References of "Luxen, André"
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See detailInterplay between spontaneous and induced brain activity during human non-rapid eye movement sleep.
Dang Vu, Thien Thanh ULg; Bonjean, Maxime; Schabus, Manuel et al

in Proceedings of the National Academy of Sciences of the United States of America (2011), 108(37), 15438-43

Humans are less responsive to the surrounding environment during sleep. However, the extent to which the human brain responds to external stimuli during sleep is uncertain. We used simultaneous EEG and ... [more ▼]

Humans are less responsive to the surrounding environment during sleep. However, the extent to which the human brain responds to external stimuli during sleep is uncertain. We used simultaneous EEG and functional MRI to characterize brain responses to tones during wakefulness and non-rapid eye movement (NREM) sleep. Sounds during wakefulness elicited responses in the thalamus and primary auditory cortex. These responses persisted in NREM sleep, except throughout spindles, during which they became less consistent. When sounds induced a K complex, activity in the auditory cortex was enhanced and responses in distant frontal areas were elicited, similar to the stereotypical pattern associated with slow oscillations. These data show that sound processing during NREM sleep is constrained by fundamental brain oscillatory modes (slow oscillations and spindles), which result in a complex interplay between spontaneous and induced brain activity. The distortion of sensory information at the thalamic level, especially during spindles, functionally isolates the cortex from the environment and might provide unique conditions favorable for off-line memory processing. [less ▲]

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See detailNeural precursors of delayed insight
Darsaud, Annabelle ULg; Wagner, Ullrich; Balteau, Evelyne ULg et al

in Journal of Cognitive Neuroscience (2011), 23(8), 1900-1910

The solution of a problem left unresolved in the evening can sometimes pop into mind as a sudden insight after a night of sleep in the following morning. Although favorable effects of sleep on insightful ... [more ▼]

The solution of a problem left unresolved in the evening can sometimes pop into mind as a sudden insight after a night of sleep in the following morning. Although favorable effects of sleep on insightful behavior have been experimentally confirmed, the neural mechanisms determining this delayed insight remain unknown. Here, using functional magnetic resonance imaging (fMRI), we characterize the neural precursors of delayed insight in the number reduction task (NRT), in which a hidden task structure can be learned implicitly, but can also be recognized explicitly in an insightful process, allowing immediate qualitative improvement in task performance. Normal volunteers practiced the NRT during two fMRI sessions (training and retest), taking place 12 hours apart after a night of sleep. After this delay, half of the subjects gained insight into the hidden task structure ("solvers," S), whereas the other half did not ("nonsolvers," NS). Already at training, solvers and nonsolvers differed in their cerebral responses associated with implicit learning. In future solvers, responses were observed in the superior frontal sulcus, posterior parietal cortex, and the insula, three areas mediating controlled processes and supporting early learning and novice performance. In contrast, implicit learning was related to significant responses in the hippocampus in nonsolvers. Moreover, the hippocampus was functionally coupled with the basal ganglia in nonsolvers and with the superior frontal sulcus in solvers, thus potentially biasing participants' strategy towards implicit or controlled processes of memory encoding, respectively. Furthermore, in solvers but not in nonsolvers, response patterns were further transformed overnight, with enhanced responses in ventral medial prefrontal cortex, an area previously implicated in the consolidation of declarative memory. During retest in solvers, before they gain insight into the hidden rule, significant responses were observed in the same medial prefrontal area. After insight, a distributed set of parietal and frontal areas is recruited among which information concerning the hidden rule can be shared in a so-called global workspace. [less ▲]

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See detailRadiolabeling of modified siRNA by click chemistry with fluorine-18 for PET studies
Flagothier, Jessica ULg; Mercier, Frédéric; Kaisin, Geoffroy ULg et al

in Journal of Labelled Compounds and Radiopharmaceuticals (2011)

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See detailPhotoclick chemistry: Applications to 18F radiotracers preparation
Thonon, David ULg; Goukens, Eve ULg; Kaisin, Geoffroy ULg et al

in Journal of Labelled Compounds and Radiopharmaceuticals (2011)

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See detailSynthesis and hydrolytic stability of novel 3-[18F]fluoroethoxybis(1-methylethyl)silyl]propanamine-based prosthetic groups
Balentova, Eva; Collet, Charlotte; Lamande-Langle, Sandrine et al

in Journal of Fluorine Chemistry (2011), 132(4), 250-257

Two new silicon-based prosthetic groups, derived from 3-[ethoxybis(1-methylethyl)silyl]propanamine, have been prepd. in good yields. These silicon groups bearing an acid or an azide group were coupled to ... [more ▼]

Two new silicon-based prosthetic groups, derived from 3-[ethoxybis(1-methylethyl)silyl]propanamine, have been prepd. in good yields. These silicon groups bearing an acid or an azide group were coupled to a model tripeptide (Leu-Gly- Gly) either through a classical amide bond formation or through "click chem." via the Huisgen cycloaddn. The radiolabeling with fluorine-18 by substitution of the ethoxy group at silicon has been carried out with success in 51-54% decay cor. radiochem. yields. Radiolabeled peptides were easily prepd. by direct 18F-fluorination of the silicon-bearing tripeptide or by coupling the peptide with a radiolabeled silicon-based prosthetic group. Their stabilities in physiol. medium were studied and proved poor. [less ▲]

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See detailStructure-Guided Design of Cell Wall Biosynthesis Inhibitors That Overcome beta-Lactam Resistance in Staphylococcus aureus (MRSA).
Contreras-Martel, Carlos; Amoroso, Ana Maria ULg; Woon, Esther C.Y. et al

in ACS Chemical Biology (2011)

beta-Lactam antibiotics have long been a treatment of choice for bacterial infections since they bind irreversibly to Penicillin-Binding Proteins (PBPs), enzymes that are vital for cell wall biosynthesis ... [more ▼]

beta-Lactam antibiotics have long been a treatment of choice for bacterial infections since they bind irreversibly to Penicillin-Binding Proteins (PBPs), enzymes that are vital for cell wall biosynthesis. Many pathogens express drug-insensitive PBPs rendering beta-lactams ineffective, revealing a need for new types of PBP inhibitors active against resistant strains. We have identified alkyl boronic acids that are active against pathogens including methicillin-resistant S. aureus (MRSA). The crystal structures of PBP1b complexed to 11 different alkyl boronates demonstrate that in vivo efficacy correlates with the mode of inhibitor side chain binding. Staphylococcal membrane analyses reveal that the most potent alkyl boronate targets PBP1, an autolysis system regulator, and PBP2a, a low beta-lactam affinity enzyme. This work demonstrates the potential of boronate-based PBP inhibitors for circumventing beta-lactam resistance and opens avenues for the development of novel antibiotics that target Gram-positive pathogens. [less ▲]

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See detailEffects of light on cognitive brain responses depend on circadian phase and sleep homeostasis.
Vandewalle, Gilles ULg; Archer, Simon N; Wuillaume, Catherine et al

in Journal of biological rhythms (2011), 26(3), 249-59

Light is a powerful modulator of cognition through its long-term effects on circadian rhythmicity and direct effects on brain function as identified by neuroimaging. How the direct impact of light on ... [more ▼]

Light is a powerful modulator of cognition through its long-term effects on circadian rhythmicity and direct effects on brain function as identified by neuroimaging. How the direct impact of light on brain function varies with wavelength of light, circadian phase, and sleep homeostasis, and how this differs between individuals, is a largely unexplored area. Using functional MRI, we compared the effects of 1 minute of low-intensity blue (473 nm) and green light (527 nm) exposures on brain responses to an auditory working memory task while varying circadian phase and status of the sleep homeostat. Data were collected in 27 subjects genotyped for the PER3 VNTR (12 PER3(5/5) and 15 PER3(4/4) ) in whom it was previously shown that the brain responses to this task, when conducted in darkness, depend on circadian phase, sleep homeostasis, and genotype. In the morning after sleep, blue light, relative to green light, increased brain responses primarily in the ventrolateral and dorsolateral prefrontal cortex and in the intraparietal sulcus, but only in PER3(4/4) individuals. By contrast, in the morning after sleep loss, blue light increased brain responses in a left thalamofrontoparietal circuit to a larger extent than green light, and only so in PER3(5/5) individuals. In the evening wake maintenance zone following a normal waking day, no differential effect of 1 minute of blue versus green light was observed in either genotype. Comparison of the current results with the findings observed in darkness indicates that light acts as an activating agent particularly under those circumstances in which and in those individuals in whom brain function is jeopardized by an adverse circadian phase and high homeostatic sleep pressure. [less ▲]

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See detailNew noncovalent inhibitors of penicillin-binding proteins from penicillin-resistant bacteria.
Turk, Samo; Verlaine, Olivier ULg; Gerards, Thomas ULg et al

in PloS one (2011), 6(5), 19418

BACKGROUND: Penicillin-binding proteins (PBPs) are well known and validated targets for antibacterial therapy. The most important clinically used inhibitors of PBPs beta-lactams inhibit transpeptidase ... [more ▼]

BACKGROUND: Penicillin-binding proteins (PBPs) are well known and validated targets for antibacterial therapy. The most important clinically used inhibitors of PBPs beta-lactams inhibit transpeptidase activity of PBPs by forming a covalent penicilloyl-enzyme complex that blocks the normal transpeptidation reaction; this finally results in bacterial death. In some resistant bacteria the resistance is acquired by active-site distortion of PBPs, which lowers their acylation efficiency for beta-lactams. To address this problem we focused our attention to discovery of novel noncovalent inhibitors of PBPs. METHODOLOGY/PRINCIPAL FINDINGS: Our in-house bank of compounds was screened for inhibition of three PBPs from resistant bacteria: PBP2a from Methicillin-resistant Staphylococcus aureus (MRSA), PBP2x from Streptococcus pneumoniae strain 5204, and PBP5fm from Enterococcus faecium strain D63r. Initial hit inhibitor obtained by screening was then used as a starting point for computational similarity searching for structurally related compounds and several new noncovalent inhibitors were discovered. Two compounds had promising inhibitory activities of both PBP2a and PBP2x 5204, and good in-vitro antibacterial activities against a panel of Gram-positive bacterial strains. CONCLUSIONS: We found new noncovalent inhibitors of PBPs which represent important starting points for development of more potent inhibitors of PBPs that can target penicillin-resistant bacteria. [less ▲]

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See detailFully Automated Preparation and Conjugation of N-Succinimidyl 4-[(18)F]Fluorobenzoate ([ (18)F]SFB) with RGD Peptide Using a GE FASTlab Synthesizer.
Thonon, David ULg; Goblet, D.; Goukens, Eve ULg et al

in Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging (2011)

PURPOSE: The aim of this work was to automate the radiosynthesis of [(18)F]SFB, a widely used reagent for the labeling of biomolecules with (18)F on a new generation commercial synthesis module (FASTLab ... [more ▼]

PURPOSE: The aim of this work was to automate the radiosynthesis of [(18)F]SFB, a widely used reagent for the labeling of biomolecules with (18)F on a new generation commercial synthesis module (FASTLab, GE Healthcare). PROCEDURES: Two synthesis approaches were implemented on this module: the classical "two-pot radiosynthesis" and the more recently described "one-pot" method. RESULTS: The "two-pot" approach affords [(18)F]SFB with a 42% decay-corrected yield in 57 min (n = 24) with a chemical purity sufficient to avoid an intermediate HPLC purification. The recently established "one-pot" method, afforded a product with a lower chemical purity, in the conditions used in this report. The lower d.c. yield obtained (32% (n = 15)) was related to the low (18)F labeling yields obtained in MeCN compared with DMSO. The subsequent conjugation step with a RGD (PRGD2) peptide was also successfully automated. CONCLUSIONS: The formulated [(18)F]FPRGD2 was obtained without any operator manipulation with a d.c. yield of 13% +/- 3% (n = 13) in 130 min, a radiochemical purity >98% and a specific activity of 140 +/- 40 TBq/mmol. [less ▲]

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See detailGeneral Method for Labeling siRNA by Click Chemistry with Fluorine-18 for the Purpose of PET Imaging
Mercier, Frédéric; Paris, Jérôme ULg; Kaisin, Geoffroy ULg et al

in Bioconjugate Chemistry (2011), 22(1), 108-114

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See detailNeural correlates of cognitive control at the item level in the Stroop task.
Grandjean, Julien ULg; D'Ostilio, Kevin ULg; Fias, Wim et al

Poster (2010, November 15)

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See detailInfluence of brain-derived neurotrophic factor val66met human polymorphism on declarative memory consolidation
Mascetti, Laura ULg; Foret, Ariane ULg; Matarazzo, Luca et al

Poster (2010, November 15)

The Brain-Derived Neurotrophic Factor (BDNF) is a neurotrophin which in the adult brain regulates long-term potentiation. In humans, valine (val) to methionine (met) substitution in the 5’ pro-region of ... [more ▼]

The Brain-Derived Neurotrophic Factor (BDNF) is a neurotrophin which in the adult brain regulates long-term potentiation. In humans, valine (val) to methionine (met) substitution in the 5’ pro-region of the BDNF protein is associated with poorer episodic memory. Neurons transfected with met-BDNF-Green Fluorescence Protein showed lower depolarization-induced secretion, while constitutive secretion is unchanged. Here, we hypothesized that the differences in BDNF release determined by this polymorphism would influence memory consolidation and that in comparison with the val/met (=val/met or met/met), val/val individuals would show higher memory performance and different brain responses during a 16h-delayed rather than immediate retrieval session. Participants encoded a series of neutral faces in the afternoon. Retrieval sessions took place one hour after the encoding session, and in the following morning, during the acquisition of functional Magnetic Resonance Imaging (fMRI) time series with a 3 Tesla Allegra scanner. During retrieval, studied faces and new ones were presented in random order. For each stimulus, the subjects indicated whether they could retrieve the encoding episode with (“Remember”), or without details (“Know”), or if they thought the item had not been presented during encoding (“New”). A repeated-measure ANOVA on discrimination index (d’) showed significant effects of group (F(1, 27)=8.65, p=0.007, n(val/val)=14, n(val/met)=15) and session (F(1, 27)=24.64, p=0.000), although the group by session interaction was not significant (F(1, 27)=1.29, p=0.267). fMRI results showed a significant genotype (val/val > val/met) by session (delayed > immediate retrieval) by memory type (Remember > Know) interaction in the right inferior occipital gyrus (x=42, y=-78, z=0, p=0.004, Z=3.77), the left inferior parietal lobule (x=-56, y=-40, z=48, p=0.013, Z=3.43), the posterior cingulate cortex (x=14, y=-42, z=42, p=0.019, Z=3.29) and the right hippocampus (x=28, y=-22, z=-22, p=0.03, Z=3.11). Val/val individuals demonstrate higher memory performance than met-carriers but the change in memory performance between immediate and delayed retests is similar in both allelic groups. In contrast, neural correlates of recollection change between sessions differently according to genotype: responses increase significantly more in val/val than in val/met individuals in brain areas involved in the retrieval, accumulation and binding of perceptual memory details during delayed, relative to immediate retest. These data suggest that activity-dependent BDNF release promotes memory consolidation during the first post-training hours. [less ▲]

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See detailIN VIVO PET IMAGING OF THE EFFECT OF THE NMDA ANTAGONIST MEMANTINE ON GLUCOSE METABOLISM IN THE RODENT BRAIN
Warnock, Geoffrey ULg; Dedeurwaerdere, Stefanie; Bahri, Mohamed Ali ULg et al

Poster (2010, September)

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See detailTHE EFFECT OF BETA MICROPROBE IMPLANTATION ON THE BLOOD BRAIN BARRIER
Warnock, Geoffrey ULg; Dedeurwaardere, Stefanie; Bahri, Mohamed Ali ULg et al

Poster (2010, September)

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See detailPolymer micelles decorated by gadolinium complexes as MRI blood contrast agents: design, synthesis and properties
Grogna, Mathurin ULg; Cloots, Rudi ULg; Luxen, André ULg et al

in Polymer Chemistry (2010), 1

New micellar macrocontrast agents with improved contrast at high frequencies were designed by grafting a gadolinium based contrast agent onto functional stealth micelles formed by poly(ethylene oxide)-b ... [more ▼]

New micellar macrocontrast agents with improved contrast at high frequencies were designed by grafting a gadolinium based contrast agent onto functional stealth micelles formed by poly(ethylene oxide)-b-poly(ε-caprolactone) (PEO-b-PCL) in water. As evidenced by relaxometry measurements and the hemolytic CH50 test, the new contrast agents are of interest as MRI blood pool agents. [less ▲]

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See detailClick chemistry : radiolabelling of oligonucleotides with fluorine- 18 for PET
Kaisin, Geoffroy ULg; Flagothier, Jessica ULg; Mercier, Frédéric ULg et al

Poster (2010, June)

Oligonucleotides (ONs), especially small interfering RNA (siRNA), are promising therapeutic agents, but their pharmacokinetics and biodistributions are widely unknown. Positron Emission Tomography (PET ... [more ▼]

Oligonucleotides (ONs), especially small interfering RNA (siRNA), are promising therapeutic agents, but their pharmacokinetics and biodistributions are widely unknown. Positron Emission Tomography (PET) using fluorine-18 is a suitable technique to image and quantify such biological processes. The challenge for the radiochemist is to introduce this short half-life isotope (t1/2(18F)=109.7 min) onto oligonucleotides or, more generally, biomolecules. The most common technique requires the coupling of a prosthetic group bearing the radiotracer with the biomolecule. Current methods for labeling ONs with fluorine-18 have sub-optimal yields and require a long synthesis time.1 Click chemistry, e.g. 1,3-dipolar Huisgen cycloaddition of azides to alkynes, could be an efficient way to increase yields and reduce synthesis time. Conjugations with ONs are usually performed at 3’-ends using a well-chosen linker in order to limit degradation by exonucleases and to avoid alteration of hybridization properties and siRNA gene silencing efficiency. This also allows the development of universal solid supports used for the solidphase synthesis of ONs. Here we report the synthesis of three alkyne-bearing linkers , the synthesis and radiosynthesis of the complementary azido-bearing prosthetic groups (1-(azidomethyl)-4-[18F]- fluorobenzene) and coupling with functionalized ONs. [less ▲]

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See detailAutomated radiosynthesis of [18F]MPPF derivatives for imaging 5-HT1A receptors
Goblet, David ULg; Thonon, David ULg; Plenevaux, Alain ULg et al

Poster (2010, May 30)

TOPIC: Molecular Neuroimaging: from Bench to Bedside Automated radiosynthesis of [18F]MPPF derivatives for imaging 5-HT1A receptors Introduction: Dysfunction of the cerebral serotoninergic system is ... [more ▼]

TOPIC: Molecular Neuroimaging: from Bench to Bedside Automated radiosynthesis of [18F]MPPF derivatives for imaging 5-HT1A receptors Introduction: Dysfunction of the cerebral serotoninergic system is implicated in numerous neurodegenerative disorders such as Alzheimer disease’s, dementia, depression, anxiety, schizophrenia, and Parkinson disease’s. The 5-HT1A serotonin receptors are involved in several physiological functions including sleep, mood, neurogenesis and learning [1]. Consequently, there have been huge efforts in finding ligands for this receptor. [11C]WAY-100635 is a high affinity radioligand used for quantifying serotonin 5-HT1A receptors with positron emission tomography. An 18F-labeled radioligand is advantageous because of higher specific activity and physical/nuclear properties (t1/2= 109 min, 97% of positron decay and positron energy of 635 keV maximum). [18F]MPPF, a selective 5-HT1A antagonist derived from WAY-100635, is currently one of the most successful PET ligand used for 5-HT1A receptor imaging [2]. However the affinity is lower then WAY-100635 and the amount of [18F]MPPF reaching the brain is relatively low since MPPF is a substrate for p-glycoprotein [3]. Methods: In order to improve the brain uptake of the radiotracer, a desmethylated analog has been developed in our lab and preliminary in vitro studies show positive results [4]. Nevertheless, the radiosynthesis take place in two steps as a protecting group removal is needed. A one step procedure with a MPPF derivative could be of very great interest. We have synthesized many MPPF derivatives in our lab (modification on the phenylpiperazine moiety) and developed an automated radiosynthesis procedure for the production of these radiotracers. [18F]MPPF was chosen as the model compound. We used a GE Healthcare FASTlabTM module and made modifications to the [18F]FDG synthesis sequence and cassette. [18F]MPPF was synthesized by coupling of [18F]FBA with the corresponding amine. After coupling, the crude solution was diluted with water and passed through a tC18 cartridge for prepurification. After elution, the [18F]MPPF was purified by semi-preparative HPLC. Results: Total synthesis time, including purification was approximately 100 min. [18F]FBA and [18F]MPPF were obtained at a corrected yield of 55% (n=20) and 25% (n=5) respectively. The radiochemical purity, checked by radio-TLC and UPLC, was >95%. Conclusions: We have developed an automated method for [18F]MPPF and derivatives production using a commercial synthesizer (FASTlabTM from GE Healthcare) and a conventional HPLC system resulting in good yields and high (radio)chemical purity. By simply switching the vial containing the modified amine, an 18F-labeled MPPF derivative could be obtained. Radiosynthesis is still under optimization and the radiotracers synthesized need to be tested as suitable 5-HT1A radioligands. Acknowledgement: This work was supported by the Fondation Rahier. References: [1] Filip M., Bader M. et Al, Pharmacol Rep. 2009 Sep-Oct; 61(5):761-77 [2] Aznavour N, Zimmer L. Et Al, Neuropharmacology. 2007 Mar; 52(3):695-707 [3] Laćan G., Plenevaux A. et Al, Eur J Nucl Med Mol Imaging. 2008 Dec;35(12):2256-66 [4] Defraiteur C., Plenevaux A. et Al., Br J Pharmacol. 2007 Nov; 152(6):952-8 [less ▲]

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