autoimmune, and cardiovascular disease biomarker. Further, we evaluate the genetic determinants of persistent EBV DNA via genome-wide and exome-wide association studies, uncovering protein-altering variants from 147 genes. Single-cell and pathway-scale enrichment analyses implicate variable antigen processing and presentation as a primary genetic determinant of latent EBV persistence, with gene programs expressed in B cells and antigen-presenting cells. Using predicted viral epitope presentation affinities, we implicate genetic variation in MHC class II as a key modulator of EBV DNA persistence. Our analyses demonstrate how existing WGS data can derive novel molecular biomarkers, which may generalize to dozens of viruses comprising the blood virome1.

genetics↗

bioRxiv2023

Actin-Driven Nanotopography Enhances Integrin Molecular Clutch in Developing Tissue

Morphogenesis requires building stable macromolecular structures from highly dynamic proteins. Muscles are anchored by long-lasting integrin adhesions to resist contractile force. However, the mechanisms governing integrin diffusion, immobilization, and activation within developing tissues remain elusive. Here, we show that actin polymerisation-driven membrane protrusions form nanotopographies that enable strong adhesion at Drosophila muscle attachment sites (MAS). Super-resolution microscopy revealed that integrins assemble adhesive belts around Arp2/3-dependent actin protrusions, forming invadosome-like structures with membrane nanotopographies. Single protein tracking showed that, during MAS development, integrins became immobile and confined within diffusion traps formed by the membrane nanotopographies. Actin filaments also displayed restricted motion and confinement, indicating strong mechanical connection with integrins. Using isolated muscles cells, we show that substrate nanotopography, rather than rigidity, drives adhesion maturation by regulating actin protrusion, integrin diffusion and immobilization. These results thus demonstrate that actin-polymerisation driven membrane protrusions are essential for the formation of strong integrin adhesions sites in the developing embryo, and highlight the important contribution of geometry to morphogenesis.

cell biology↗

bioRxiv2022

When mechanical engineering inspired from physiology improves postural-related somatosensory processes

Being the first stimulated by the relative movement of foot skin and the underneath moving support surface, the plantar tactile receptors (i.e., mechanoreceptors) play an important role in the sensorimotor transformation giving rise to a postural reaction. In this light, a biomimetic surface, i.e., complying with the characteristics of the mechanoreceptors and the skin dermatoglyphs (i.e., pattern of the ridges) should facilitate the cortical processes in response to the somatosensory stimulation involved in the balance recovery motor control. Healthy young adults (n = 21) were standing still either on a biomimetic surface or on two control surfaces (i.e., grooved or smooth), when a sudden but low acceleration of the supporting surface along the lateral direction was triggered. A shorter and more robust evoked somatosensory response (i.e., SEP) was observed when participants were standing on the biomimetic surface. As well, a lower oscillatory response in the theta (5-7 Hz) time-frequency domain in the left posterior parietal cortex (PPC) was observed with the biomimetic surface. The greater shear forces induced by the interaction between the feet and the biomimetic surface during the platform motion was likely at the origin of the increased SEP. Besides, the decrease of theta power suggests that the balance task became less challenging. This interpretation was tested in a second experiment by adding a cognitive task, which should be less detrimental for the postural reaction when standing on a biomimetic surface. Consistent with this hypothesis, a more efficient postural reaction (i.e., shorter latency and greater amplitude) was observed when the cognitive task was performed while standing on the biomimetic surface.

neuroscience↗

bioRxiv2022

Cortical facilitation of somatosensory inputs using gravity-related tactile information in patients with bilateral vestibular loss

A few years after their bilateral vestibular loss, individuals usually show a motor repertoire that is almost back to normal. This recovery is thought to involve an up-regulation of the visual and proprioceptive information that compensates for the lack of vestibular information. Here, we investigated whether plantar tactile inputs, which provide body information relative to the ground and to the Earth-vertical, contribute to this compensation. More specifically, we tested the hypothesis that somatosensory cortex response to electric stimulation of the plantar sole in standing adults will be greater in patients (n = 10) with bilateral vestibular loss than in an aged-matched healthy group (n = 10). Showing significant greater somatosensory evoked potentials (i.e., P1N1) in patients than in controls, the electroencephalographic recordings supported this hypothesis. Furthermore, we found evidence that increasing the differential pressure between both feet, by adding a 1 kg mass at each pending wrist, enhanced the internal representation of body orientation and motion relative to a gravitational reference frame. The large decreased in alpha/beta power in the right posterior parietal cortex (and not in the left) is in line with this assumption. Finally, our behavioral analyses showed smaller body sway oscillations for patients, likely originated from a tactile-based control strategy. Conversely, healthy subjects showed smaller head oscillations suggesting a vestibular-based control strategy, the head serving as a reference for balance control. HighlightsO_LISomatosensory cortex excitability is greater in patients with bilateral vestibular loss than in aged-matched healthy individuals C_LIO_LITo control balance, healthy individuals "locked" the head while vestibular patients "locked" their pelvis C_LIO_LIFor vestibular patients, increasing loading/unloading mechanism enhances the internal representation of body state in the posterior parietal cortex C_LI

neuroscience↗

bioRxiv2021

Clonal dynamics of haematopoiesis across the human lifespan

Age-related change in human haematopoiesis causes reduced regenerative capacity1, cytopenias2, immune dysfunction3 and increased risk of blood cancer. The cellular alterations that underpin the abruptness of this functional decline after the age of 70 years remain elusive. We sequenced 3579 genomes from single-cell-derived colonies of haematopoietic stem cell/multipotent progenitors (HSC/MPPs) across 10 haematologically normal subjects aged 0-81 years. HSC/MPPs accumulated 17 mutations/year after birth and lost 30bp/year of telomere length. Haematopoiesis in adults aged <65 was massively polyclonal, with high indices of clonal diversity and a stable population of 20,000-200,000 HSC/MPPs contributing evenly to blood production. In contrast, haematopoiesis in individuals aged >75 showed profoundly decreased clonal diversity. In each elderly subject, 30-60% of haematopoiesis was accounted for by 12-18 independent clones, each contributing 1-34% of blood production. Most clones had begun their expansion before age 40, but only 22% had known driver mutations. Genome-wide selection analysis estimated that 1/34 to 1/12 non-synonymous mutations were drivers, occurring at a constant rate throughout life, affecting a wider pool of genes than identified in blood cancers. Loss of Y chromosome conferred selective benefits on HSC/MPPs in males. Simulations from a simple model of haematopoiesis, with constant HSC population size and constant acquisition of driver mutations conferring moderate fitness benefits, entirely explained the abrupt change in clonal structure in the elderly. Rapidly decreasing clonal diversity is a universal feature of haematopoiesis in aged humans, underpinned by pervasive positive selection acting on many more genes than currently identified.

genomics↗