157 research outputs found
No inherent left and right side in human âmental number line': evidence from right brain damage
Spatial reasoning has a relevant role in mathematics and helps daily computational activities. It is widely assumed that in cultures with left-to-right reading, numbers are organized along the mental equivalent of a ruler, the mental number line, with small magnitudes located to the left of larger ones. Patients with right brain damage can disregard smaller numbers while mentally setting the midpoint of number intervals. This has been interpreted as a sign of spatial neglect for numbers on the left side of the mental number line and taken as a strong argument for the intrinsic left-to-right organization of the mental number line. Here, we put forward the understanding of this cognitive disability by discovering that patients with right brain damage disregard smaller numbers both when these are mapped on the left side of the mental number line and on the right side of an imagined clock face. This shows that the right hemisphere supports the representation of small numerical magnitudes independently from their mapping on the left or the right side of a spatial-mental layout. In addition, the study of the anatomical correlates through voxel-based lesion-symptom mapping and the mapping of lesion peaks on the diffusion tensor imaging-based reconstruction of white matter pathways showed that the rightward bias in the imagined clock-face was correlated with lesions of high-level middle temporal visual areas that code stimuli in object-centred spatial coordinates, i.e. stimuli that, like a clock face, have an inherent left and right side. In contrast, bias towards higher numbers on the mental number line was linked to white matter damage in the frontal component of the parietal-frontal number network. These anatomical findings show that the human brain does not represent the mental number line as an object with an inherent left and right side. We conclude that the bias towards higher numbers in the mental bisection of number intervals does not depend on left side spatial, imagery or object-centred neglect and that it rather depends on disruption of an abstract non-spatial representation of small numerical magnitude
Prandial states modify the reactivity of the gustatory cortex using gustatory evoked potentials in humans
Previous functional Magnetic Resonance Imaging studies evaluated the role of satiety on cortical taste area activity and highlighted decreased activation in the orbito-frontal cortex when food was eaten until satiation. The modulation of orbito-frontal neurons (secondary taste area) by ad libitum food intake has been associated with the pleasantness of the food's flavor. The insula and frontal operculum (primary taste area) are also involved in reward processing. The aim was to compare human gustatory evoked potentials (GEP) recorded in the primary and secondary gustatory cortices in a fasted state with those after food intake. Fifteen healthy volunteers were enrolled in this observational study. In each of two sessions, two GEP recordings were performed (at 11:00 am and 1:30 pm) in response to sucrose gustatory stimulation, and a sucrose-gustatory threshold was determined. During one session, a standard lunch was provided between the two GEP recordings. During the other session, subjects had nothing to eat. Hunger sensation, wanting, liking, and the perception of the solution's intensity were evaluated with visual analog scales. GEP latencies measured in the Pz (p < 0.001), Cz (p < 0.01), Fz (p < 0.001) recordings (primary taste area) were longer after lunch than in the pre-prandial condition. Fp1 and Fp2 latencies (secondary taste area) tended to be longer after lunch, but the difference was not significant. No difference was observed for the sucrose-gustatory threshold regardless of the session and time. Modifications in the primary taste area activity during the post-prandial period occurred regardless of the nature of the food eaten and could represent the activity of the frontal operculum and insula, which was recently shown to be modulated by gut signals (GLP-1, CCK, ghrelin, or insulin) through vagal afferent neurons or metabolic changes of the internal milieu after nutrient absorption. This trial was registered at clinicalstrials.gov as NCT02472444
Quelle R&D Mener pour le DĂ©veloppement Des RĂ©seaux D'Ă©nergie De Demain ? Les Propositions de L'ancre en 2015
Feuille de route sur les rĂ©seaux Ă©lectriques et stockage Ă©laborĂ©e par le GP10 RĂ©seaux et Stockages de l'Energie de l'ANCRECette feuille de route concerne les rĂ©seaux dâĂ©nergie Ă©lectrique, de chaleur et de froid, les rĂ©seaux de gaz (hydrogĂšne, gaz naturel), leurs stockages associĂ©s, ainsi que leurs couplages Ă venir dans le cadre de la transition Ă©nergĂ©tique et des Ă©volutionsqui lâaccompagneront, que ce soit sur les modes de production dâĂ©nergie ou sur lâĂ©volution des usages.Le focus est portĂ© sur les rĂ©seaux Ă©lectriques qui seront les premiers impactĂ©s par cette transition Ă©nergĂ©tique. Hormisquelques Ă©lĂ©ments trĂšs spĂ©cifiques aux rĂ©seaux Ă©lectriques (et qui seront notĂ©s dans le texte par une couleur diffĂ©rente)il est Ă souligner que la quasi-totalitĂ© des considĂ©rations et axes de R&D Ă©voquĂ©s pour les rĂ©seauxĂ©lectriques et le dĂ©veloppement de leur « intelligence » et/ou de leur flexibilitĂ© sâappliquentĂ©galement aux autres rĂ©seaux dâĂ©nergie. Par ailleurs, si le groupe programmatique« RĂ©seaux et Stockage » de lâANCRE (GP10) sâest largement appuyĂ© sur les nombreuses feuilles de route Ă©mises tant au niveau national, dont celles de lâADEME, quâeuropĂ©en, il a Ă©galement souhaitĂ© sâen dĂ©marquer en insistantlargement et en dĂ©taillant les recherches scientifiques et technologiques Ă mener face aux verrous actuellement identifiĂ©s
Establishment and analysis of a reference transcriptome for Spodoptera frugiperda
International audienceBackground Spodoptera frugiperda (Noctuidae) is a major agricultural pest throughout the American continent. The highly polyphagous larvae are frequently devastating crops of importance such as corn, sorghum, cotton and grass. In addition, the Sf9 cell line, widely used in biochemistry for in vitro protein production, is derived from S. frugiperda tissues. Many research groups are using S. frugiperda as a model organism to investigate questions such as plant adaptation, pest behavior or resistance to pesticides.ResultsIn this study, we constructed a reference transcriptome assembly (Sf_TR2012b) of RNA sequences obtained from more than 35âS. frugiperda developmental time-points and tissue samples. We assessed the quality of this reference transcriptome by annotating a ubiquitous gene family - ribosomal proteins - as well as gene families that have a more constrained spatio-temporal expression and are involved in development, immunity and olfaction. We also provide a time-course of expression that we used to characterize the transcriptional regulation of the gene families studied.ConclusionWe conclude that the Sf_TR2012b transcriptome is a valid reference transcriptome. While its reliability decreases for the detection and annotation of genes under strong transcriptional constraint we still recover a fair percentage of tissue-specific transcripts. That allowed us to explore the spatial and temporal expression of genes and to observe that some olfactory receptors are expressed in antennae and palps but also in other non related tissues such as fat bodies. Similarly, we observed an interesting interplay of gene families involved in immunity between fat bodies and antennae
RĂFLEXIONS SUR LA MATĂRIALITĂ
International audienceRecueil de réflexions sur la matérialité en architecture
Apoptotic HPV Positive Cancer Cells Exhibit Transforming Properties
Previous studies have shown that DNA can be transferred from dying engineered cells to neighboring cells through the phagocytosis of apoptotic bodies, which leads to cellular transformation. Here, we provide evidence of an uptake of apoptotic-derived cervical cancer cells by human mesenchymal cells. Interestingly, HeLa (HPV 18+) or Ca Ski (HPV16+) cells, harboring integrated high-risk HPV DNA but not C-33 A cells (HPV-), were able to transform the recipient cells. Human primary fibroblasts engulfed the apoptotic bodies effectively within 30 minutes after co-cultivation. This mechanism is active and involves the actin cytoskeleton. In situ hybridization of transformed fibroblasts revealed the presence of HPV DNA in the nucleus of a subset of phagocytosing cells. These cells expressed the HPV16/18 E6 gene, which contributes to the disruption of the p53/p21 pathway, and the cells exhibited a tumorigenic phenotype, including an increased proliferation rate, polyploidy and anchorage independence growth. Such horizontal transfer of viral oncogenes to surrounding cells that lack receptors for HPV could facilitate the persistence of the virus, the main risk factor for cervical cancer development. This process might contribute to HPV-associated disease progression in vivo
RĂŽle de la protĂ©ine p53 dans lâhypertension artĂ©rielle pulmonaire humaine et expĂ©rimentale
Pulmonary artery hypertension (PAH) is a severe pulmonary vascular disease characterized by a progressive increase of the pulmonary arterial pressure (PAP), defined by a mean PAP greater than or equal to 25 mmHg at rest. The main symptom is a shortness of breath. An intense pulmonary arterial remodeling that leads to an obstruction of the small pulmonary vessels is responsible of the disease. PAH is a rare but severe disease that develops into right ventricular cardiac failure leading to the patient's death.The general framework of our study was to improve the understanding of the pathophysiology of PAH in order to identify new potential therapeutic targets and improve the clinical management of patients. In particular, we were interested in the âcancer-like phenotypeâ of PAH patient pulmonary arterial smooth muscle cells (PA-SMCs). PA-SMCs play a key role in the pulmonary vascular remodeling of PAH. These cells share characteristics with cancerous cells, such as: exaggerated proliferation, apoptosis resistance, metabolic disorders and genomic instability. Owing to the growth-suppressive and pro-apoptotic functions of p53 protein and its inactivation largely described in cancer, we hypothesized that the p53 pathway could also be altered during PAH development in PA-SMCs.The results of in vitro studies on PA-SMCs of late stage patients with idiopathic PAH (iPAH) versus control patients suggest that the p53 protein nor pathway is not altered in iPAH PA-SMCs. Indeed, the coding sequence of the TP53 gene presented no mutations in iPAH PA-SMCs. Analysis of mRNA and protein levels of p53 and its target proteins showed no difference between controls and iPAH PA-SMCs, neither in a basal state or in response to various cellular stresses such as etoposide and H2O2. However, regulation of p53 may be altered in iPAH PA-SMCs as we observed an increase of the MDM2 (the main p53 regulator) protein level compared to control. This last result may be considered as a âcancer-likeâ characteristic of iPAH PA-SMCs and also be a determining factor in the mechanism of action of Nutlin-3a, which had more important anti-proliferative effects in iPAH PA-SMCs than in control cells.In vivo studies in rats revealed, however, that the p53 pathway may play a role in the initiation stage of PAH pathogenesis. Indeed, kinetics evaluation of p53 lung expression in the PAH model, induced by a single injection of monocrotaline (MCT), revealed a decrease in the p53 protein level during the first week, followed by a normalization by the second week. PAH symptoms are developed in MCT rats after two weeks. Similarly, the protein levels of p21, a p53 target, and MDM2, the major p53 regulator, and also a transcriptional target of p53, decreased during the first week in the MCT-PAH model. In addition, daily treatment in rats with an inhibitor of p53 transcriptional activity, pifithrin-α (PFT), led to the development of PAH in 14 days, similarly to MCT, and worsened the PAH induced by MCT. Pro-apoptotic and anti-proliferative effects of PFT on PA-SMCs indicate that inhibition of p53 transcriptional activity causes an excessive proliferation and an apoptosis resistance, which are two key components of the pulmonary vascular remodeling and development of human and experimental PAH.In conclusion, these results demonstrate the involvement of the p53 pathway inactivation in the initiation stage of PAH development, whereas in late and severe stages of disease, its role seems to be less implicated. In contrast, the increased expression of MDM2 observed in PA-SMCs of PAH patients may be a potential therapeutic target.Le terme dâ« hypertension artĂ©rielle pulmonaire » (HTAP) dĂ©crit une maladie vasculaire pulmonaire caractĂ©risĂ©e par une augmentation progressive des pressions artĂ©rielles pulmonaires (PAP), dĂ©finie par une PAP moyenne supĂ©rieure ou Ă©gale Ă 25 mmHg au repos et dont le principal symptĂŽme est un essoufflement Ă lâeffort. Un remodelage artĂ©riel pulmonaire intense conduisant Ă une obstruction des petits vaisseaux pulmonaires est responsable de la maladie. Câest une maladie rare mais nĂ©anmoins grave car pouvant aboutir Ă une insuffisance ventriculaire droite et entraĂźner le dĂ©cĂšs du patient.Le cadre gĂ©nĂ©ral de notre Ă©tude est lâamĂ©lioration de la comprĂ©hension des mĂ©canismes physiopathologiques de lâHTAP afin dâidentifier de nouvelles cibles thĂ©rapeutiques potentielles. Nous nous sommes intĂ©ressĂ©s plus particuliĂšrement au phĂ©notype « pseudo-tumoral » des cellules musculaires lisses des artĂšres pulmonaires (CML-AP) des patients atteints dâHTAP qui jouent un rĂŽle primordial dans le remodelage vasculaire pulmonaire de lâHTAP et qui prĂ©sentent des caractĂ©ristiques communes avec les cellules cancĂ©reuses, notamment une hyper-prolifĂ©ration, une rĂ©sistance Ă lâapoptose, des dĂ©sordres mĂ©taboliques et une instabilitĂ© gĂ©nomique. Etant donnĂ© que la protĂ©ine p53, un des plus importants suppresseurs de tumeur, est largement dĂ©crite comme inactivĂ©e dans la plupart des cancers, nous avons Ă©mis lâhypothĂšse quâelle pourrait Ă©galement jouer un rĂŽle important dans le dĂ©veloppement de lâHTAP. Les rĂ©sultats des Ă©tudes in vitro menĂ©es sur des CML-AP de patients atteints d'HTAP idiopathiques (HTAPi) versus des sujets contrĂŽles semblent indiquer que la protĂ©ine p53 nâest pas altĂ©rĂ©e dans les CML-AP HTAPi. En effet, la sĂ©quence codante du gĂšne TP53 ne prĂ©sente pas de mutation dans les CML-AP HTAPi, les expressions gĂ©nique et protĂ©ique de p53 (et de certaines de ses protĂ©ines cibles) ne semblent pas ĂȘtre diffĂ©rentes entre contrĂŽles et HTAPi, ni Ă lâĂ©tat basal ni en rĂ©ponse Ă diffĂ©rents stress cellulaires inducteurs de p53 (Ă©toposide et H2O2). Cependant, la rĂ©gulation de p53 semble altĂ©rĂ©e puisque nous avons observĂ© une augmentation du taux protĂ©ique de MDM2, principal rĂ©gulateur de p53, dans les CML-AP HTAPi. Ce rĂ©sultat peut ĂȘtre considĂ©rĂ© comme une des caractĂ©ristiques « pseudo-tumorales » des CML-AP HTAPi mais Ă©galement ĂȘtre un Ă©lĂ©ment dĂ©terminant du mĂ©canisme dâaction de la Nutlin-3a, qui a montrĂ© des effets anti-prolifĂ©ratifs accrus dans les CML-AP HTAPi.Dans des Ă©tudes in vivo menĂ©es chez le rat, la protĂ©ine p53 semble jouer un rĂŽle dans lâinitiation de la pathogĂ©nĂšse dâune HTAP. En effet, les taux protĂ©iques pulmonaires de p53, de sa cible p21 et de son rĂ©gulateur (mais Ă©galement cible transcriptionnelle) MDM2 sont diminuĂ©s lors de la premiĂšre semaine dans un modĂšle dâinduction dâHTAP par mono-injection de monocrotaline (MCT) chez le rat, au cours duquel la pathologie se dĂ©veloppe Ă partir de la 2Ăšme semaine. De plus, lâadministration quotidienne Ă des rats dâun inhibiteur de lâactivitĂ© transcriptionnelle de p53, le pifithrin-α (PFT), conduit au dĂ©veloppement dâune HTAP en 14 jours, au mĂȘme titre quâune mono-injection de MCT, et aggrave lâHTAP induite par la MCT. Des effets pro-prolifĂ©ratifs et anti-apoptotiques du PFT rĂ©vĂ©lĂ©s sur des CML-AP indiquent que lâinhibition de lâactivitĂ© transcriptionnelle de p53 est Ă l'origine d'une prolifĂ©ration exagĂ©ree et une rĂ©sistance Ă l'apoptose, deux composantes clĂ©s dans le remaniement vasculaire pulmonaire et le dĂ©veloppement de l'HTAP.En conclusion, ces rĂ©sultats mettent en Ă©vidence lâimplication de lâinactivation de la voie de p53 lors de la phase initiatrice du dĂ©veloppement de lâHTAP, alors quâaux stades tardifs et sĂ©vĂšres de la maladie, il semble il y avoir une normalisation de p53. En revanche, lâaugmentation de lâexpression de son principal rĂ©gulateur MDM2 observĂ©e dans les CML-AP de patients HTAP semble ĂȘtre une cible thĂ©rapeutique potentiellement intĂ©ressante
Jacques Waardenburg. L'Islam, une religion. Suivi d'un débat : "Quels types d'approches requiert le phénomÚne religieux ?"
Jacquin Sophie. Jacques Waardenburg. L'Islam, une religion. Suivi d'un dĂ©bat : "Quels types d'approches requiert le phĂ©nomĂšne religieux ?". In: Politique Ă©trangĂšre, n°3 - 1989 - 54á”annĂ©e. p. 539
Christiane Hurtig. Les maharajahs et la politique dans l'Inde contemporaine
Jacquin Sophie. Christiane Hurtig. Les maharajahs et la politique dans l'Inde contemporaine. In: Politique Ă©trangĂšre, n°3 - 1989 - 54á”annĂ©e. pp. 543-544
Role of p53 protein in human and experimental pulmonary arterial hypertension
Le terme dâ« hypertension artĂ©rielle pulmonaire » (HTAP) dĂ©crit une maladie vasculaire pulmonaire caractĂ©risĂ©e par une augmentation progressive des pressions artĂ©rielles pulmonaires (PAP), dĂ©finie par une PAP moyenne supĂ©rieure ou Ă©gale Ă 25 mmHg au repos et dont le principal symptĂŽme est un essoufflement Ă lâeffort. Un remodelage artĂ©riel pulmonaire intense conduisant Ă une obstruction des petits vaisseaux pulmonaires est responsable de la maladie. Câest une maladie rare mais nĂ©anmoins grave car pouvant aboutir Ă une insuffisance ventriculaire droite et entraĂźner le dĂ©cĂšs du patient.Le cadre gĂ©nĂ©ral de notre Ă©tude est lâamĂ©lioration de la comprĂ©hension des mĂ©canismes physiopathologiques de lâHTAP afin dâidentifier de nouvelles cibles thĂ©rapeutiques potentielles. Nous nous sommes intĂ©ressĂ©s plus particuliĂšrement au phĂ©notype « pseudo-tumoral » des cellules musculaires lisses des artĂšres pulmonaires (CML-AP) des patients atteints dâHTAP qui jouent un rĂŽle primordial dans le remodelage vasculaire pulmonaire de lâHTAP et qui prĂ©sentent des caractĂ©ristiques communes avec les cellules cancĂ©reuses, notamment une hyper-prolifĂ©ration, une rĂ©sistance Ă lâapoptose, des dĂ©sordres mĂ©taboliques et une instabilitĂ© gĂ©nomique. Etant donnĂ© que la protĂ©ine p53, un des plus importants suppresseurs de tumeur, est largement dĂ©crite comme inactivĂ©e dans la plupart des cancers, nous avons Ă©mis lâhypothĂšse quâelle pourrait Ă©galement jouer un rĂŽle important dans le dĂ©veloppement de lâHTAP. Les rĂ©sultats des Ă©tudes in vitro menĂ©es sur des CML-AP de patients atteints d'HTAP idiopathiques (HTAPi) versus des sujets contrĂŽles semblent indiquer que la protĂ©ine p53 nâest pas altĂ©rĂ©e dans les CML-AP HTAPi. En effet, la sĂ©quence codante du gĂšne TP53 ne prĂ©sente pas de mutation dans les CML-AP HTAPi, les expressions gĂ©nique et protĂ©ique de p53 (et de certaines de ses protĂ©ines cibles) ne semblent pas ĂȘtre diffĂ©rentes entre contrĂŽles et HTAPi, ni Ă lâĂ©tat basal ni en rĂ©ponse Ă diffĂ©rents stress cellulaires inducteurs de p53 (Ă©toposide et H2O2). Cependant, la rĂ©gulation de p53 semble altĂ©rĂ©e puisque nous avons observĂ© une augmentation du taux protĂ©ique de MDM2, principal rĂ©gulateur de p53, dans les CML-AP HTAPi. Ce rĂ©sultat peut ĂȘtre considĂ©rĂ© comme une des caractĂ©ristiques « pseudo-tumorales » des CML-AP HTAPi mais Ă©galement ĂȘtre un Ă©lĂ©ment dĂ©terminant du mĂ©canisme dâaction de la Nutlin-3a, qui a montrĂ© des effets anti-prolifĂ©ratifs accrus dans les CML-AP HTAPi.Dans des Ă©tudes in vivo menĂ©es chez le rat, la protĂ©ine p53 semble jouer un rĂŽle dans lâinitiation de la pathogĂ©nĂšse dâune HTAP. En effet, les taux protĂ©iques pulmonaires de p53, de sa cible p21 et de son rĂ©gulateur (mais Ă©galement cible transcriptionnelle) MDM2 sont diminuĂ©s lors de la premiĂšre semaine dans un modĂšle dâinduction dâHTAP par mono-injection de monocrotaline (MCT) chez le rat, au cours duquel la pathologie se dĂ©veloppe Ă partir de la 2Ăšme semaine. De plus, lâadministration quotidienne Ă des rats dâun inhibiteur de lâactivitĂ© transcriptionnelle de p53, le pifithrin-α (PFT), conduit au dĂ©veloppement dâune HTAP en 14 jours, au mĂȘme titre quâune mono-injection de MCT, et aggrave lâHTAP induite par la MCT. Des effets pro-prolifĂ©ratifs et anti-apoptotiques du PFT rĂ©vĂ©lĂ©s sur des CML-AP indiquent que lâinhibition de lâactivitĂ© transcriptionnelle de p53 est Ă l'origine d'une prolifĂ©ration exagĂ©ree et une rĂ©sistance Ă l'apoptose, deux composantes clĂ©s dans le remaniement vasculaire pulmonaire et le dĂ©veloppement de l'HTAP.En conclusion, ces rĂ©sultats mettent en Ă©vidence lâimplication de lâinactivation de la voie de p53 lors de la phase initiatrice du dĂ©veloppement de lâHTAP, alors quâaux stades tardifs et sĂ©vĂšres de la maladie, il semble il y avoir une normalisation de p53. En revanche, lâaugmentation de lâexpression de son principal rĂ©gulateur MDM2 observĂ©e dans les CML-AP de patients HTAP semble ĂȘtre une cible thĂ©rapeutique potentiellement intĂ©ressante.Pulmonary artery hypertension (PAH) is a severe pulmonary vascular disease characterized by a progressive increase of the pulmonary arterial pressure (PAP), defined by a mean PAP greater than or equal to 25 mmHg at rest. The main symptom is a shortness of breath. An intense pulmonary arterial remodeling that leads to an obstruction of the small pulmonary vessels is responsible of the disease. PAH is a rare but severe disease that develops into right ventricular cardiac failure leading to the patient's death.The general framework of our study was to improve the understanding of the pathophysiology of PAH in order to identify new potential therapeutic targets and improve the clinical management of patients. In particular, we were interested in the âcancer-like phenotypeâ of PAH patient pulmonary arterial smooth muscle cells (PA-SMCs). PA-SMCs play a key role in the pulmonary vascular remodeling of PAH. These cells share characteristics with cancerous cells, such as: exaggerated proliferation, apoptosis resistance, metabolic disorders and genomic instability. Owing to the growth-suppressive and pro-apoptotic functions of p53 protein and its inactivation largely described in cancer, we hypothesized that the p53 pathway could also be altered during PAH development in PA-SMCs.The results of in vitro studies on PA-SMCs of late stage patients with idiopathic PAH (iPAH) versus control patients suggest that the p53 protein nor pathway is not altered in iPAH PA-SMCs. Indeed, the coding sequence of the TP53 gene presented no mutations in iPAH PA-SMCs. Analysis of mRNA and protein levels of p53 and its target proteins showed no difference between controls and iPAH PA-SMCs, neither in a basal state or in response to various cellular stresses such as etoposide and H2O2. However, regulation of p53 may be altered in iPAH PA-SMCs as we observed an increase of the MDM2 (the main p53 regulator) protein level compared to control. This last result may be considered as a âcancer-likeâ characteristic of iPAH PA-SMCs and also be a determining factor in the mechanism of action of Nutlin-3a, which had more important anti-proliferative effects in iPAH PA-SMCs than in control cells.In vivo studies in rats revealed, however, that the p53 pathway may play a role in the initiation stage of PAH pathogenesis. Indeed, kinetics evaluation of p53 lung expression in the PAH model, induced by a single injection of monocrotaline (MCT), revealed a decrease in the p53 protein level during the first week, followed by a normalization by the second week. PAH symptoms are developed in MCT rats after two weeks. Similarly, the protein levels of p21, a p53 target, and MDM2, the major p53 regulator, and also a transcriptional target of p53, decreased during the first week in the MCT-PAH model. In addition, daily treatment in rats with an inhibitor of p53 transcriptional activity, pifithrin-α (PFT), led to the development of PAH in 14 days, similarly to MCT, and worsened the PAH induced by MCT. Pro-apoptotic and anti-proliferative effects of PFT on PA-SMCs indicate that inhibition of p53 transcriptional activity causes an excessive proliferation and an apoptosis resistance, which are two key components of the pulmonary vascular remodeling and development of human and experimental PAH.In conclusion, these results demonstrate the involvement of the p53 pathway inactivation in the initiation stage of PAH development, whereas in late and severe stages of disease, its role seems to be less implicated. In contrast, the increased expression of MDM2 observed in PA-SMCs of PAH patients may be a potential therapeutic target
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