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See detailDEVELOPMENT OF PHARMACOLOGICAL TOOLS FOR THE IDENTIFICATION OF G PROTEIN-COUPLED RECEPTORS LIGANDS
Gilissen, Julie ULg

Doctoral thesis (2016)

G protein-coupled receptors (GPCRs) represent the protein family most successfully targeted for treating human diseases. They couple to G proteins to mobilize second messenger pathways that lead to ... [more ▼]

G protein-coupled receptors (GPCRs) represent the protein family most successfully targeted for treating human diseases. They couple to G proteins to mobilize second messenger pathways that lead to cellular responses and ultimately to physiological changes. However many are poorly characterized with few ligands reported or remain completely orphans. Therefore, there is a growing need for screening-compatible and sensitive assays in order to identify new ligands. The present project aims at developing pharmacological tools to characterize the pharmacology and physiology of GPCRs. Our approach rely on i) development of receptor models and assays for the identification of ligands, ii) screening of chemical and virtual small molecules libraries and iii) analysis of structure-activity relationships study of active molecules. The project has been divided in two parts. To set-up assays for the evaluation of GPCRs activation, we selected the understudied succinate receptor 1 (SUCNR1) that is proposed to affect cellular metabolism and pathophysiology of diseases in multiple organs. Nevertheless the receptor has never been validated as a drug target because very few ligands have been described. So, developing pharmacological tools for SUCNR1 remains of great interest in therapeutic drug discovery. First, we have started by examining SUCNR1 signaling pathways in HEK293 cells. Our investigations have highlighted the efficient coupling to Gαi and thus the negative modulation of intracellular cAMP levels. Consequently we have implemented an assay sensitive to cAMP variations to identify ligands able to induce SUCNR1 activation. However, an important drawback to track agonists for Gαi-coupled receptors is the mandatory stimulation of cAMP levels. Inducers such as forskolin must be used and are sources of variations and errors. In order to avoid these artifacts we have set-up and validated a cAMP-inducer free method based on the GloSensor biosensor. This real time assay was amenable to high-throughput screening for the detection of Gαi-coupled receptors agonists. The strategy monitoring basal cAMP levels compared to the stimulated cAMP levels allowed to decrease recording time and artifcats from forskolin use, leading to the identification of fewer false positives and unidentified false negatives. Although both methods found agonists in the chemical library screened, no active new scaffolds on SUCNR1 were discovered. We infer that this method could facilitate the study and screening of Gαi-coupled receptors for active ligands. Secondly, given the interesting potential of SUCNR1 for promising therapeutic advances, we have carried out the study of the receptor interaction with its natural ligand, succinate. We have optimized the previous three-dimensional model for SUCNR1 binding pocket by means of more detailed structure-activity relationships study of succinate related molecules. The study of structure-activity relationships performed by Pierre Geubelle, in parallel to this work, allowed the deduction of the structural elements required to be active on SUCNR1. Thus we have defined a pharmacophore for activity on the receptor and subsequently evaluated various cycloalkanes. With our cAMP assay, Pierre Geubelle has highlighted the (1R, 2S)-1,2-cyclopropanedicarboxylate to be able to activate SUCNR1. We confirmed the activity of this compound on SUCNR1 capacity to recruit arrestin 3 and determined the pharmacological properties of this new ligand as SUCNR1 agonist, in vitro and in vivo. To confirm our in vitro results, we have also assessed the hypertensive properties of this cyclic analogue. Intravenous addition at the dose of 0.1 mg.kg-1 in rats has been demonstrated to increase blood pressure in the same range as succinate. Consequently we have demonstrated that (1R, 2S)-1,2-cyclopropanedicarboxylate could be regarded as an original synthetic full agonist for SUCNR1. In addition, the pharmacophore for SUCNR1 should help to generate synthetic compounds characterized by an increased potency and/or efficacy compared to succinate. [less ▲]

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See detailDevelopment of photo- or thermo-reversible cross-linked recyclable shape-memory materials
Defize, Thomas ULg; Riva, Raphaël ULg; Thomassin, Jean-Michel ULg et al

Conference (2015, September 01)

Shape-memory polymers (SMPs) are remarkable materials able to switch from a stressed deformed state (temporary shape) to their initial relaxed state (permanent shape) by the application of a stimulus ... [more ▼]

Shape-memory polymers (SMPs) are remarkable materials able to switch from a stressed deformed state (temporary shape) to their initial relaxed state (permanent shape) by the application of a stimulus, such as heat or light. Typically, the shape-memory property is generally observed for chemically or physically cross-linked polymers that exhibit an elastomeric behavior above a phase transition, e.g. glass or melting transition. As an example, cross-linked semi-crystalline poly(ε-caprolactone) (PCL) is widely studied for the development of SMPs. As most of SMPs are irreversibly cross-linked material, their reprocessing is impossible preventing any recycling. Thereby, reversible reactions, allowing the formation/cleavage of the network, raise tremendous interest for the development of new SMPs. Recently, we reported the preparation reversibly cross-linked PCL-based SMP using the Diels-Alder (DA) reaction between furan and maleimide end-groups of 4-arm star-shaped PCL, well-known to create reversible bonds. After implementation, this shape-memory material was demonstrated to be recyclable, and was characterized by excellent fixity and recovery before and after recycling experiments. However, the relatively low retro DA temperature of the furan-maleimide adducts led to an inelastic deformation during shape-memory tensile cycles. In order to get rid of this drawback, an alternative approach was investigated. The substitution of the DA reaction by a photo-reversible reaction, typically the photo-induced (2+2) cycloaddition of coumarins, was proposed to prepare cross-linked PCL matrix presenting one-way and two-way memory properties, since photolabile adducts are supposed to be stable during shape-memory tensile cycles. [less ▲]

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See detailDevelopment of pH–responsive nanocarriers using trimethylchitosans and methacrylic acid copolymer for siRNA delivery
Dehousse, Vincent ULg; Garbacki, Nancy ULg; Colige, Alain ULg et al

in Biomaterials (2010), 31

RNA interference-based therapies are dependent on intracellular delivery of siRNA. The release of siRNA from the endosomal compartment may be a rate limiting step in the transfection process. The purpose ... [more ▼]

RNA interference-based therapies are dependent on intracellular delivery of siRNA. The release of siRNA from the endosomal compartment may be a rate limiting step in the transfection process. The purpose of this study was to produce pH–responsive nanocarriers made of trimethylchitosan (TMC). To this end, pHsensitive methacrylic acid (MAA) copolymer was added to TMC–siRNA formulations. Four different TMCs associated or not with MAA were evaluated as siRNA carriers. Nanoparticles were characterized in terms of size, surface charge, morphology and interaction with siRNA. A swelling behaviour due to a decrease in pH was observed and was found to be dependent on MAA content in the complexes. In vitro experiments aimed at evaluating how the capacity of the nanocarriers to transfect siRNA in L929 cells was affected by MAA content. Confocal microscopy experiments showed that fluorescent MAA-containing particles exhibit a different distribution pattern inside the cells comparing to their counterpart without this pH-sensitive polymer. Transfection efficiency was investigated by RhoA mRNA expression inhibition. MAA–TMC–siRNA complexes were able to transfect L929 cells with greater efficiency than corresponding TMC–siRNA complexes. This study gives an insight into the opportunity of pH-sensitive nanocarriers for siRNA delivery. Such formulations may represent an attractive strategy to improve endosomal escape of siRNA. [less ▲]

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See detailDevelopment of pilot Trans-European service (Rhine-Main-Danube) for combined freight transport between Walloon region and the Black Sea
Marchal, Jean ULg; Kicheva, D.; Petkov, N. et al

in Eigth international conference on Marine sciences and Technologies “Balack Sea 2006” (2006, September)

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See detailDevelopment of polymer-based systems for healthcare applications
Grandfils, Christian ULg

Conference (2016, October 06)

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See detailDevelopment of Procedural Learning in Children : The “Toy Task”
Lejeune, Caroline ULg; Meulemans, Thierry ULg

Poster (2008)

The authors generally agree that procedural learning abilities play an important role in the child development and that they are present early in childhood. However, few studies have been carried out in ... [more ▼]

The authors generally agree that procedural learning abilities play an important role in the child development and that they are present early in childhood. However, few studies have been carried out in this area because of the difficulty to develop tests specifically designed for the evaluation of these capacities in young children. In this study, we presented a new task aimed to evaluate visuo-motor skill learning in the young child. The purpose of the present study was to explore whether procedural learning abilities are present in the same extent in 4-year as 7- and 10-year-old children. Our sample is composed of 60 children divided into 3 age-groups. The task is composed of 5 blocks of 12 trials during which each subject has to use a reversed mouse of a computer in order to “catch” different toys appearing on the screen; 2 blocks of 12 trials was administered after a 15 minutes delay. Our results show an important difference between the groups for the first block; on the other hand, for the next blocks, the results show an absence of age-related difference between participants in our perceptive-motor skill learning task, confirming the idea according to which procedural learning abilities are efficient early in development (the difference observed during the first block being probably due to the intervention of executive mechanisms). [less ▲]

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See detailDevelopment of process control system for potential use of direct injection spraying technology
Aissaoui, Abdellah; Lebeau, Frédéric ULg; el bahir, et al

in Progress in Agricultural Engineering Sciences (2011), 7(1), 33-45

Small-scale farmers face to actual difficulties of applying pesticides accurately and safely on vegetables crops. They mainly use hand operated sprayers. As an issue, a small direct injection system based ... [more ▼]

Small-scale farmers face to actual difficulties of applying pesticides accurately and safely on vegetables crops. They mainly use hand operated sprayers. As an issue, a small direct injection system based on a five meter’s parallel boom layout was designed to improve chemical application. The boom layout was optimized to obtain the same minimal time lag response for the ten nozzles. The dynamic of the system was modeled using Simulink TM as first order model with delay. Two control strategies were implemented using PID (Proportional Integral Derivative) feedback control loops to monitor tracer injection (fluorescing) proportionally to simulated forward speed (from 0.6 to 1.2 m/s) and to control the constant operating pressure (constant carrier flow strategy) or the variable operating pressure proportionally to the injected chemical amount (variable total flow strategy). Different forward speed changes were induced using steps up and down, ramps, sine waves and sweeps excitations to evaluate the control feedback. The system stability was tested for its ability to maintain the expected concentration and application rate. The results show that the time lag remains less than 3 s (dead time < 2 s, time constant < 1 s) and the system keeps stable for the maximal speed variation (ΔV) and acceleration (ā) tested (ΔV = 200%, ā = 0.48 m/s2) which induce less than 10% variation of application rate. [less ▲]

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See detailDevelopment of products for GNSS users at the Belgian Solar-Terrestrial Centre of Excellence
Warnant, René ULg; Lejeune, Sandrine; Stankov, Stanimir et al

Conference (2008, December)

Detailed reference viewed: 121 (22 ULg)
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See detailDevelopment of PSII photochemistry after a single white flash in etiolated barley leaves
Franck, Fabrice ULg

in Baltscheffsky, M. (Ed.) Current Research in Photosynthesis (1990)

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See detailDevelopment of psoriasiform skin lesions under anti-TNF therapy: a genetic link?
Cleynen, I.; Claes, B.; Nuytten, H. et al

in Conference Abstract Book (2008)

Detailed reference viewed: 23 (3 ULg)
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See detailDevelopment of pure prolactin receptor antagonists
Bernichtein, Sophie; Kayser, Christine; Dillner, Karin et al

in Journal of Biological Chemistry (2003), 278(38), 35988-99

Prolactin (PRL) promotes tumor growth in various experimental models and leads to prostate hyperplasia and mammary neoplasia in PRL transgenic mice. Increasing experimental evidence argues for the ... [more ▼]

Prolactin (PRL) promotes tumor growth in various experimental models and leads to prostate hyperplasia and mammary neoplasia in PRL transgenic mice. Increasing experimental evidence argues for the involvement of autocrine PRL in this process. PRL receptor antagonists have been developed to counteract these undesired proliferative actions of PRL. However, all forms of PRL receptor antagonists obtained to date exhibit partial agonism, preventing their therapeutic use as full antagonists. In the present study, we describe the development of new human PRL antagonists devoid of agonistic properties and therefore able to act as pure antagonists. This was demonstrated using several in vitro bioassays, including highly sensitive assays able to detect extremely low levels of receptor activation. These new compounds also act as pure antagonists in vivo, as assessed by analyzing their ability to competitively inhibit PRL-triggered signaling cascades in various target tissues (liver, mammary gland, and prostate). Finally, by using transgenic mice expressing PRL specifically in the prostate, which exhibit constitutively activated signaling cascades paralleling hyperplasia, we show that these new PRL analogs are able to completely revert PRL-activated events. These second generation human PRL antagonists are good candidates to be used as inhibitors of growth-promoting actions of PRL. [less ▲]

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See detailDevelopment of Purkinje cells in the ovine brain
Salouci, Moustafa ULg; Engelen, Virginie; Gyan, Mathilda et al

Scientific conference (2012)

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See detailDevelopment of Purkinje cells in the ovine brain
Salouci, Moustafa ULg; Engelen, Virginie; Gyan, Mathilda et al

Poster (2013, July 18)

Purkinje cells are involved in many vital functions within the body. Twenty ovine fetuses ranging from 2 to 5 months of gestation, two lambs in the first week after birth and three adult sheep were ... [more ▼]

Purkinje cells are involved in many vital functions within the body. Twenty ovine fetuses ranging from 2 to 5 months of gestation, two lambs in the first week after birth and three adult sheep were studied. Sections of the cerebellum were stained with haematoxylin and eosin, cresyl violet and Klu¨ver–Barrera. This study indicates that Purkinje cells began to appear after the 15th week of gestation. There were varying degrees of development of Purkinje cells in different zones of the cerebellum. Our findings in sheep fetuses suggest that the maturation of Purkinje cells starts in the caudal regions of the cerebellum and that the process begins in the vermis before it does in the cerebellar hemispheres. The alignment of Purkinje cells was found to be very regular in the caudal regions of the cerebellum. A partial absence of Purkinje cells in the rostral regions of the cerebellum was observed in both sheep fetuses and adult sheep. In the first post-natal week, some ectopic Purkinje cells were found in the white matter of the cerebellum. [less ▲]

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See detailDevelopment of Purkinje cells in the ovine brain
Salouci, Moustafa ULg; Engelen, Virginie; Gyan, Mathilda et al

in Anatomia, Histologia, Embryologia (2012), 41(3), 227232

Purkinje cells are involved in many vital functions within the body. Twenty ovine fetuses ranging from 2 to 5 months of gestation, two lambs in the first week after birth and three adult sheep were ... [more ▼]

Purkinje cells are involved in many vital functions within the body. Twenty ovine fetuses ranging from 2 to 5 months of gestation, two lambs in the first week after birth and three adult sheep were studied. Sections of the cerebellum were stained with haematoxylin and eosin, cresyl violet and Klu¨ver–Barrera. This study indicates that Purkinje cells began to appear after the 15th week of gestation. There were varying degrees of development of Purkinje cells in different zones of the cerebellum. Our findings in sheep fetuses suggest that the maturation of Purkinje cells starts in the caudal regions of the cerebellum and that the process begins in the vermis before it does in the cerebellar hemispheres. The alignment of Purkinje cells was found to be very regular in the caudal regions of the cerebellum. A partial absence of Purkinje cells in the rostral regions of the cerebellum was observed in both sheep fetuses and adult sheep. In the first post-natal week, some ectopic Purkinje cells were found in the white matter of the cerebellum. [less ▲]

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See detailDevelopment of quantification methods applied to HSS alloys for carbides volume fraction and grain size assessments
Tchuindjang, Jérôme Tchoufack ULg; Paydas, Hakan ULg; Hashemi, Seyedeh Neda ULg et al

Poster (2015, July)

High speed steels (HSS) are used in applications where enhanced mechanical properties together with hot oxidation and wear resistances are required. Such an improved physico-chemical behaviour is mainly ... [more ▼]

High speed steels (HSS) are used in applications where enhanced mechanical properties together with hot oxidation and wear resistances are required. Such an improved physico-chemical behaviour is mainly due to the presence of primary carbides within the microstructure. Depending of the initial chemical composition several types of carbides can precipitate in HSS such as MC (Nb and V-rich), M2C (Mo and W-rich), Cr-rich M7C3, etc. Two groups of HSS were analysed in this study, which are the so-called cast HSS grades that are manufactured by a centrifugal casting process and the cladded HSS manufactured by laser cladding. Purpose: Quantify the carbide volume fractions and the grain size within HSS grades in order to set correlations between the microstructure and both the mechanical and the tribological properties of the materials. Findings: The metallurgical features such as carbides nature and shape have been determined that are related to the manufacturing process of the studied material, and several methods have been used to quantify the carbide volume fractions and to assess the grain size. [less ▲]

Detailed reference viewed: 54 (8 ULg)