High genetic variability and low local diversity in a population of arbuscular mycorrhizal fungi.

Arbuscular mycorrhizal fungi (AMF) are ecologically important root symbionts of most terrestrial plants. Ecological studies of AMF have concentrated on differences between species; largely assuming little variability within AMF species. Although AMF are clonal, they have evolved to contain a surprisingly high within-species genetic variability, and genetically different nuclei can coexist within individual spores. These traits could potentially lead to within-population genetic variation, causing differences in physiology and symbiotic function in AMF populations, a consequence that has been largely neglected. We found highly significant genetic and phenotypic variation among isolates of a population of Glomus intraradices but relatively low total observed genetic diversity. Because we maintained the isolated population in a constant environment, phenotypic variation can be considered as variation in quantitative genetic traits. In view of the large genetic differences among isolates by randomly sampling two individual spores, <50% of the total observed population genetic diversity is represented. Adding an isolate from a distant population did not increase total observed genetic diversity. Genetic variation exceeded variation in quantitative genetic traits, indicating that selection acted on the population to retain similar traits, which might be because of the multigenomic nature of AMF, where considerable genetic redundancy could buffer the effects of changes in the genetic content of phenotypic traits. These results have direct implications for ecological research and for studying AMF genes, improving commercial AMF inoculum, and understanding evolutionary mechanisms in multigenomic organisms.

Monoclonal antibodies to carcinoembryonic antigen: ionic strength as a factor in the selection of antibodies for immunoscintigraphy.

As part of an ongoing effort to improve the technique of immunoscintigraphy for the detection of human carcinomas with radiolabeled monoclonal antibodies (MABs) to carcinoembryonic antigen (CEA), we have developed a series of MABs to CEA and have studied the effects of low- and physiological molarity buffers on their CEA binding and affinity, as well as their cross-reactivity with granulocyte glycoprotein(s). These in vitro results in different buffer systems were then correlated with the use of these MABs to CEA in the detection of human colon carcinoma grafts in nude mice. Our results show that the binding of CEA by some MABs is influenced by ionic strength and that this may be an important factor in their successful use for the immunolocalization of carcinomas in vivo.

Organizing principles across the senses

ABSTRACT This thesis is composed of two main parts. The first addressed the question of whether the auditory and somatosensory systems, like their visual counterpart, comprise parallel functional pathways for processing identity and spatial attributes (so-called `what' and `where' pathways, respectively). The second part examined the independence of control processes mediating task switching across 'what' and `where' pathways in the auditory and visual modalities. Concerning the first part, electrical neuroimaging of event-related potentials identified the spatio-temporal mechanisms subserving auditory (see Appendix, Study n°1) and vibrotactile (see Appendix, Study n°2) processing during two types of blocks of trials. `What' blocks varied stimuli in their frequency independently of their location.. `Where' blocks varied the same stimuli in their location independently of their frequency. Concerning the second part (see Appendix, Study n°3), a psychophysical task-switching paradigm was used to investigate the hypothesis that the efficacy of control processes depends on the extent of overlap between the neural circuitry mediating the different tasks at hand, such that more effective task preparation (and by extension smaller switch costs) is achieved when the anatomical/functional overlap of this circuitry is small. Performance costs associated with switching tasks and/or switching sensory modalities were measured. Tasks required the analysis of either the identity or spatial location of environmental objects (`what' and `where' tasks, respectively) that were presented either visually or acoustically on any given trial. Pretrial cues informed participants of the upcoming task, but not of the sensory modality. - In the audio-visual domain, the results showed that switch costs between tasks were significantly smaller when the sensory modality of the task switched versus when it repeated. In addition, switch costs between the senses were correlated only when the sensory modality of the task repeated across trials and not when it switched. The collective evidence not only supports the independence of control processes mediating task switching and modality switching, but also the hypothesis that switch costs reflect competitive interterence between neural circuits that in turn can be diminished when these neural circuits are distinct. - In the auditory and somatosensory domains, the findings show that a segregation of location vs. recognition information is observed across sensory systems and that these happen around 100ms for both sensory modalities. - Also, our results show that functionally specialized pathways for audition and somatosensation involve largely overlapping brain regions, i.e. posterior superior and middle temporal cortices and inferior parietal areas. Both these properties (synchrony of differential processing and overlapping brain regions) probably optimize the relationships across sensory modalities. - Therefore, these results may be indicative of a computationally advantageous organization for processing spatial anal identity information.

The Pseudomonas aeruginosa toxin L-2-amino-4-methoxy-trans-3-butenoic acid inhibits growth and induces encystment in Acanthamoeba castellanii.

L-2-Amino-4-methoxy-trans-3-butenoic acid (AMB) is a toxic antimetabolite produced by the opportunistic pathogen Pseudomonas aeruginosa. To evaluate its importance as a potential virulence factor, we tested the host response towards AMB using an Acanthamoeba castellanii cell model. We found that AMB (at concentrations ≥ 0.5 mM) caused amoebal encystment in salt buffer, while inhibiting amoebal growth in rich medium in a dose-dependent manner. However, no difference in amoebal plaque formation was observed on bacterial lawns of wild type and AMB-negative P. aeruginosa strains. We thereby conclude that AMB may eventually act as a virulence factor, but only at relatively high concentrations.

Rapid affinity purification of erythropoietin from biological samples using disposable monoliths.

Identification of post-translational modifications of proteins in biological samples often requires access to preanalytical purification and concentration methods. In the purification step high or low molecular weight substances can be removed by size exclusion filters, and high abundant proteins can be removed, or low abundant proteins can be enriched, by specific capturing tools. In this paper is described the experience and results obtained with a recently emerged and easy-to-use affinity purification kit for enrichment of the low amounts of EPO found in urine and plasma specimens. The kit can be used as a pre-step in the EPO doping control procedure, as an alternative to the commonly used ultrafiltration, for detecting aberrantly glycosylated isoforms. The commercially available affinity purification kit contains small disposable anti-EPO monolith columns (6 ?L volume, Ø7 mm, length 0.15 mm) together with all required buffers. A 24-channel vacuum manifold was used for simultaneous processing of samples. The column concentrated EPO from 20 mL urine down to 55 ?L eluate with a concentration factor of 240 times, while roughly 99.7% of non-relevant urine proteins were removed. The recoveries of Neorecormon (epoetin beta), and the EPO analogues Aranesp and Mircera applied to buffer were high, 76%, 67% and 57%, respectively. The recovery of endogenous EPO from human urine was 65%. High recoveries were also obtained when purifying human, mouse and equine EPO from serum, and human EPO from cerebrospinal fluid. Evaluation with the accredited EPO doping control method based on isoelectric focusing (IEF) showed that the affinity purification procedure did not change the isoform distribution for rhEPO, Aranesp, Mircera or endogenous EPO. The kit should be particularly useful for applications in which it is essential to avoid carry-over effects, a problem commonly encountered with conventional particle-based affinity columns. The encouraging results with EPO propose that similar affinity monoliths, with the appropriate antibodies, should constitute useful tools for general applications in sample preparation, not only for doping control of EPO and other hormones such as growth hormone and insulin but also for the study of post-translational modifications of other low abundance proteins in biological and clinical research, and for sample preparation prior to in vitro diagnostics.

Simultaneous determination of antidementia drugs in human plasma: Procedure transfer from HPLC-MS to UPLC-MS/MS.

A previously developed high performance liquid chromatography mass spectrometry (HPLC-MS) procedure for the simultaneous determination of antidementia drugs, including donepezil, galantamine, memantine, rivastigmine and its metabolite NAP 226-90, was transferred to an ultra performance liquid chromatography system coupled to a tandem mass spectrometer (UPLC-MS/MS). The drugs and their internal standards ([(2)H(7)]-donepezil, [(13)C,(2)H(3)]-galantamine, [(13)C(2),(2)H(6)]-memantine, [(2)H(6)]-rivastigmine) were extracted from 250μL human plasma by protein precipitation with acetonitrile. Chromatographic separation was achieved on a reverse phase column (BEH C18 2.1mm×50mm; 1.7μm) with a gradient elution of an ammonium acetate buffer at pH 9.3 and acetonitrile at a flow rate of 0.4mL/min and an overall run time of 4.5min. The analytes were detected on a tandem quadrupole mass spectrometer operated in positive electrospray ionization mode, and quantification was performed using multiple reaction monitoring. The method was validated according to the recommendations of international guidelines over a calibration range of 1-300ng/mL for donepezil, galantamine and memantine, and 0.2-50ng/mL for rivastimgine and NAP 226-90. The trueness (86-108%), repeatability (0.8-8.3%), intermediate precision (2.3-10.9%) and selectivity of the method were found to be satisfactory. Matrix effects variability was inferior to 15% for the analytes and inferior to 5% after correction by internal standards. A method comparison was performed with patients' samples showing similar results between the HPLC-MS and UPLC-MS/MS procedures. Thus, this validated UPLC-MS/MS method allows to reduce the required amount of plasma, to use a simplified sample preparation, and to obtain a higher sensitivity and specificity with a much shortened run-time.

A CRTC1 deficient mouse line study : relevance to mood disorders

Summary Mood disorders are among the most prevalent, psychosocial^ debilitating, chronic and relapsing forms of psychiatric illnesses. Despite considerable advances in their characterization, the heterogeneous nature of susceptibility factors and patient's symptoms could account for the lack of totally effective and remissive treatment. The neurobiological hypothesis of mood disorders etiology has evolved since the monoamine and neurotrophin theories and current evidence is pointing toward their integration in a broader polygenic epistatic model resulting in defective neuroplasticity of circuitries involved in emotion processing. Consequently, the unraveling of molecular underpinning pathways involved in neuronal plasticity, commonly altered among mood disorder syndromes and symptoms, should shed light on their etiology and provide new drug target. The transcription factor CREB has been critically involved in the long-lasting forms of neuronal plasticity and in the regulation of several mood disorders susceptibility genes. In addition, altered CREB activity has been associated with mood disorders pathophysiology and pharmacotherapy. Interestingly, the newly-identified protein CREB-regulated transcription coactivator 1 (CRTC1) was shown by previous studies in the laboratory to be a neuroactivity- dependent cAMP and calcium sensor, a potent activator of CREB-dependent transcription and involved in neuroplasticity mechanisms associated with long-term synaptic potentiation. Furthermore, the major mood disorder susceptibility gene Bdnf was suggested to be transcriptional regulated by CRTC1. Therefore, we aimed to investigate a role for CRTC1 in mood disorders by generating and characterizing a Crtcl deficient mouse model at the behavioral and molecular levels. Interestingly, their comprehensive characterization revealed a behavioral profile mirroring several major symptoms comorbid in mood disorders, including altered social interactions, aggressive behaviors, obesity, psychomotor retardation, increased emotional response to stress, decreased sexual drive and depression-like behaviors. To investigate the molecular mechanisms underlying these pathological behaviors and the implication of CRTC1 in the regulation of CREB-regulated genes in vivo, we also quantified transcript levels of several relevant CREB-regulated susceptibility genes in brain structures involved in the pathophysiology of mood disorders. Strikingly, we found the underexpression of primary components of the neurotrophin system: Bdnf and its cognate receptor TrkB, a marked decrease in the Nr4a family of transcription factors, implicated in neuroplasticity and associated with dopamine-related disorders, as well as in several other relevant CREB regulated genes. Moreover, neurochemical analysis revealed that Crtcl null mice presented alteration in prefrontal cortical monoamine turnover as well as in hippocampal and accumbal serotonin levels, similarly associated with mood disorders etiology and pharmacotherapy. Together, the present thesis supports the involvement of CRTC1 pathway hypofunction in the pathogenesis of mood disorders and specifically in pathological aggression, obesity and depression-related behavior comorbidities. Ultimately, CRTC1 may represent an interesting antidepressant, antiaggressive or mood stabilizer drug target candidate through the modulation of major CREB regulated susceptibility genes. Les troubles de l'humeur comptent parmi les maladies psychiatriques les plus prévalentes, psychosocialement débilitantes, chroniques et avec le plus grand risque de rechute. Malgré de considérable avancées dans leur caractérisation, la nature hétérogène des facteurs de susceptibilité et des symptômes présentés par les patients, semble justifier l'absence de traitement entraînant une rémission complète de la maladie. L'hypothèse de l'étiologie neurobiologique des troubles de l'humeur a évolué depuis la théorie des monoamines et des neurotrophines. Actuellement, elle tend à les englober dans un modèle polygénique épistatique induisant une déficience de la neuroplasticité des circuits impliqué dans la régulation des émotions. Par conséquent, il apparaît particulièrement relevant de caractériser des voies moléculaires impliquées dans la plasticité neuronale, communément altérées parmi les différents syndromes et symptômes des maladies de l'humeur, afin d'améliorer leur compréhension ainsi que de proposer de nouvelles cibles thérapeutiques potentielles. Le facteur de transcription CREB a été de façon répétée et cohérente impliqué dans les mécanismes à long terme de la plasticité neuronale, ainsi que dans la régulation de plusieurs gènes de susceptibilité aux maladies de l'humeur. De plus, une altération dans l'activité de CREB a été impliqué dans leur étiologie et pharmacothérapie. De façon intéressante, des résultats préliminaires sur la protéine récemment découverte CREB-regulated transcription coactivator 1 (CRTC1) ont indiqué que son activation était dépendante de l'activité neuronale, qu'il était un senseur du calcium et de l'AMPc, ainsi qu'un coactivateur de CREB requis et puissant impliqué dans les mécanismes de plasticité neuronale associés à la potentialisation à long terme. En outre, des résultats ont suggéré que le gène majeur de susceptibilité Bdnf est régulé par CRTC1. Ainsi, notre objectif a été d'investiguer un rôle éventuel de CRTC1 dans les maladies de l'humeur en générant et caractérisant une lignée de souris déficiente pour Crtcl, tant au niveau comportemental que moléculaire. De façon intéressante, leur caractérisation détaillée a révélé un profil comportemental reflétant de nombreux aspects des maladies de l'humeur incluant une altération des interactions sociales, une agression pathologique, l'obésité, un retard psychomoteur, une réponse émotionnelle au stress accrue, une diminution de la motivation sexuelle, et des comportements reliés à la dépression. Afin d'investiguer les mécanismes moléculaires sous- jacents cette altération du comportement, ainsi que l'implication de CRTC1 dans l'expression des gènes régulés par CREB in vivo, nous avons quantifié les niveaux de transcrits de plusieurs gènes de susceptibilité régulés par CREB et impliqués dans la physiopathologie des maladies de l'humeur. Remarquablement, nous avons trouvé la sous-expression de composants primordiaux du système neurotrophique: Bdnf et son récepteur TrkB, une diminution majeure de la famille des facteurs de transcription Nr4a, impliqués dans la neuroplasticité et associés à des désordres liés à la dopamine, ainsi que de nombreux autres gènes relevants régulés par CREB. De plus, une analyse neurochimique a révélé que les souris déficientes pour Crtcî présentent une altération du turn-over des monoamines du cortex préfrontal ainsi que des niveaux hippocampaux et accumbaux de sérotonine, associés de façon similaire dans l'étiologie et la pharmacothérapie des maladies de l'humeur. Vue dans son ensemble, la présente thèse supporte l'implication d'une sous-régulation de la voie de CRTCI dans la pathogenèse des maladies de l'humeur ainsi que dans la comorbidité de l'agression pathologique, l'obésité et la dépression. En conclusion, CRTCI pourrait représenter une cible médicamenteuse intéressante aux propriétés antidépressante, antiagressive ou stabilisatrice de l'humeur au travers de la modulation de gènes de susceptibilité majeurs régulés par CREB.

Thyroid hormone in biodegradable nerve guides stimulates sciatic nerve regeneration: a potential therapeutic approach for human peripheral nerve injuries.

It has been already demonstrated that thyroid hormone (T3) is one of the most important stimulating factors in peripheral nerve regeneration. We have recently shown that local administration of T3 in silicon tubes at the level of the transected rat sciatic nerve enhanced axonal regeneration and improved functional recovery. Silicon, however, cannot be used in humans because it causes a chronic inflammatory reaction. Therefore, in order to provide future clinical applications of thyroid hormone in human peripheral nerve lesions, we carried out comparative studies on the regeneration of transected rat sciatic nerve bridged either by biodegradable P(DLLA-(-CL) or by silicon nerve guides, both guides filled with either T3 or phosphate buffer. Our macroscopic observation revealed that 85% of the biodegradable guides allowed the expected regeneration of the transected sciatic nerve. The morphological, morphometric and electrophysiological analysis showed that T3 in biodegradable guides induces a significant increase in the number of myelinated regenerated axons (6862 +/- 1831 in control vs. 11799 +/- 1163 in T3-treated). Also, T3 skewed the diameter of myelinated axons toward larger values than in controls. Moreover, T3 increases the compound muscle action potential amplitude of the flexor and extensor muscles of the treated rats. This T3 stimulation in biodegradable guides was equally well to that obtained by using silicone guides. In conclusion, the administration of T3 in biodegradable guides significantly improves sciatic nerve regeneration, confirming the feasibility of our technique to provide a serious step towards future clinical application of T3 in human peripheral nerve injuries.

Simultaneous determination of antidementia drugs by HPLC-MS: validation data of the method and plasma level determinations in 300 patients

Aims: A rapid and simple HPLC-MS method was developed for the simultaneousdetermination of antidementia drugs, including donepezil, galantamine, rivastigmineand its major metabolite NAP 226 - 90, and memantine, for TherapeuticDrug Monitoring (TDM). In the elderly population treated with antidementiadrugs, the presence of several comorbidities, drug interactions resulting frompolypharmacy, and variations in drug metabolism and elimination, are possiblefactors leading to the observed high interindividual variability in plasma levels.Although evidence for the benefit of TDM for antidementia drugs still remains tobe demonstrated, an individually adapted dosage through TDM might contributeto minimize the risk of adverse reactions and to increase the probability of efficienttherapeutic response. Methods: A solid-phase extraction procedure with amixed-mode cation exchange sorbent was used to isolate the drugs from 0.5 mL ofplasma. The compounds were analyzed on a reverse-phase column with a gradientelution consisting of an ammonium acetate buffer at pH 9.3 and acetonitrile anddetected by mass spectrometry in the single ion monitoring mode. Isotope-labeledinternal standards were used for quantification where possible. The validatedmethod was used to measure the plasma levels of antidementia drugs in 300patients treated with these drugs. Results: The method was validated accordingto international standards of validation, including the assessment of the trueness(-8 - 11 %), the imprecision (repeatability: 1-5%, intermediate imprecision:2 - 9 %), selectivity and matrix effects variability (less than 6 %). Furthermore,short and long-term stability of the analytes in plasma was ascertained. Themethod proved to be robust in the calibrated ranges of 1 - 300 ng/mL for rivastigmineand memantine and 2 - 300 mg/mL for donepezil, galantamine and NAP226 - 90. We recently published a full description of the method (1). We found ahigh interindividual variability in plasma levels of these drugs in a study populationof 300 patients. The plasma level measurements, with some preliminaryclinical and pharmacogenetic results, will be presented. Conclusion: A simpleLC-MS method was developed for plasma level determination of antidementiadrugs which was successfully used in a clinical study with 300 patients.

Late Proterozoic thrust tectonics, high-pressure metamorphism and Uranium mineralization in the domes area, Lufilian arc, northwestern Zambia

The following main lithostratigraphic units have been distinguished in the Domes Area. The Kibaran basement complex composed of gneisses, migmatites with amphibolite bands and metagranites is exposed in dome structures; metamorphic features of Kibaran age have been almost completely obliterated by extensive Lufilian reactivation. The post-Kibaran cover sequence is subdivided into the Lower Roan Group consisting of well-preserved quartzites with high Mg content, talc-bearing, extremely foliated schists intercalated with pseudo-conglomerates of tectonic origin and the Upper Roan Group including dolomitic marbles with rare stromatolites, metapelites and a sequence of detrital metasediments, with local volcano-sedimentary components and interlayered banded ironstones. The sediments of the Lower Roan Group are interpreted as continental to lagoonal-evaporitic deposits partly converted into the talc-kyanite + garnet assemblage characteristic of ``white schists''. The dolomites and metapelites of the Upper Roan Group are attributed to a carbonate platform sequence progressively subsiding under terrigenous deposits, whilst the detrital metasediments and BIF may be interpreted as a basinal sequence, probably deposited on oceanic crust grading laterally into marbles. Metagabbros and metabasalts are considered as remnants of an ocean-floor-type crustal unit probably related to small basins. Alkaline stocks of Silurian age intruded the post-Kibaran cover. Significant ancestral tectonic discontinuities promoted the development of a nappe pile that underwent high-pressure metamorphism during the Lufilian orogeny and all lithostratigraphic units. Rb-Sr and K-Ar and U-Pb data indicate an age of 700 Ma for the highest grade metamorphism and 500 Ma for blocking of the K-Ar and Rb-Sr system in micas, corresponding to the time when the temperature dropped below 350-degrees-400-degrees-C and to an age of about 400 Ma for the emplacement of hypabyssal syenitic bodies. A first phase of crustal shortening by decoupling of basement and cover slices along shallow shear zones has been recognized. Fluid-rich tectonic slabs of cover sediments were thus able to transport fluids into the anhydrous metamorphic basement or mafic units. During the subsequent metamorphic re-equilibration stage of high pressure, pre-existing thrusts horizons were converted into recrystallized mylonites. Due to uplift, rocks were re-equilibrated into assemblages compatible with lower pressures and slightly lower temperatures. This stage occurs under a decompressional (nearly adiabatic) regime, with P(fluid) almost-equal-to P(lithostatic). It is accompanied by metasomatic development of minerals, activated by injection of hot fluids. New or reactivated shear zones and mylonitic belts were the preferred conduits of fluids. The most evident regional-scale effect of these processes is the intense metasomatic scapolitization of formerly plagioclase-rich lithologies. Uraninite mineralization can probably be assigned to the beginning of the decompressional stage. A third regional deformation phase characterized by open folds and local foliation is not accompanied by significant growth of new minerals. However, pitchblende mineralization can be ascribed to this phase as late-stage, short-range remobilization of previously existing deposits. Finally, shallow alkaline massifs were emplaced when the level of the Domes Area now exposed was already subjected to exchange with meteoric circuits, activated by residual geothermal gradients generally related to intrusions or rifting. Most of the superficial U-showings with U-oxidation products were probably generated during this relatively recent phase.

Evolving olfactory systems on the fly.

The detection of odour stimuli in the environment is universally important for primal behaviours such as feeding, mating, kin interactions and escape responses. Given the ubiquity of many airborne chemical signals and the similar organisation of animal olfactory circuits, a fundamental question in our understanding of the sense of smell is how species-specific behavioural responses to odorants can evolve. Recent comparative genomic, developmental and physiological studies are shedding light on this problem by providing insights into the genetic mechanisms that underlie anatomical and functional evolution of the olfactory system. Here we synthesise these data, with a particular focus on insect olfaction, to address how new olfactory receptors and circuits might arise and diverge, offering glimpses into how odour-evoked behaviours could adapt to an ever-changing chemosensory world.

7

Evidence of altered antioxidant systems and signs of elevated oxidative stress are reported in peripheral tissue and brain of schizophrenic patients, including low levels of glutathione (GSH), a major thiol antioxidant and redox buffer. Functional and genetic data indicate that an impaired regulation of GSH synthesis is a vulnerability factor for the disease. Impaired GSH synthesis from a genetic origin combined with environmental risk factors generating oxidative stress (e.g., malnutrition, exposure to toxins, maternai infection and diabetes, obstetrical complications, and psychological stress) could lead to redox dysregulation. This could subsequently perturb normal brain development and maturation with delayed functional consequences emerging in early adulthood. Depending on the nature and the time of occurrence of the environmental insults, the structural and functional delayed consequences could vary, giving rise to various endophenotypes. The use of animal models of GSH deficit represents a valuable approach to investigate how interactions between genetic and environmental factors lead to the emergence of pathologies found in the disease. Moreover, these models of GSH can be useful to investigate links between schizophrenia and comorbid somatic disorders, as dysregulation of the GSH system and elevated oxidative stress are also found in cardiovascular diseases and diabetes. This chapter reviews pharmacological and genetic rodent models of GSH synthesis dysregulation used to address some of the aforementioned issues. Up to date, these models revealed that GSH deficits lead to morphological, physiological, and behavioral alterations that are quite analogous to pathologies observed in patients. This includes hypofunction of NMDA receptors, alteration of dopamine neurotransmission, anomalies in parvalbumin-immunoreactive fast-spiking interneurons, and reduced myelination. In addition, a GSH deficit affects the brain in a region-specific manner, the anterior cingulate cortex and the ventral hippocampus being the most vulnerable regions investigated. Interestingly, a GSH deficit during a limited period of postnatal development is sufficient to have long-lasting consequences on the integrity of PV-IR interneurons in the anterior cingulate cortex and impairs cognitive functions in adulthood. Finally, these animal models of GSH deficit display behavioral impairments that could be related to schizophrenia. Altogether, current data strongly support a contributing role of a redox dysregulation on the development of pathologies associated with the illness and demonstrate the usefulness of these models to better understand the biological mechanisms leading to schizophrenia.

Thyroid hormone enhances transected axonal regeneration and muscle reinnervation following rat sciatic nerve injury.

Improvement of nerve regeneration and functional recovery following nerve injury is a challenging problem in clinical research. We have already shown that following rat sciatic nerve transection, the local administration of triiodothyronine (T3) significantly increased the number and the myelination of regenerated axons. Functional recovery is a sum of the number of regenerated axons and reinnervation of denervated peripheral targets. In the present study, we investigated whether the increased number of regenerated axons by T3-treatment is linked to improved reinnervation of hind limb muscles. After transection of rat sciatic nerves, silicone or biodegradable nerve guides were implanted and filled with either T3 or phosphate buffer solution (PBS). Neuromuscular junctions (NMJs) were analyzed on gastrocnemius and plantar muscle sections stained with rhodamine alpha-bungarotoxin and neurofilament antibody. Four weeks after surgery, most end-plates (EPs) of operated limbs were still denervated and no effect of T3 on muscle reinnervation was detected at this stage of nerve repair. In contrast, after 14 weeks of nerve regeneration, T3 clearly enhanced the reinnervation of gastrocnemius and plantar EPs, demonstrated by significantly higher recovery of size and shape complexity of reinnervated EPs and also by increased acetylcholine receptor (AChRs) density on post synaptic membranes compared to PBS-treated EPs. The stimulating effect of T3 on EP reinnervation is confirmed by a higher index of compound muscle action potentials recorded in gastrocnemius muscles. In conclusion, our results provide for the first time strong evidence that T3 enhances the restoration of NMJ structure and improves synaptic transmission.

Brain structure in movement disorders: a neuroimaging perspective.

Purpose of review: An overview of recent advances in structural neuroimaging and their impact on movement disorders research is presented. Recent findings: Novel developments in computational neuroanatomy and improvements in magnetic resonance image quality have brought further insight into the pathophysiology of movement disorders. Sophisticated automated techniques allow for sensitive and reliable in-vivo differentiation of phenotype/genotype related traits and their interaction even at presymptomatic stages of disease. Summary: Voxel-based morphometry consistently demonstrates well defined patterns of brain structure changes in movement disorders. Advanced stages of idiopathic Parkinson's disease are characterized by grey matter volume decreases in basal ganglia. Depending on the presence of cognitive impairment, volume changes are reported in widespread cortical and limbic areas. Atypical Parkinsonian syndromes still pose a challenge for accurate morphometry-based classification, especially in early stages of disease progression. Essential tremor has been mainly associated with thalamic and cerebellar changes. Studies on preclinical Huntington's disease show progressive loss of tissue in the caudate and cortical thinning related to distinct motor and cognitive phenotypes. Basal ganglia volume in primary dystonia reveals an interaction between genotype and phenotype such that brain structure changes are modulated by the presence of symptoms under the influence of genetic factors. Tics in Tourette's syndrome correlate with brain structure changes in limbic, motor and associative fronto-striato-parietal circuits. Computational neuroanatomy provides useful tools for in-vivo assessment of brain structure in movement disorders, allowing for accurate classification in early clinical stages as well as for monitoring therapy effects and/or disease progression.

Of housing and politics : mapping political opportunities for mobilising in Bangalore, India

Quelles sont les conditions pour l'émergence d'une mobilisation sociale en faveur du logement convenable dans la métropole de Bangalore (Inde)? Cette question, qui est au coeur de cette thèse, est particulièrement pertinente dans le contexte d'une ville où 1,7 million de personnes, soit un cinquième de la population, vit dans des bidonvilles. L'absence d'un mouvement mettant en cause l'échec des politiques publiques du logement est intéressante dans la mesure où l'Inde a hérité un système de gouvernance colonial et d'une tradition de mouvements sociaux. Pour répondre à ce questionnement, un cadre théorique issu de la littérature sur les mouvements sociaux est développé. Il s'articule autour des liens entre les opportunités politiques au niveau macro et les répertoires d'action des organisations de mouvement social (OMS) au niveau méso, de la tension entre la formalité de la loi et des politiques publiques et l'informalité des circuits d'échange, de la corruption et du clientélisme, et enfin, se focalise sur les systèmes de discours de caste et de la citoyenneté et de leur concrétisation dans des systèmes d'organisations et de réseaux sociaux. Ce cadre théorique permet d'étudier empiriquement la question à travers quatre OMS dans la ville de Bangalore. Les résultats mettent en avant l'existence de mécanismes complexes. Les opportunités politiques formelles n'étant ouvertes que sur le plan rhétorique, elles ne peuvent être véritablement utilisées que par des moyens légaux ou contentieux, ce qui nécessite des compétences sociales dont la plupart des habitants des bidonvilles sont dépourvus. L'inadéquation entre les ressources à disposition pour les logements sociaux et les besoins très importants des pauvres, donne un poids politique considérable aux acteurs en charge de l'attribution de ces ressources rares. Cet état de fait a des répercussions sur la politique électorale. Les habitants des bidonvilles représentant un poids électoral important, ils sont mobilisés à travers de pratiques clientélistes. La corruption et le clientélisme se nourrissent mutuellement pour maintenir une certaine dépendance des habitants. Les OMS qui développent un répertoire discursif remettant en cause le système de caste et qui encouragent une conscience citoyenne, se sont avérées les plus durables pour résister à la cooptation des forces politiques. Cette recherche empirique met en lumière l'inadéquation entre les prescriptions formelles dans le domaine de la gouvernance des besoins humains, tels que le logement, et les pratiques réelles sur le terrain. Cette recherche appelle à réfléchir au-delà de la diffusion du discours sur la « bonne gouvernance » vers des formes de « gouvernance vernaculaire » qui prendrait au sérieux l'informalité en développant une compréhension des avantages à court terme pour les personnes marginalisées dans la ville et les effets à long terme sur la pratique démocratique. - What are the conditions for the emergence of a social movement on the issue of adequate housing in the metropolitan city of Bangalore (India)? This question is at the heart of this dissertation and is particularly pertinent against the background that an estimated 1.7 million or about 20% of the city's population lives in slums. The absence of a movement addressing the failure of public housing policy despite India having inherited colonial systems of governance and traditions of movement is noteworthy. Answers are sought within a theoretical framework stemming from social movement theories that incorporates three linkages articulating around: Macro-level political opportunities and meso-level action repertoires of social movement organisations (SMOs), tensions between the formality of law, policy and the informality of exchange circuits of corruption and clientelism and finally around systems of discourses of caste and citizenship and their instantiation in concrete systems of social organisations and networks. This thesis is empirically investigated through a qualitative case study research design involving four sampled social movement organisations. The results bring complex mechanisms to the fore. Formal political opportunities are only rhetorically open and have to be cracked through legal weaponry or contentious escalation, which requires considerable social skills that slum-dwellers often lack. The inadequacy between the few housing resources and the vast number of slum-dwellers transform housing benefits and urban service provisions into political currency. Such a state of affairs has serious repercussions on conditions for mobilisation. They become imbricated with electoral logic, in which slum-dwellers represent large vote-banks and where corruption and clientelism feed each other to maintain a certain dependency of the poor. SMOs deploying a discursive repertoire that questioned the caste system and encouraged a pursuit of citizenship proved to be the most sustainable to resist co-option from political forces. This empirical investigation brings to light the mismatch between the formal prescriptions in the domain of the governance of basic human needs such as housing and the real practices on the ground. This research calls to reflect beyond the inadequacy of the diffused « good governance » discourse towards forms of « vernacular governance » that take informality seriously in understanding the short-term benefits for the marginalised in the city and the long-term effects on democratic practice.