Biology subjects

Fabre, A.

Publications and source records attributed to Fabre, A..

7 recordsLinked to original sources

bioRxiv2026

IMU-based upper limb kinematics validation: sensor fusion optimisation, sensor-to-segment alignment, and joint angle accuracy.

Conventional clinical assessment of upper limb kinematics relies on goniometry or visual estimation, methods that provide limited information on multi-segment 3D kinematics and can have poor inter-rater reliability. Inertial measurement units (IMUs) represent a viable alternative; however, extracting anatomically meaningful joint angles from skin-mounted sensors remains challenging owing to sensor-to-segment misalignment, soft-tissue artefact, and suboptimal orientation estimation under dynamic conditions. This study developed and validated a multi-segment IMU-based framework for upper limb kinematic assessment, addressing three stages of the measurement pipeline: (i) sensor fusion gain optimisation as a function of task mean segment angular velocity; (ii) accuracy of an anatomical landmark registration-based alignment method; and (iii) comparative evaluation of landmark-based alignment against manual and neutral-pose alignment approaches. Twenty participants with typical shoulder function performed clinical and functional upper limb tasks, recorded simultaneously with an optoelectronic motion capture system and six IMUs tracking the thorax, clavicle, scapula, humerus, forearm, and hand. Orientation estimation used a gradient-descent complementary filter with velocity-dependent gain modulation. Sensor-to-segment alignment was achieved via manual, neutral-pose, and landmark registration methods. Mean sensor orientation errors ranged from 1.5 to 3 degrees across segments/tasks and increased with angular velocity. Landmark registration produced substantially lower joint angle errors than manual and neutral-pose alignment across all joints (root mean square error range: 3.7-7.8 degrees; manual: 8.3-24.2 degrees; neutral: 15.5-35.5 degrees). These results indicate that IMU-derived kinematic accuracy is context-dependent, varying with joint and movement type, suggesting that accuracy should be established for the specific movements and joints relevant to each clinical application.

bioengineering↗

bioRxiv2024

A TEMPORAL MODEL OF TUMOR-IMMUNE DYNAMICS IN HIGH GRADE SEROUS OVARIAN CANCER

Patients with high-grade serous ovarian cancer (HGSOC) typically present with widespread metastasis, obscuring a temporal understanding of tumor-immune dynamics. We performed multi-site global proteomics and matched immunohistochemistry (IHC) of CD4+ and CD8+ tumor infiltrating lymphocytes (TILs) in patient samples. The protein expression profiles were ordered by pseudotime, recapitulating metastatic progression observed in the clinic, and providing a framework to explore tumor-immune dynamics from localized to metastatic disease. Metastatic progression correlated with immune cell infiltration and the recruitment of Tregs to counterbalance the effect of {gamma}{delta} and CD4+ T cells. Whilst later-stage metastases recruited Tregs via chemokines induced by SNX8, early-stage tumors relied more on antigen presentation. The exclusion of CD4+ TILs from the epithelium was correlated with metastatic progression, whereas CD8+ TILs were not, likely due to a predominance of exhausted CD8+ T cells. In early-stage tumors, keratin-expressing cancer cells recruited Tregs via MHC class II, resulting in an inflammatory phenotype characterized by limited IFN{gamma} production and non-clonally expanded T cells. Additionally, IFI44L expression on macrophages caused immune exclusion by downregulating CD53 on T cells. Our findings reveal novel mechanisms of immune escape associated with localized disease and metastatic progression in HGSOC, highlighting potential targets to improve the efficacy of immunotherapy.

cancer biology↗

bioRxiv2024

Spatial proteomics and transcriptomics of placenta accreta spectrum

In severe Placenta Accreta Spectrum (PAS), trophoblasts gain deep access in the myometrium (placenta increta). This study investigated alterations at the fetal-maternal interface in PAS cases using a systems biology approach consisting of immunohistochemistry, spatial transcriptomics and proteomics. We identified spatial variation in the distribution of CD4+, CD3+ and CD8+ T-cells at the maternal-interface in placenta increta cases. Spatial transcriptomics identified transcription factors involved in promotion of trophoblast invasion such as AP-1 subunits ATF-3 and JUN, and NFKB were upregulated in regions with deep myometrial invasion. Pathway analysis of differentially expressed genes demonstrated that degradation of extracellular matrix (ECM) and class 1 MHC protein were increased in increta regions, suggesting local tissue injury and immune suppression. Spatial proteomics demonstrated that increta regions were characterised by excessive trophoblastic proliferation in an immunosuppressive environment. Expression of inhibitors of apoptosis such as BCL-2 and fibronectin were increased, while CTLA-4 was decreased and increased expression of PD-L1, PD-L2 and CD14 macrophages. Additionally, CD44, which is a ligand of fibronectin that promotes trophoblast invasion and cell adhesion was also increased in increta regions. We subsequently examined ligand receptor interactions enriched in increta regions, with interactions with ITG{beta}1, including with fibronectin and ADAMS, emerging as central in increta. These ITG{beta}1 ligand interactions are involved in activation of epithelial-mesenchymal transition and remodelling of ECM suggesting a more invasive trophoblast phenotype. In PAS, we suggest this is driven by fibronectin via AP-1 signalling, likely as a secondary response to myometrial scarring. Overall, this study suggests the biological processes leading to deep trophoblast invasion in the myometrium in placenta increta are as a result of upregulation of transcription factors and subsequent genes and proteins which promote trophoblast invasion. This occurs in a locally immune suppressed environment, with increased ECM degradation suggesting these findings are secondary to iatrogenic uterine injury. Significance statementPlacenta Accreta Spectrum (PAS) is a rare pregnancy complication, where the placenta fails to separate from the womb resulting in severe bleeding, which is associated with significant maternal morbidity and mortality. As Caesarean section rates increase, the incidence of PAS is increasing. The underlying pathophysiology of PAS is poorly understood. Here, we apply a spatial multi-omic approach to explore the biologic changes at the maternal-fetal interface in severe PAS (placenta increta). Using spatial transcriptomics and proteomics, we identified genes and proteins that are dysregulated in severe PAS involving processes such as extracellular matrix degradation, local immune suppression and promotion of epithelial-mesenchymal transition. This study provides new insights into the biological changes and underlying pathophysiology leading to placenta increta.

bioinformatics↗

bioRxiv2023

SARS-CoV-2 infects neurons, astrocytes, choroid plexus epithelial cells and pericytes of the human central nervous system

SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic, is associated with a range of neurological manifestations including haemorrhage, thrombosis and ischaemic necrosis and encephalitits. However, the mechanism by which this occurs is unclear. Neurological disease associated with SARS-CoV-2 infection has been proposed to occur following direct infection of the central nervous system and/or indirect sequelae as a result of peripheral inflammation. We profiled ACE2 and TMPRSS2 in brain tissue from five healthy human donors, and observed expression of these proteins in astrocytes, neurons and choroid plexus epithelium within frontal cortex and medulla. Primary human astrocytes, neurons and choroid plexus epithelial cells supported productive SARS-CoV-2 infection in an ACE2- dependent manner. Infected cells supported the full viral lifecycle, releasing infectious virus particles. In contrast, primary brain microvascular endothelial cells, pericytes and microglia were refractory to SARS-CoV-2 infection. These data support a model whereby SARS-CoV-2 is neurotropic, and this may in part explain the neurological sequelae of infection. ImportanceA subset of patients with COVID-19 develop neurological symptoms, but the underlying cause is poorly understood. We observed that cells within normal human brain express the SARS-CoV-2 entry factors ACE-2 and TMPRRS2, with expression mainly observed within astrocytes, neurons and choroid plexus epithelium. Primary human astrocytes, neurons and choroid plexus epithelial cells cultured in vitro supported the full SARS-CoV-2 life cycle with a range of SARS-CoV-2 variants. This study demonstrates that cells of the human central nervous system express SARS-CoV-2 entry factors in vivo and support viral infection in vitro, thus supporting a model where neurological symptoms seen in some COVID-19 patients may be as a result of direct viral infection of the central nervous system. Furthermore, these data highlight the importance of investigating the ability of therapeutics to clear virus from this potential reservoir of infection.

microbiology↗

bioRxiv2023

First Eurasian cases of SARS-CoV-2 seropositivity in a free-ranging urban population of wild fallow deer

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infects wildlife. Recent studies highlighted that variants of concern (VOC) may expand into novel animal reservoirs with the potential for reverse zoonosis. North American white-tailed deer are the only deer species in which SARS-CoV-2 has been documented, raising the question whether further reservoir species exist as new VOC emerge. Here, we report the first cases of deer SARS-CoV-2 seropositivity in Eurasia, in a city population of fallow deer in Dublin, Ireland. Deer were seronegative in 2020 (circulating variant in humans: Alpha), one animal was seropositive in 2021 (Delta variant), and 57% of animals tested in 2022 were seropositive (Omicron variant). Ex vivo, a clinical isolate of Omicron BA.1 infected fallow deer precision cut lung slice type-2 pneumocytes, also a major target of infection in human lungs. Our findings suggest a change in host tropism as new variants emerged in the human reservoir, highlighting the importance of continued wildlife disease monitoring and limiting human-wildlife contacts. Teaser: This study is the first report of SARS-CoV-2 seropositivity in fallow deer, highlighting expansion of viral variants into new host reservoirs.

microbiology↗

bioRxiv2021

Pseudohypoxic HIF pathway activation dysregulates collagen structure-function in human lung fibrosis

Extracellular matrix (ECM) stiffening with downstream activation of mechanosensitive pathways is strongly implicated in fibrosis. We previously reported that altered collagen nanoarchitecture is a key determinant of pathogenetic ECM structure-function in human fibrosis (Jones et al., 2018). Here, through human tissue, bioinformatic and ex vivo studies we show that hypoxia-inducible factor (HIF) pathway activation is a critical pathway for this process regardless of oxygen status (pseudohypoxia). Whilst TGF{beta} increased rate of fibrillar collagen synthesis, HIF pathway activation was required to dysregulate post-translational modification of fibrillar collagen, promoting bone-type cross-linking, altering collagen nanostructure, and increasing tissue stiffness. In vitro, knock down of Factor Inhibiting HIF (FIH) or oxidative stress caused pseudohypoxic HIF activation in normal fibroblasts. In contrast, endogenous FIH activity was reduced in fibroblasts from patients with lung fibrosis in association with significantly increased normoxic HIF pathway activation. In human lung fibrosis tissue, HIF mediated signalling was increased at sites of active fibrogenesis whilst subpopulations of IPF lung mesenchymal cells had increases in both HIF and oxidative stress scores. Our data demonstrate that oxidative stress can drive pseudohypoxic HIF pathway activation which is a critical regulator of pathogenetic collagen structure-function in fibrosis.

cell biology↗

bioRxiv2017

Osteo-Oto-Hepato-Enteric Syndrome (O2HE) is caused by loss of function mutations in UNC45A

Despite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with hitherto unknown syndromic manifestations. Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing and bone fragility, a clinical entity we have termed O2HE (Osteo-Oto-Hepato-enteric) syndrome. Whole exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A), as a likely driver for this disorder. Subsequent in vitro and in vivo functional studies of the candidate gene indicated a loss of function paradigm, wherein mutations attenuated or abolished protein activity with concomitant defects in gut development and function.

genetics↗