Biology subjects

Bartolucci, P.

Publications and source records attributed to Bartolucci, P..

4 recordsLinked to original sources

bioRxiv2025

Additive Manufacturing of real-scale carotid artery models: The content-container interaction in sickle cell disease-related cerebral vasculopathy

Sickle cell disease-related cerebral vasculopathy depends on patient-specific vascular geometry and hemodynamics that are not captured by conventional experimental systems or animal models. To address this limitation, we developed an additively manufactured artery scaffold representing the container and integrated it into a controlled fluidic circuit reproducing physiological flow profiles, pressures, and viscosities, the content. Validation with clinical imaging confirmed the anatomical accuracy and flow fidelity of the additively manufactured models. Mechanosensitive cells, including endothelial cells and platelets, were incorporated into the model for biological analysis. This study serves as a proof of concept demonstrating how the Container-Content model can enhance the mechanistic understanding of vascular biology under physiologically relevant conditions. The ethically responsible platform bridges computational simulations and in vitro experimentation, offering a versatile foundation for investigating cerebrovascular complications in sickle cell disease and advancing the field of personalized medicine.

bioengineering↗

bioRxiv2023

Soluble LIGHT (TNFSF14) activates endothelial cells, thereby priming the first vessel-occlusive events in acute sickle cell disease

In sickle cell disease (SCD), the red blood cells carry a mutated form of hemoglobin (HbS) leading to altered shape and deformability. The mutation causes abnormal hemorheological properties, mechanical hemolysis, and adhesion. The chronic vascular inflammation observed in SCD and hemolysis-related endothelium activation may trigger the vaso-occlusion of blood vessels. The prothrombotic and pro-inflammatory LIGHT/TNFSF14 is a tumor necrosis factor (TNF)- superfamily cytokine implicated in various inflammatory diseases. It is expressed by various immune cells and is considered an actor in T cell-mediated immunity and immune cell recruitment. LIGHT has also been shown to activate endothelial cells (ECs) strongly. LIGHT levels are high in the plasma of SCD patients, and platelets are a major source of its circulating form. We studied a cohort of 82 homozygous adult patients with SCD (n=108 samples) to determine whether LIGHT levels were linked to the clinical state of patients included in the Basal steady state or during an Acute crisis. Soluble LIGHT levels were high in the plasma of SCD patients during acute phases of the disease, particularly during painful occlusive crises. LIGHT levels were associated with Hb levels and inflammatory markers (mainly interferon-{gamma} and tumor necrosis factor-, specifically in acute SCD patients). Our findings confirm that LIGHT is a strong activator of cultured ECs, inducing a type II inflammatory cytokine profile and the expression of adhesion molecules. Using a physiological flow adhesion test on biochips, we showed that the LIGHT-induced activation of ECs led to the adhesion of both sickle platelets (but not their AA counterparts), and in a less extend sickle RBCs to activated HUVECs, potentially constituting the first step in vaso-occlusion. Indeed, the pretreatment of HUVECs with neutralizing polyclonal Abs against LIGHT, but not the non-specific counterpart, showed a reversal of both the inflammation process activated by LIGHT treatment and platelet adhesion to endothelial cells. Soluble LIGHT appears to be a promising therapeutic target for preventing adverse occlusive events in SCD through the blockade of its receptor, to prevent the adhesion of blood cell components to the endothelium. Future studies should consider whether soluble LIGHT contributes to other clinical complications in SCD. HIGHLIGHTSO_LIIn patients with SCD, plasma LIGHT is mainly secreted during acute phases, including VOCs. C_LIO_LIBoth Hb levels and IFN{gamma} levels are correlated with plasma LIGHT with SCD patients in acute phase disease. C_LIO_LIThe LIGHT-induced activation of endothelial cells leads to the flow adherence of both sickle (SS) platelets and red blood cells. C_LIO_LIBoth endothelial priming by LIGHT and platelet adherence are abolished by anti-LIGHT polyclonal Abs. C_LI

cell biology↗

bioRxiv2023

Gene-metabolite annotation with shortest reactional distance enhances metabolite genome-wide association studies results

Studies combining metabolomics and genetics, known as metabolite genome-wide association studies (mGWAS), have provided valuable insights into our understanding of the genetic control of metabolite levels. However, the biological interpretation of these associations remains challenging due to a lack of existing tools to annotate mGWAS gene-metabolite pairs beyond the use of conservative statistical significance threshold. Here, we computed the shortest reactional distance (SRD) based on the curated knowledge of the KEGG database to explore its utility in enhancing the biological interpretation of results from three independent mGWAS, including a case study on sickle cell disease patients. Results show that, in reported mGWAS pairs, there is an excess of small SRD values and that SRD values and p-values significantly correlate, even beyond the standard conservative thresholds. The added-value of SRD annotation is shown for identification of potential false negative hits, exemplified by the finding of gene-metabolite associations with SRD [≤]1 that did not reach standard genome-wide significance cut-off. The wider use of this statistic as an mGWAS annotation would prevent the exclusion of biologically relevant associations and can also identify errors or gaps in current metabolic pathway databases. Our findings highlight the SRD metric as an objective, quantitative and easy-to-compute annotation for gene-metabolite pairs that can be used to integrate statistical evidence to biological networks.

systems biology↗

bioRxiv2019

Causal role of L-glutamine in sickle cell disease painful crises: a Mendelian randomization analysis

In a recent clinical trial, the metabolite L-glutamine was shown to reduce painful crises in sickle cell disease (SCD) patients. To confirm this observation and identify other metabolites implicated in SCD clinical heterogeneity, we profiled 129 metabolites in the plasma of 705 SCD patients. We tested correlations between metabolite levels and six SCD-related complications (painful crises, cholecystectomy, retinopathy, leg ulcer, priapism, aseptic necrosis) or estimated glomerular filtration rate (eGFR), and used Mendelian randomization (MR) to assess causality. We found a causal relationship between L-glutamine levels and painful crises (N=1,278, odds ratio (OR) [95% confidence interval] = 0.68 [0.52 - 0.89], P=0.0048). In two smaller SCD cohorts (N=299 and 406), the protective effect of L-glutamine was observed (OR=0.82 [0.50-1.34]), although the MR result was not significant (P=0.44). We identified 66 significant correlations between the levels of other metabolites and SCD-related complications or eGFR. We tested these correlations for causality using MR analyses and found no significant causal relationship. The baseline levels of quinolinic acid was associated with prospectively ascertained survival in SCD patients, and this effect was dependent on eGFR. Metabolomics provide a promising approach to prioritize small molecules that may serve as biomarkers or drug targets in SCD.

genetics↗