Biology subjects

Bourgeois, A.

Publications and source records attributed to Bourgeois, A..

9 recordsLinked to original sources

bioRxiv2026

Within-Trial Noise Accounts for Inhibition of Return

Inhibition of return (IOR) refers to the slowing of response times (RTs) for stimuli presented at previously inspected locations relative to novel locations. However, the exact processing stage(s) at which IOR occurs, and its nature across different response modalities, remain debated. By reanalyzing RT data from a target-target IOR paradigm with a single noisy accumulator model, we tested whether IOR could occur at sensory or attentional stages of processing, or at later stages of decision and action selection. We considered IOR under two conditions: manual and saccadic responses. The within-trial Gaussian noise parameter best explained both manual and saccadic IOR, suggesting that in both modalities, IOR may result from a more fluctuating accumulation of evidence for repeated locations. These results support the hypothesis that target-target IOR may primarily involve attentional-level mechanisms. Significance statementWe respond more slowly to a stimulus that is presented within a short interval in the same location ("inhibition of return"), a bias thought to promote efficient visual exploration. Using evidence-accumulation modeling of manual and eye-movement reaction times from two previous studies, we found that the key change linked to inhibition of return is greater within-trial variability (noise) in evidence accumulation, not a higher decision threshold. Understanding which processing stage is affected can help connect behavioral effects to the brain networks that support attention and orienting.

neuroscience↗

bioRxiv2025

Exploring the Role of Hypusine Signaling in Vascular Smooth Muscle Cells for Mitigating Restenosis in Coronary Artery Disease.

BackgroundPost-surgical restenosis in patients with coronary artery disease (CAD) is a pathological vascular remodeling process characterized by neointimal hyperplasia, mainly driven by vascular smooth muscle cells (VSMCs) phenotypic switching toward synthetic and proliferative state. This study identifies novel signaling pathway promoting pro-proliferative phenotype of VSMC and contributing to the neointimal hyperplasia development. MethodsThe expression of hypusine signaling components was evaluated in human primary culture of coronary artery smooth muscle cells (CoASMCs) isolated from controls and patients with CAD, using comparative proteomic analysis and western blotting, as well as in three preclinical animal models of restenosis; rat carotid injury, mice carotid ligation and canine coronary artery bypass graft. CAD-CoASMCs proliferation was assessed by western blot and immunofluorescence with pharmacological (GC7) and molecular (shRNA) inhibitors of deoxyhypusine synthase (DHPS). The contribution of hypusine signaling to neointimal hyperplasia was investigated using both pharmacological and smooth muscle cell-specific knockout mice approaches. Additionally, human saphenous vein and human coronary artery tissue cultures were employed to explore the translational potential of targeting hypusine signaling to prevent neointimal hyperplasia. ResultsAll components of the hypusine pathway (eukaryote translational initiation factor 5A (eIF5A), deoxyhypusine hydroxylase (DOHH) and DHPS) were significantly overexpressed in CAD-CoASMCs and in preclinical animal models of restenosis. Pharmacological and molecular inhibition of DHPS reduced eIF5A hypusination, VSMC proliferation and expression of extracellular matrix proteins. Proteomic and KEGG analyses demonstrated disruption of cell cycle and DNA replication pathways, including a downregulation of threonine tyrosine kinase (TTK). Our findings suggest that TTK acts as a downstream effector of hypusine signaling, partly mediating to the proliferative effects observed in CAD-CoASMCs. In vivo, pharmacological and genetic inhibition of DHPS significantly reduced neointimal hyperplasia without adverse effects. Finally, ex vivo human tissue culture confirmed that GC7 mitigates growth factor-induced vascular remodeling. ConclusionsHypusine signaling is a critical regulator of VSMC proliferation for neointimal hyperplasia. Inhibiting DHPS reduces vascular remodeling, making it a promising target for preventing restenosis after coronary interventions. Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIHypusine signaling is markedly upregulated in coronary artery smooth muscle cells (CoASMCs) from patients with coronary artery disease (CAD) and in multiple preclinical models of restenosis. C_LIO_LIProteomic profiling identifies DHPS, the rate-limiting enzyme for eIF5A hypusination, as a key driver of vascular smooth muscle cell (VSMC) pro-proliferative phenotype and extracellular matrix production. C_LIO_LIPharmacological (GC7) and genetic inhibition of DHPS effectively suppress eIF5A hypusination, attenuate the synthetic and proliferative CAD-CoASMCs phenotype, and significantly reduce neointimal hyperplasia in rodent models of vascular injury. C_LIO_LIEx vivo human tissue demonstrates that DHPS inhibition prevents neointimal hyperplasia, providing strong translational evidence. C_LI What Are the Clinical Implications?O_LIThese findings establish hypusine signaling as a previously unrecognized regulator of pathological VSMC activation in CAD and restenosis. C_LIO_LIDHPS inhibition emerges as a promising therapeutic strategy to prevent neointimal hyperplasia following coronary interventions such as angioplasty, stenting, or bypass grafting. C_LIO_LICollectively, our data support the clinical development of selective DHPS inhibitors as a novel class of therapeutics to improve long-term outcomes after coronary revascularization and potentially other occlusive vascular diseases. C_LI

pathology↗

bioRxiv2024

Exploring Integrin α5β1 as a Potential Therapeutic Target for Pulmonary Arterial Hypertension: Insights from Comprehensive Multicenter Preclinical Studies

Pulmonary arterial hypertension (PAH) is characterized by obliterative vascular remodeling of the small pulmonary arteries (PA) and progressive increase in pulmonary vascular resistance (PVR) leading to right ventricular (RV) failure. Although several drugs are approved for the treatment of PAH, mortality remains high. Accumulating evidence supports a pathological function of integrins in vessel remodeling, which are gaining renewed interest as drug targets. However, their role in PAH remains largely unexplored. We found that the arginine-glycine-aspartate (RGD)-binding integrin 5{beta}1 is upregulated in PA endothelial cells (PAEC) and PA smooth muscle cells (PASMC) from PAH patients and remodeled PAs from animal models. Blockade of the integrin 5{beta}1 or depletion of the 5 subunit resulted in mitotic defects and inhibition of the pro-proliferative and apoptosis-resistant phenotype of PAH cells. Using a novel small molecule integrin inhibitor and neutralizing antibodies, we demonstrated that 5{beta}1 integrin blockade attenuates pulmonary vascular remodeling and improves hemodynamics and RV function in multiple preclinical models. Our results provide converging evidence to consider 5{beta}1 integrin inhibition as a promising therapy for pulmonary hypertension. One sentence summaryThe 5{beta}1 integrin plays a crucial role in pulmonary vascular remodeling.

pathology↗

bioRxiv2024

ATP Citrate Lyase Drives Vascular Remodeling Diseases Development Through Metabolic-Epigenetic Reprograming.

Our study explores the previously uncharted role of ATP-citrate lyase (ACLY) in vascular remodeling within the pulmonary and coronary arteries, providing novel insights into the pathogenesis of pulmonary hypertension and coronary artery diseases. ACLY, involved in de novo lipid synthesis and histone acetylation, has emerged as a key regulator in sustaining vascular smooth muscle cell (VSMC) proliferation and survival. Utilizing human coronary and pulmonary artery tissues, our findings reveal an upregulation of ACLY expression during vascular remodeling processes. Inhibition of ACLY, achieved through pharmacological and molecular interventions in humans primary cultured VSMCs, leads to decreased proliferation, migration, and resistance to apoptosis. Mechanistically, these effects are associated with diminished glycolysis, lipid synthesis, GCN5-dependent histone acetylation, and FOXM1 activation. In vivo experiments, combining pharmacological and VSMC-specific ACLY knockout mice, ACLY inhibition demonstrates its efficacy in mitigating coronary artery remodeling and reducing pulmonary hypertension. Notably, initiating ACLY inhibition post-disease onset reverses pathological conditions, positioning ACLY as a promising therapeutic target. Human ex vivo tissue culture further supports our findings, showing reduced vascular remodeling in cultured human coronary artery rings and a reversal of pulmonary artery remodeling in precision-cut lung slices upon ACLY inhibition. This study introduces a groundbreaking concept, linking disparate abnormalities in vascular diseases to a common pathogenetic denominator, ACLY. The identified "multiple hit" therapeutic approach presents potential targets for addressing complex vascular diseases, offering avenues for future clinical interventions. ONE SENTENCE SUMMARYOur study delineates the pivotal role of ATP-citrate lyase in orchestrating vascular remodeling, establishing it as a compelling translational target for therapeutic interventions in pulmonary hypertension and coronary artery disease.

physiology↗

bioRxiv2022

The Interplay of Attention and Conscious Perception: Evidence from Human Intracerebral Recordings and Computational Modeling

How do attention and consciousness interact in the human brain? Rival theories of consciousness disagree on the role of fronto-parietal attentional networks in conscious perception. We recorded neural activity from 727 intracerebral contacts in 13 epileptic patients, while they detected near-threshold targets preceded by attentional cues. Unsupervised clustering revealed three patterns: (1) Attention-enhanced conscious report accompanied sustained right-hemisphere fronto-temporal activity, in networks connected by the superior longitudinal fasciculus (SLF) II-III, and late accumulation in bilateral dorso-prefrontal and right-hemisphere orbitofrontal cortex (SLF I-III). (2) Attentional reorienting affected conscious report through early, sustained activity in a right-hemisphere network (SLF III). (3) Conscious report accompanied left-hemisphere dorsolateral-prefrontal activity. Task modeling with recurrent neural networks identified specific excitatory and inhibitory interactions between attention and consciousness, and their causal contribution to conscious perception of near-threshold targets. Thus, distinct, hemisphere-asymmetric fronto-parietal networks support attentional gain and reorienting in shaping human conscious experience. One-Sentence SummaryIntracerebral recordings, tractography and modeling reveal the interaction of attention and consciousness in the human brain.

neuroscience↗

bioRxiv2021

{-}CardiOvascular examination in awake Orangutans (Pongo pygmaeus pygmaeus): Low-stress Echocardiography including Speckle Tracking imaging (the COOLEST method)

IntroductionCardiovascular diseases have been identified as a major cause of mortality and morbidity in Borneo orangutans (Pongo pygmaeus pygmaeus). Transthoracic echocardiography is usually performed under anesthesia in great apes, which may be stressful and risky in cardiac animals. The aim of the present pilot study was hence to develop a quick and non-stressful echocardiographic method (i.e., the COOLEST method) in awake Borneo orangutans (CardiOvascular examination in awake Orangutans: Low-stress Echocardiography including Speckle Tracking imaging) and assess the variability of corresponding variables. Materials and MethodsFour adult Borneo orangutans trained to present their chest to the trainers were involved. A total of 96 TTE examinations were performed on 4 different days by a trained observer examining each orangutans 6 times per day. Each examination included four two-dimensional views, with offline assessment of 28 variables (i.e., two-dimensional (n=12), M-mode and anatomic M-mode (n=6), Doppler (n=7), and speckle tracking imaging (n=3)), representing a total of 2,688 measurements. A general linear model was used to determine the within-day and between-day coefficients of variation. ResultsMean{+/-}SD (minimum-maximum) images acquisition duration was 3.8{+/-}1.6 minutes (1.3-6.3). All within-day and between-day coefficients of variation but one (n=55/56, 98%) were <15%, and most (51/56, 91%) were <10% including those of speckle tracking systolic strain variables (2.7% to 5.4%). DiscussionHeart morphology as well as global and regional myocardial function can be assessed in awake orangutans with good to excellent repeatability and reproducibility. ConclusionsThis non-stressful method may be used for longitudinal cardiac follow-up in awake orangutans.

zoology↗

bioRxiv2021

Spatiotemporal dynamics of human attention revealed byintracerebral recording

Exogenous attention, the process that makes external salient stimuli pop-out of a visual scene, is essential for survival. How attention-capturing events modulate human brain processing remains unclear. Here we show how the psychological construct of exogenous attention gradually emerges over large-scale gradients in the human cortex, by analyzing activity from 1,403 intracortical contacts implanted in 28 individuals, while they performed an exogenous attention task. The timing, location and task-relevance of attentional events defined a spatiotemporal gradient of three neural clusters, which mapped onto cortical gradients and presented a hierarchy of timescales. Visual attributes modulated neural activity at one end of the gradient, while at the other end it reflected the upcoming response timing, with attentional effects occurring at the intersection of visual and response signals. These findings challenge multi-step models of attention, and suggest that frontoparietal networks, which process sequential stimuli as separate events sharing the same location, drive exogenous attention phenomena such as inhibition of return.

neuroscience↗

bioRxiv2020

LATER but FORTIOR: diffusion modelling of inhibition of return

Inhibition of return (IOR) refers to the slowing of response times (RTs) for stimuli repeated at previously inspected locations, as compared with novel ones. However, the exact processing stage(s) at which IOR occurs, and its nature across different response modalities, remain debated. We tested predictions on these issues originating from the FORTIOR model (fronto-parietal organization of response times in IOR; Seidel Malkinson & Bartolomeo, 2018), and from evidence accumulation models. We reanalysed RT data from a target-target IOR paradigm (Bourgeois et al.,2013a, 2013b) by using a LATER-like evidence accumulation model (Carpenter & Williams, 1995), to test the predictions of FORTIOR, and specifically whether IOR could occur at sensory/attentional stages of processing, or at stages of decision and action selection. We considered the following conditions: manual or saccadic response modality, before or after TMS perturbation over four cortical regions. Results showed that the Gaussian noise parameter best explained both manual and saccadic IOR, suggesting that in both response modalities IOR may result from slower accumulation of evidence for repeated locations. Additionally, across stimulated regions, TMS affected only manual RTs, lowering them equally in the conditions with repeated targets (Return) and non-repeated targets (Non-return). Accordingly, the modelling results show that TMS stimulation did not significantly alter the pattern between model parameters, with the Gaussian noise parameter remaining the parameter best explaining the Return - Non-return RT difference. Moreover, TMS over the right intra-parietal sulcus (IPS) perturbed IOR by shortening the Return RT. When directly testing this effect by modelling the TMS impact in the Return condition, the Bayesian information criterion of the Gaussian noise parameter was the smallest, but this effect did not reach significance. These results support the hypothesis that target-target IOR is a predominantly sensory/attentional phenomenon, and may be modulated by activity in fronto-parietal networks.

neuroscience↗

bioRxiv2019

Sex chromosome pairing mediated by euchromatic homology in Drosophila male meiosis

To maintain proper ploidy, haploid sex cells must undergo two subsequent meiotic divisions. During meiosis I, homologs pair and remain conjoined until segregation at anaphase. Drosophila melanogaster spermatocytes are unique in that the canonical events of meiosis I including synaptonemal complex (SC) formation, double-strand DNA breaks, and chiasmata are absent. Sex chromosomes pair at intergenic spacer sequences within the heterochromatic rDNA while euchromatin is required to pair and segregate autosomal homologies, suggesting that pairing may be limited to specific sequences. However, previous work generated from genetic segregation assays or observations of late prophase I/prometaphase I chromosome associations fail to differentiate pairing from conjunction. Here, we separately examined the capability of X euchromatin to pair and conjoin using an rDNA-deficient X and a series of Dp(1;Y) chromosomes. Genetic assays showed that duplicated X euchromatin can substitute for endogenous rDNA pairing sites. Segregation was not proportional to homology length, and pairing could be mapped to nonoverlapping sequences within a single Dp(1;Y). Using fluorescent in situ hybridization (FISH) to early prophase I spermatocytes, we showed that pairing occurred with high fidelity at all homologies tested. Pairing was unaffected by the presence of X rDNA, nor could it be explained by rDNA magnification. By comparing genetic and cytological data, we determined that centromere proximal pairings were best at segregation. Segregation was dependent on the conjunction protein Stromalin in Meiosis while the autosomal-specific Teflon was dispensable. Overall, our results suggest that pairing may occur at all homologies, but there may be sequence or positional requirements for conjunction. ARTICLE SUMMARYDrosophila males have evolved a unique system of chromosome segregation in meiosis that lacks recombination. Chromosomes pair at selected sequences suggesting that early steps of meiosis may also differ in this organism. Using Y chromosomes carrying portions of X material, we show that pairing between sex chromosomes can be mediated by sequences other than the previously identified rDNA pairing sites. We propose that pairing may simply be homology-based and may not differ from canonical meiosis observed in females. The main difference in males may be that conjunctive mechanisms that join homologs in the absence of crossovers.

genetics↗