Nouveaux concepts pour une imagerie fonctionnelle des récepteurs sérotoninergiques 5-HT1A et 5-HT6 lors de processus neurodégénératifs

PET imaging using 5-HT1A radiotracers shows a modified expression of this serotonin receptor in the hippocampus of Alzheimer’s disease (AD) patients. However, these antagonists PET radioligands bind indiscriminately to the functional and the non-functional states of 5-HT1A receptors. The comparison of a PET agonist, binding selectively to the functional receptors, with a PET antagonist would therefore provide original information on 5-HT1A receptor impairment during AD. We found that [18F]F15599 in vitro binding decreased in dentate gyrus of AD patients. In contrast, binding of [18F]MPPF was unchanged. These results support the concept of functional PET imaging using agonist radiotracers in clinical studies. Then, we compared with functional MRI (PhMRI) the pharmacological profile of three 5-HT1A agonists (8-OH-DPAT, F13714 and F15599) and one antagonist (MPPF). PhMRI revealed that each molecule has its specific activation pattern, opening new ways in pharmacology or imaging. Finally, we developed in collaboration with chemists several 5-HT6 radioligand-candidates and evaluated their characteristics for PET imaging. Three radiotracers were evaluated in vitro and in vivo in rodent and feline models. We concluded that [18F]2FNQ1P is the first radioligand with suitable characteristics for PET imaging of 5-HT6 receptors, justifying further evaluationsL'imagerie TEP des récepteurs 5-HT1A a montré des modifications de la fixation hippocampique du radioligand antagoniste [18F]MPPF chez des patients souffrant de maladie d'Alzheimer (MA). Si les antagonistes se fixent indistinctement sur les récepteurs fonctionnels et non fonctionnels, les agonistes 5-HT1A, comme le ligand TEP [18F]F15599, ciblent les récepteurs fonctionnels (couplés aux protéines G). Notre objectif est de montrer que le ratio entre les récepteurs 5-HT1A couplés et non couplés varie avec l'évolution de la MA. Ainsi, l'analyse post-mortem d'hippocampes de patients à différents stades de la MA a montré une diminution significative du marquage au [18F]F15599 dès les stades précoces de la MA. Puis nous avons précisé le profil pharmacologique de trois agonistes 5-HT1A : le 8-OH-DPAT, le F13714 et le F15599. L'imagerie IRM fonctionnelle lors de stimuli pharmacologiques (IRMph) permet l'exploration de réseaux neuronaux activés par une molécule. Nous avons comparé chez le rat les cartes d'activation des trois agonistes 5-HT1A et d'un antagoniste, le MPPF. Chaque molécule présente un schéma d'activation spécifique, ouvrant le champ à un ciblage distinct, tant pour la thérapeutique que pour l'imagerie. Enfin, nous avons travaillé à la mise au point d'un radioligand TEP des récepteurs 5-HT6, également impliqués dans la MA. En collaboration avec une équipe de chimistes, nous avons évalué in vitro et in vivo trois radioligands 5-HT6 potentiels. Nous montrons que le radioligand [18F]2FNQ1P est le premier à montrer un ciblage spécifique des récepteurs 5-HT6 in viv

A single events microkinetic model for hydrocracking of vacuum gas oil

International audienceThe single events microkinetic modeling approach is extended to include saturated and unsaturated cyclic molecules, in addition to straight chained paraffins. The model is successfully applied to hydrocracking (HCK) of a hydrotreated Vacuum Gas Oil (VGO) residue in a pilot plant, under industrial operating conditions, on a commercial bi-functional catalyst. The molecular composition of the VGO feed is obtained by reconstruction based on a combination of analytical data (SIMDIS, GCxGC, mass spectroscopy). The necessary extensions to the single events methodology, which has previously only been applied to much simpler reacting systems (i.e. HCK of paraffins) are detailed in this work. Feeds typically used in the petrochemical industry typically contain a far more complex mixture of hydrocarbons, including cyclic species (i.e. naphtenes & aromatics). A more complex reaction network is therefore required in order to apply a single events model to such feeds. Hydrogenation, as well as endo-and exo-cyclic reactions have been added to the well-known acyclic β-scission and PCP-isomerization reactions. A model for aromatic ring hydrogenation was included in order to be able to simulate the reduction in aromatic rings, which is an important feature of HCK units. The model was then applied to 8 mass balances with a wide range of residue conversion (20 – 90%). The single events model is shown to be capable of correctly simulate the macroscopic effluent characteristics, such as residue conversion, yield structure, and weight distribution of paraffinic, naphthenic, and aromatic compounds in the standard cuts. This validates the overall model. The single events model provides far more detail about the fundamental chemistry of the system. This is shown in a detailed analysis of the reaction kinetics. The evolution of molecule size (i.e. carbon number), number of saturated/unsaturated rings, or the ratio of branched and un-branched species can be followed along the reactor. This demonstrates the explanatory power of this type of model. Calculations are performed on the IFPEN high performance computing cluster, with parallelization via MPI (message passing interface). This was very useful in order to reduce time consuming problems especially for the parameter fitting step.

Exploring with [18F]UCB-H the in vivo cariations in SV2A expression through the kainic acid rat model of temporal lobe epilepsy

Purpose The main purpose of this study was to understand how the positron emission tomography (PET) measure of the synaptic vesicle 2A (SV2A) protein varies in vivo during the development of temporal lobe epilepsy (TLE) in the kainic acid rat model. Procedures Twenty Sprague Dawley male rats were administered with multiple systemic doses of saline (control group, n = 5) or kainic acid (5 mg/kg/injection, epileptic group, n = 15). Both groups were scanned at the four phases of TLE (early, latent, transition, and chronic phase) with the [F-18]UCB-H PET radiotracer and T2-structural magnetic resonance imaging. At the end of the scans (3 months post-status epilepticus), rats were monitored for 7 days with electroencephalography for the detection of spontaneous electrographic seizures. Finally, the immunofluorescence staining for SV2A expression was performed. Results Control rats presented a significant increase in [F-18]UCB-H binding at the last two scans, compared with the first ones (p < 0.001). This increase existed but was lower in epileptic animals, producing significant group differences in all the phases of the disease (p < 0.028). Furthermore, the quantification of the SV2A expression in vivo with the [F-18]UCB-H radiotracer or ex vivo with immunofluorescence led to equivalent results, with a positive correlation between both. Conclusions Even if further studies in humans are required, the ability to detect a progressive decrease in SV2A expression during the development of temporal lobe epilepsy supports the use of [F-18]UCB-H as a useful tool to differentiate, in vivo, between healthy and epileptic animals along with the development of the epileptic disease

Diverging trends and drivers of Arctic flower production in Greenland over space and time

The Arctic is warming at an alarming rate. While changes in plant community composition and phenology have been extensively reported, the effects of climate change on reproduction remain poorly understood. We quantified multidecadal changes in flower density for nine tundra plant species at a low- and a high-Arctic site in Greenland. We found substantial changes in flower density over time, but the temporal trends and drivers of flower density differed both between species and sites. Total flower density increased over time at the low-Arctic site, whereas the high-Arctic site showed no directional change. Within and between sites, the direction and rate of change differed among species, with varying effects of summer temperature, the temperature of the previous autumn and the timing of snowmelt. Finally, all species showed a strong trade-off in flower densities between successive years, suggesting an effective cost of reproduction. Overall, our results reveal region- and taxon-specific variation in the sensitivity and responses of co-occurring species to shared climatic drivers, and a clear cost of reproductive investment among Arctic plants. The ultimate effects of further changes in climate may thus be decoupled between species and across space, with critical knock-on effects on plant species dynamics, food web structure and overall ecosystem functioning

Simultaneous X-ray radiography and diffraction topography imaging applied to silicon for defect analysis during melting and crystallization

International audienceSynopsis A setup for simultaneous, time-resolved X-ray radiography and diffraction topography imaging is presented. It is used to study defect generation and growth mechanisms during heating, solidification and cooling of a silicon crystal. Abstract One of the key issues to be resolved to improve the performance of silicon solar cells is to reduce crystalline defect formation and propagation during the growth process fabrication step. For this purpose, the generation of structural defects such as grain boundaries and dislocations in silicon must be understood and characterised. We combine in situ X-ray diffraction imaging, historically named topography, with radiography imaging to analyse the development of crystal defects before, during and after crystallisation. Two individual indirect detector systems are implemented to record simultaneously the crystal structure (topographs) and the solid-liquid morphology evolution (radiographs) at high temperature. This allows for a complete synchronisation of the images and for an increased image acquisition rate compared to previous studies that used X-ray sensitive films to record the topographs. The experiments are performed with X-ray synchrotron radiation at beamline ID19 at the European Synchrotron Radiation Facility (ESRF). We present in situ observations of the heating, melting, solidification and holding stages of silicon samples to demonstrate that with the upgraded setup detailed investigations of time-dependent phenomena are now possible. The motion of dislocations is recorded during the entire experiment, so that their interaction with grain boundaries and their multiplication through the activation of Frank-Read sources can be observed. Moreover, the capability to record with two camera-based detectors allows for the study of the relationship between strain distribution, twinning and nucleation events. In conclusion, the simultaneous recording of topographs and radiographs has great potential for further detailed investigations of the interaction and generation of grains and defects that influence the growth process and the final crystalline structure in silicon and other crystalline materials

Tests with a Carlina-type diluted telescope; Primary coherencing

Studies are under way to propose a new generation of post-VLTI interferometers. The Carlina concept studied at the Haute- Provence Observatory is one of the proposed solutions. It consists in an optical interferometer configured like a diluted version of the Arecibo radio telescope: above the diluted primary mirror made of fixed cospherical segments, a helium balloon (or cables suspended between two mountains), carries a gondola containing the focal optics. Since 2003, we have been building a technical demonstrator of this diluted telescope. First fringes were obtained in May 2004 with two closely-spaced primary segments and a CCD on the focal gondola. We have been testing the whole optical train with three primary mirrors. The main aim of this article is to describe the metrology that we have conceived, and tested under the helium balloon to align the primary mirrors separate by 5-10 m on the ground with an accuracy of a few microns. The servo loop stabilizes the mirror of metrology under the helium balloon with an accuracy better than 5 mm while it moves horizontally by 30 cm in open loop by 10-20 km/h of wind. We have obtained the white fringes of metrology; i.e., the three mirrors are aligned (cospherized) with an accuracy of {\approx} 1 micron. We show data proving the stability of fringes over 15 minutes, therefore providing evidence that the mechanical parts are stabilized within a few microns. This is an important step that demonstrates the feasibility of building a diluted telescope using cables strained between cliffs or under a balloon. Carlina, like the MMT or LBT, could be one of the first members of a new class of telescopes named diluted telescopes.Comment: 18 pages, 17 figures, A&A, accepte

Optical Probing of Ultrafast Laser-Induced Solid-to-Overdense-Plasma Transitions

Understanding the target dynamics during its interaction with a relativistic ultrashort laser pulse is a challenging fundamental multi-physics problem involving at least atomic and solid-state physics, plasma physics, and laser physics. Already, the properties of the so-called pre-plasma formed as the laser pulse's rising edge ionizes the target are complicated to access in experiments and modeling, and many aspects of this laser-induced transition from solid to overdense plasma over picosecond time scales are still open questions. At the same time, applications like laser-driven ion acceleration require precise knowledge and control of the pre-plasma because the efficiency of the acceleration process itself crucially depends on the target properties at the arrival of the relativistic intensity peak of the pulse. By capturing the dynamics of the initial stage of the interaction, we report on a detailed visualization of the pre-plasma formation and evolution. Nanometer-thin diamond-like carbon foils are shown to transition from solid to plasma during the laser rising edge with intensities < 10^16 W/cm^2. Single-shot near-infrared probe transmission measurements evidence sub-picosecond dynamics of an expanding plasma with densities above 10^23 cm^-3 (about 100 times the critical plasma density). The complementarity of a solid-state interaction model and a kinetic plasma description provides deep insight into the interplay of ionization, collisions, and expansion

Investigation of subgrains in directionally solidified cast mono-seeded silicon and their interactions with twin boundaries

Directional solidification of a cast mono silicon seed and of a float-zone (FZ) silicon seed was performed and the grain and defect structures of the seeds as well as of the regrown parts are analyzed. In situ X-ray diffraction imaging enabled the observation of the dislocation arrangements. During the heating process, in the FZ seed, mobile dislocations glide on {111} planes, whereas in the cast mono seed dislocations are arranged in a mainly immobile cellular structure. Ex situ grain orientation mappings reveal the presence of subgrains with misorientations up to 3◦ in the regrown part of the cast mono-seeded sample, which are not observed in the regrown part of the FZ-seeded sample. Subgrain boundaries characterized by misorientations around the [001] growth axis propagate roughly along the growth axis and increase their misorientation by merging with new subgrain boundaries appearing in their vicinity. Although the first inception of subgrain formation cannot be revealed, the comparison of the dislocation arrangements in the two seeds strongly suggests an influence of the latter on subgrain formation. In the regrown part, interactions between subgrain boundaries and twin boundaries show that they can follow Σ3{111} and Σ9{221} grain boundaries or cross Σ3{111} grain boundaries. Whether Σ3 {111} GBs are crossed or not depends among other things on the orientation of the grains on either side of the twin. It demonstrates that the grain orientation relationship and not only the grain boundary character play an important role in the subgrain structure evolution and redistribution in a multicrystalline silicon ingot

The asparagine-transamidosome from Helicobacter pylori: a dual-kinetic mode in non-discriminating aspartyl-tRNA synthetase safeguards the genetic code

Helicobacter pylori catalyzes Asn-tRNAAsn formation by use of the indirect pathway that involves charging of Asp onto tRNAAsn by a non-discriminating aspartyl-tRNA synthetase (ND-AspRS), followed by conversion of the mischarged Asp into Asn by the GatCAB amidotransferase. We show that the partners of asparaginylation assemble into a dynamic Asn-transamidosome, which uses a different strategy than the Gln-transamidosome to prevent the release of the mischarged aminoacyl-tRNA intermediate. The complex is described by gel-filtration, dynamic light scattering and kinetic measurements. Two strategies for asparaginylation are shown: (i) tRNAAsn binds GatCAB first, allowing aminoacylation and immediate transamidation once ND-AspRS joins the complex; (ii) tRNAAsn is bound by ND-AspRS which releases the Asp-tRNAAsn product much slower than the cognate Asp-tRNAAsp; this kinetic peculiarity allows GatCAB to bind and transamidate Asp-tRNAAsn before its release by the ND-AspRS. These results are discussed in the context of the interrelation between the Asn and Gln-transamidosomes which use the same GatCAB in H. pylori, and shed light on a kinetic mechanism that ensures faithful codon reassignment for Asn

In vivo exploration of synaptic projections in frontotemporal dementia.

The purpose of this exploratory research is to provide data on synaptopathy in the behavioral variant of frontotemporal dementia (bvFTD). Twelve patients with probable bvFTD were compared to 12 control participants and 12 patients with Alzheimer’s disease (AD). Loss of synaptic projections was assessed with ­[18F]UCBH-PET. Total distribution volume was obtained with Logan method using carotid artery derived input function. Neuroimages were analyzed with SPM12. Verbal fluency, episodic memory and awareness of cognitive impairment were equally impaired in patients groups. Compared to controls, ­[18F]UCBH uptake tended to decrease in the right anterior parahippocampal gyrus of bvFTD patients. Loss of synaptic projections was observed in the right hippocampus of AD participants, but there was no significant difference in ­[18F]UCBH brain uptake between patients groups. Anosognosia for clinical disorder was correlated with synaptic density in the caudate nucleus and the anteromedial prefrontal cortex. This study suggests that synaptopathy in bvFTD targets the temporal social brain and self-referential processes