References of "Thiry, Marc"
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See detailDUSP3 Phosphatase Deficiency or Inhibition Limit Platelet Activation and Arterial Thrombosis
Musumeci, Lucia ULg; Kuijpers, Marijke; Gilio, Karen et al

in Circulation (in press)

Background A limitation of current antiplatelet therapies is their inability to separate thrombotic events from bleeding occurrences. Better understanding of the molecular mechanisms leading to platelet ... [more ▼]

Background A limitation of current antiplatelet therapies is their inability to separate thrombotic events from bleeding occurrences. Better understanding of the molecular mechanisms leading to platelet activation is of importance for the development of improved therapies. Recently, protein tyrosine phosphatases (PTPs) have emerged as critical regulators of platelet function. Methods and Results This is the first report implicating the dual-specificity phosphatase 3 (DUSP3) in platelet signaling and thrombosis. This phosphatase is highly expressed in human and mouse platelets. Platelets from DUSP3-deficient mice displayed a selective impairment of aggregation and granule secretion mediated through the collagen receptor glycoprotein VI (GPVI) and the C-type lectin-like receptor 2 (CLEC-2). DUSP3-deficient mice were more resistant to collagen- and epinephrine-induced thromboembolism, compared to wild-type mice, and showed severely impaired thrombus formation upon ferric chloride-induced carotid artery injury. Intriguingly, bleeding times were not altered in DUSP3-deficient mice. At the molecular level, DUSP3 deficiency impaired Syk tyrosine phosphorylation, subsequently reducing phosphorylation of PLCγ2 and calcium fluxes. To investigate DUSP3 function in human platelets, a novel small-molecule inhibitor of DUSP3 was developed. This compound specifically inhibited collagen and CLEC-2-induced human platelet aggregation, thereby phenocopying the effect of DUSP3 deficiency in murine cells. Conclusions DUSP3 plays a selective and essential role in collagen- and CLEC-2-mediated platelet activation and thrombus formation in vivo. Inhibition of DUSP3 may prove therapeutic for arterial thrombosis. This is the first time a PTP, implicated in platelet signaling, has been targeted with a small-molecule drug. [less ▲]

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See detailLa symétrie du vivant : des organismes aux molécules
Thiry, Marc ULg

in Bulletin de la Société Royale des Sciences de Liège (2014, October 28), 83

Les êtres vivants possèdent des caractéristiques communes de symétrie et de dissymétrie. Celles-ci ne concernent pas uniquement l’organisation externe des organismes vivants mais impliquent aussi tous ... [more ▼]

Les êtres vivants possèdent des caractéristiques communes de symétrie et de dissymétrie. Celles-ci ne concernent pas uniquement l’organisation externe des organismes vivants mais impliquent aussi tous leurs niveaux d’organisation jusqu’aux molécules qui les constituent. Le monde vivant se singularise du monde inanimé par l’homochiralité des molécules biologiques. [less ▲]

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See detailUnveiling the effects of berenil, a DNA-binding drug, on Trypanosoma cruzi: implications for kDNA ultrastructure and replication.
Zuma, Aline Araujo; Cavalcanti, Danielle Pereira; Zogovich, Marcelo et al

in Parasitology research (2014)

Trypanosoma cruzi, the etiological agent of Chagas disease, exhibits a single mitochondrion with an enlarged portion termed kinetoplast. This unique structure harbors the mitochondrial DNA (kDNA ... [more ▼]

Trypanosoma cruzi, the etiological agent of Chagas disease, exhibits a single mitochondrion with an enlarged portion termed kinetoplast. This unique structure harbors the mitochondrial DNA (kDNA), composed of interlocked molecules: minicircles and maxicircles. kDNA is a hallmark of kinetoplastids and for this reason constitutes a valuable target in chemotherapeutic and cell biology studies. In the present work, we analyzed the effects of berenil, a minor-groove-binding agent that acts preferentially at the kDNA, thereby affecting cell proliferation, ultrastructure, and mitochondrial activity of T. cruzi epimastigote form. Our results showed that berenil promoted a reduction on parasite growth when high concentrations were used; however, cell viability was not affected. This compound caused significant changes in kDNA arrangement, including the appearance of membrane profiles in the network and electron-lucent areas in the kinetoplast matrix, but nuclear ultrastructure was not modified. The use of the TdT technique, which specifically labels DNA, conjugated to atomic force microscopy analysis indicates that berenil prevents the minicircle decatenation of the network, thus impairing DNA replication and culminating in the appearance of dyskinetoplastic cells. Alterations in the kinetoplast network may be associated with kDNA lesions, as suggested by the quantitative PCR (qPCR) technique. Furthermore, parasites treated with berenil presented higher levels of reactive oxygen species and a slight decrease in the mitochondrial membrane potential and oxygen consumption. Taken together, our results reveal that this DNA-binding drug mainly affects kDNA topology and replication, reinforcing the idea that the kinetoplast represents a potential target for chemotherapy against trypanosomatids. [less ▲]

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See detailβ 5 tubulin and 15-protofilament microtubules appeared in supporting cells of the Corti’s organ during development in rodents
Renauld, Justine ULg; Thelen, Nicolas ULg; Johnen, Nicolas et al

Conference (2014, August 31)

A feature of the organ of Corti’s supporting cells is the presence of an abundant cytoskeleton which is mainly composed of microtubules. These supporting cells have also been shown to contain a minor ... [more ▼]

A feature of the organ of Corti’s supporting cells is the presence of an abundant cytoskeleton which is mainly composed of microtubules. These supporting cells have also been shown to contain a minor mammalian tubulin, the β5-tubulin [1], recently related as a biomarker for cancer outcome [2] and cell proliferation [3]. It was shown that a β-tubulin isoform can specified the microtubule architecture, such as the expression of the Moth β2 in the Drosophila testes imposed the 16 protofilaments (16pf) structure on the corresponding subset of Drosophila microtubules, which normally contain 13pf [4]. Moreover, supporting cell microtubules are formed by 15pf instead of the canonical 13, a unique fact among vertebrates [5]. Such a protofilament configuration has been observed in C. elegans’ neurons which are responsible for the mechanosensory sense of touch [6]. It was also shown that these 15pf microtubules were essential to the proper functioning of these mechanosensory neurons [6]. To determine the role of this particular tubulin in the auditory organ and its possible involvement in the formation of the unusual 15pf microtubules of supporting cells, we studied the spatiotemporal localization of β5-tubulin during development in rats from embryonic day 18 until P25 (25th postnatal day). We also analyzed the localization of β5-tubulin mRNA expression in the Corti’s organ. Then we examined the fine structure of microtubules at the electron microscope level. For these experiments, we used an early postnatal stage and a late postnatal stage. Our results showed that β5-tubulin, contrary to other β-tubulins, had a unique distribution in the cochlea. This β-tubulin appeared at a postnatal stage, before the opening of the Corti’s tunnel and being restricted to supporting cells, especially in pillar and Deiters cells,. The same localization of β5-tubulin mRNA was observed by in Situ Hybridization. Electron microscopy indicated further that Pillar and Deiters cells were composed by 15-protofilament microtubules at the late postnatal stage (P25). In conclusion, all these data strongly suggest that there is a relationship between the presence of β5-tubulin and 15-protofilament microtubules in the supporting cells of the auditory organ. Further studies are now needed to elucidate their role. [less ▲]

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See detailThe Transcription Factor EGR1 Localizes to the Nucleolus and Is Linked to Suppression of Ribosomal Precursor Synthesis
Ponti, Donatella; Bellenchi, Gian Carlo; Puca, Rosa et al

in PLoS ONE (2014), 9(5),

EGR1 is an immediate early gene with a wide range of activities as transcription factor, spanning from regulation of cell growth to differentiation. Numerous studies show that EGR1 either promotes the ... [more ▼]

EGR1 is an immediate early gene with a wide range of activities as transcription factor, spanning from regulation of cell growth to differentiation. Numerous studies show that EGR1 either promotes the proliferation of stimulated cells or suppresses the tumorigenic growth of transformed cells. Upon interaction with ARF, EGR1 is sumoylated and acquires the ability to bind to specific targets such as PTEN and in turn to regulate cell growth. ARF is mainly localized to the periphery of nucleolus where is able to negatively regulate ribosome biogenesis. Since EGR1 colocalizes with ARF under IGF-1 stimulation we asked the question of whether EGR1 also relocate to the nucleolus to interact with ARF. Here we show that EGR1 colocalizes with nucleolar markers such as fibrillarin and B23 in the presence of ARF. Western analysis of nucleolar extracts from HeLa cells was used to confirm the presence of EGR1 in the nucleolus mainly as the 100 kDa sumoylated form. We also show that the level of the ribosomal RNA precursor 47S is inversely correlated to the level of EGR1 transcripts. The EGR1 iseffective to regulate the synthesis of the 47S rRNA precursor. Then we demonstrated that EGR1 binds to the Upstream Binding Factor (UBF) leading us to hypothesize that the regulating activity of EGR1 is mediated by its interaction within the transcriptional complex of RNA polymerase I. These results confirm the presence of EGR1 in the nucleolus and point to a role for EGR1 in the control of nucleolar metabolism. [less ▲]

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See detailBiologie cellulaire. Exercices et méthodes
Thiry, Marc ULg; Racano, Sandra; Rigo, Pierre

Book published by Dunod (2014)

Cet ouvrage propose aux étudiants des premières années d’études supérieures une méthode progressive et conviviale pour comprendre et appliquer les concepts fondamentaux de la biologie cellulaire. Des ... [more ▼]

Cet ouvrage propose aux étudiants des premières années d’études supérieures une méthode progressive et conviviale pour comprendre et appliquer les concepts fondamentaux de la biologie cellulaire. Des bonus web avec des exercices d'entrainement supplémentaires complètent l'ouvrage. Cet ouvrage propose aux étudiants des premières années d’études supérieures une méthode progressive et conviviale pour comprendre et appliquer les concepts fondamentaux de la biologie cellulaire. À la suite de rappels de cours, sous forme de fiches, chaque chapitre propose des exercices de difficulté croissante pour s’évaluer : QCM, questions Vrai/Faux et exercices de synthèse. Les corrigés détaillés mettent en évidence la méthodologie. Des bonus web avec des exercices d’entraînement supplémentaires complètent l’ouvrage. [less ▲]

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See detailVaricella-zoster virus induces the formation of dynamic nuclear capsid aggregates.
Lebrun, Marielle ULg; Thelen, Nicolas ULg; Thiry, Marc ULg et al

in Virology (2014), 454-455

The first step of herpesviruses virion assembly occurs in the nucleus. However, the exact site where nucleocapsids are assembled, where the genome and the inner tegument are acquired, remains ... [more ▼]

The first step of herpesviruses virion assembly occurs in the nucleus. However, the exact site where nucleocapsids are assembled, where the genome and the inner tegument are acquired, remains controversial. We created a recombinant VZV expressing ORF23 (homologous to HSV-1 VP26) fused to the eGFP and dually fluorescent viruses with a tegument protein additionally fused to a red tag (ORF9, ORF21 and ORF22 corresponding to HSV-1 UL49, UL37 and UL36). We identified nuclear dense structures containing the major capsid protein, the scaffold protein and maturing protease, as well as ORF21 and ORF22. Correlative microscopy demonstrated that the structures correspond to capsid aggregates and time-lapse video imaging showed that they appear prior to the accumulation of cytoplasmic capsids, presumably undergoing the secondary egress, and are highly dynamic. Our observations suggest that these structures might represent a nuclear area important for capsid assembly and/or maturation before the budding at the inner nuclear membrane. [less ▲]

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See detailDifferentiation of Boettcher's cells during postnatal development of rat cochlea.
Cloes, Marie ULg; Renson, Thomas; Johnen, Nicolas et al

in Cell and tissue research (2013), 354(3), 707716

Contrary to the highly specialized epithelial cells of the mammalian auditory organ, little is known about the surrounding cells and, in particular, Boettcher's cells (BC). Our morphological studies show ... [more ▼]

Contrary to the highly specialized epithelial cells of the mammalian auditory organ, little is known about the surrounding cells and, in particular, Boettcher's cells (BC). Our morphological studies show that, in rats, these cells began their differentiation around postnatal day 8 (P8) reaching maturity around P20, when they are completely covered by Hensen's and Claudius' cells. Tight junctions were noted near the apex of BC, providing that they were in direct contact with the endolymphatic space, between approximately P8 and P16. We observed gap junctions between BC and adjacent cells before the end of the covering process suggesting the additional involvement of BC in potassium recycling into the endolymph. Adherens junctions were also seen between BC throughout their maturation. Importantly, we noticed cytoplasmic secretory granules and an accumulated material, probably a secretion, in the intercellular space, between P8 and P25. These results indicate that BC could basally take part in the secretion of the extracellular matrix of the basilar membrane. Finally, we show that the basolateral interdigitations of BC are longer and more tighlty grouped at maturity and harbour urea transporters as early as P18. Our observations thus support the view that BC perform several functions. [less ▲]

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See detailClass V β Tubulin during the development of the organ of Corti in rat
Renauld, Justine ULg; Thelen, Nicolas ULg; Johnen, Nicolas ULg et al

Poster (2013, September 13)

In eutherian mammals, the organ responsible for the transduction of sound waves into nerve impulses is called the organ of Corti. This structure located within the cochlea, a portion of the inner ear, is ... [more ▼]

In eutherian mammals, the organ responsible for the transduction of sound waves into nerve impulses is called the organ of Corti. This structure located within the cochlea, a portion of the inner ear, is composed by two types of cells: sensory hair cells and non-sensory supporting cells. All these cells are distributed according to a specific arrangement along the whole length of the cochlea. A feature of the organ of Corti’s supporting cell is the presence of an abundant cytoskeleton. This one is mainly composed of microtubules, structures make up by tubulin heterodimers. The heterodimers consist of one molecule of α tubulin and one molecule of β tubulin. β tubulin isotypes are highly conserved in evolution and differ by only a few amino acid residues, implying that the isotypes may have functional significance. Organ of Corti’s supporting cells are constituted by class V β-tubulin, a minor mammalian tubulin (Bhattacharya et al., 2008). Moreover, their microtubules are formed by 15 protofilaments instead of the canonical 13, a unique fact among vertebrates (Banerjee et al., 2008). Such a configuration of protofilaments has been observed in C. elegans’ neurons which are responsible for the mechanosensory sense of touch (Bounoutas et al., 2009). It was also shown that these 15 protofilaments microtubules were essential to the proper functioning of these mechanosensory neurons (Bounoutas et al., 2009). Here we present the spatiotemporal localization of class V β-tubulin during the development of the organ of Corti in rats from embryonic day 18 (E18) until P25 (25th postnatal day). For this purpose, we have used immunolabelings on cryosections of whole cochlea. Our preliminary results demonstrate that class V β-tubulin has a unique distribution in the cochlea, being restricted to supporting cells, especially in pillar cells. [less ▲]

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See detailHuman papillomavirus entry into NK cells requires CD16 expression and triggers cytotoxic activity and cytokine secretion
Renoux, Virginie; Bisig, Bettina; Langers, Inge ULg et al

Poster (2013, May)

Human papillomavirus (HPV) infections account for more than 50% of infection-linked cancers in women worldwide. The immune system controls, at least partially, viral infection and around 90% of HPV ... [more ▼]

Human papillomavirus (HPV) infections account for more than 50% of infection-linked cancers in women worldwide. The immune system controls, at least partially, viral infection and around 90% of HPV-infected women clear the virus within two years. However, it remains unclear which immune cells are implicated in this process and no study has evaluated the direct interaction between HPVs and NK cells, a key player in host resistance to viruses and tumors. We demonstrated an NK-cell infiltration in HPV- associated preneoplastic cervical lesions. Since HPVs cannot grow in vitro, virus-like particles (VLPs) were used as a model for studying the NK-cell response against the virus. Interestingly, NK cells displayed higher cytotoxic activity and cytokine production (TNF-a and IFN-g) in the presence of HPV-VLPs. Using flow cytometry and microscopy, we observed that NK-cell stimulation was linked to rapid VLP entry into these cells by macropinocytosis. Using CD16+ and CD16- NK-cell lines and a CD16-blocking antibody, we demonstrated that CD16 is necessary for HPV–VLP internalization, as well as for degranulation and cytokine production. Thus, we show for the first time that NK cells interact with HPVs and can participate in the immune response against HPV-induced lesions. [less ▲]

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See detailLymphangiogenesis and extracellular matrix remodeling
Erpicum, Charlotte ULg; Detry, Benoît ULg; Paupert, Jenny ULg et al

Conference (2013, January 28)

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See detailDifferentiation of Boettcher's Cells During Postnatal Development of Rat Cochlea
Cloes, Marie ULg; Renson, Thomas; Johnen, Nicolas ULg et al

Poster (2013, January 28)

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See detailThe Intercellular Transfer of Endothelial-­‐Circulating-­‐MiR-­‐503 Inhibits Tumor Growth
Bovy, Nicolas; Frères, Pierre; Carnet, Oriane et al

Conference (2013, January 28)

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See detailHuman papillomavirus entry into NK cells requires CD16 expression and triggers cytotoxic activity and cytokine secretion.
Renoux, Virginie; Langers, Inge; Dortu, Estelle et al

Conference (2013, January 28)

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See detailDifferentiation of Boettcher’s Cells during Postnatal Development of Rat Cochlea
Cloes, Marie; Renson, Thomas; Johnen, Nicolas et al

Poster (2013, January 28)

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See detailWhole organ culture in rotating bioreactor: the rat embryonic inner ear
Renauld, Justine ULg; Johnen, Nicolas ULg; Hubert, Pascale ULg et al

Poster (2013, January 28)

In eutherian mammals, the organ responsible for the transduction of sound waves into nerve impulses is called the organ of Corti. This structure located within the cochlea, a portion of the inner ear, is ... [more ▼]

In eutherian mammals, the organ responsible for the transduction of sound waves into nerve impulses is called the organ of Corti. This structure located within the cochlea, a portion of the inner ear, is composed by two types of cells: sensory hair cells and non-sensory supporting cells. All these cells are distributed according to a specific arrangement along the whole length of the cochlea. So far, the mammalian inner ear is very sensitive to damage, with no hair cell replacement or cell proliferation occurring in the cochlea. That is why understanding the mechanisms that regulate the mammalian cochlear development is important for pursuing strategies to induce sensory hair cells regeneration. Here, we present a technique of whole embryonic inner ear culture in rotating bioreactors. Besides, we compare two different culture media, DMEM and Neurobasal-A. Rat inner ears are sampled at the 16th embryonic day (E16) and grown in rotating bioreactors during 48h or six days. After 48h, semithin sections realized in the growing cochlea show the development of the ventral epithelium and ultrathin sections confirm the differentiation of the sensory hair cells. Using immunochemistry techniques on our material after 48h or six days in vitro, we show that all the cells of the organ of Corti are differentiating, whichever the culture medium used. Our preliminary results demonstrate that organ culture of the embryonic inner ear in rotating bioreactor is possible. Such a method provides an in vitro model for the investigation of developmental, regulatory, and differentiation processes that could be helpful in the understanding of the mechanisms underlying the development of the mammalian cochlea. [less ▲]

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See detailORF9p phosphorylation by ORF47p is crucial for the formation and egress of the Varicella-zoster virus (VZV) viral particles.
Riva, Laura ULg; Thiry, Marc ULg; BONTEMS, Sébastien ULg et al

in Journal of Virology (2013), 87(5), 2868-2881

The role of the tegument during the herpesvirus lytic cycle is still not clearly established, particularly at the late phase of infection, when the newly produced viral particles need to be fully ... [more ▼]

The role of the tegument during the herpesvirus lytic cycle is still not clearly established, particularly at the late phase of infection, when the newly produced viral particles need to be fully assembled before being released from the infected cell. The Varicella-zoster virus (VZV) protein coded by ORF9 (ORF9p) is an essential tegument protein and, even though its mRNA is the most expressed during the productive infection, little is known about its functions. Using a GalK positive/negative selection technique, we modified a BAC containing the complete VZV genome creating viruses expressing mutant versions of ORF9p.We showed that ORF9p is hyper-phosphorylated during the infection, especially through its interaction with the viral Ser/Thr kinase ORF47p; we identified a consensus site within ORF9p recognized by ORF47p and demonstrated its importance for ORF9p phosphorylation. Strikingly, an ultra-structural analysis revealed that the mutation of this consensus site (Glutamate 85 to Arginine) strongly affects viral assembly and release, reproducing ORF47 kinase dead VZV phenotype. It also slightly diminishes the infectivity towards immature dendritic cells. Taken together, our results identify ORF9p as a new viral substrate of ORF47p and suggest a determinant role of this phosphorylation for viral infectivity, especially during the process of viral particle formation and egress. [less ▲]

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See detailMicroRNA-146a is a therapeutic target and biomarker for peripartum cardiomyopathy.
Halkein, Julie ULg; Tabruyn, Sebastien P.; Ricke-Hoch, Melanie et al

in Journal of Clinical Investigation (2013), 123(5), 2143-54

Peripartum cardiomyopathy (PPCM) is a life-threatening pregnancy-associated cardiomyopathy in previously healthy women. Although PPCM is driven in part by the 16-kDa N-terminal prolactin fragment (16K PRL ... [more ▼]

Peripartum cardiomyopathy (PPCM) is a life-threatening pregnancy-associated cardiomyopathy in previously healthy women. Although PPCM is driven in part by the 16-kDa N-terminal prolactin fragment (16K PRL), the underlying molecular mechanisms are poorly understood. We found that 16K PRL induced microRNA-146a (miR-146a) expression in ECs, which attenuated angiogenesis through downregulation of NRAS. 16K PRL stimulated the release of miR-146a-loaded exosomes from ECs. The exosomes were absorbed by cardiomyocytes, increasing miR-146a levels, which resulted in a subsequent decrease in metabolic activity and decreased expression of Erbb4, Notch1, and Irak1. Mice with cardiomyocyte-restricted Stat3 knockout (CKO mice) exhibited a PPCM-like phenotype and displayed increased cardiac miR-146a expression with coincident downregulation of Erbb4, Nras, Notch1, and Irak1. Blocking miR-146a with locked nucleic acids or antago-miRs attenuated PPCM in CKO mice without interrupting full-length prolactin signaling, as indicated by normal nursing activities. Finally, miR-146a was elevated in the plasma and hearts of PPCM patients, but not in patients with dilated cardiomyopathy. These results demonstrate that miR-146a is a downstream-mediator of 16K PRL that could potentially serve as a biomarker and therapeutic target for PPCM. [less ▲]

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