Quantifying consistency of Event Related Potentials across subjects based on single-trial topographic analysis

Introduction: Non-invasive brain imaging techniques often contrast experimental conditions across a cohort of participants, obfuscating distinctions in individual performance and brain mechanisms that are better characterised by the inter-trial variability. To overcome such limitations, we developed topographic analysis methods for single-trial EEG data [1]. So far this was typically based on time-frequency analysis of single-electrode data or single independent components. The method's efficacy is demonstrated for event-related responses to environmental sounds, hitherto studied at an average event-related potential (ERP) level. Methods: Nine healthy subjects participated to the experiment. Auditory meaningful sounds of common objects were used for a target detection task [2]. On each block, subjects were asked to discriminate target sounds, which were living or man-made auditory objects. Continuous 64-channel EEG was acquired during the task. Two datasets were considered for each subject including single-trial of the two conditions, living and man-made. The analysis comprised two steps. In the first part, a mixture of Gaussians analysis [3] provided representative topographies for each subject. In the second step, conditional probabilities for each Gaussian provided statistical inference on the structure of these topographies across trials, time, and experimental conditions. Similar analysis was conducted at group-level. Results: Results show that the occurrence of each map is structured in time and consistent across trials both at the single-subject and at group level. Conducting separate analyses of ERPs at single-subject and group levels, we could quantify the consistency of identified topographies and their time course of activation within and across participants as well as experimental conditions. A general agreement was found with previous analysis at average ERP level. Conclusions: This novel approach to single-trial analysis promises to have impact on several domains. In clinical research, it gives the possibility to statistically evaluate single-subject data, an essential tool for analysing patients with specific deficits and impairments and their deviation from normative standards. In cognitive neuroscience, it provides a novel tool for understanding behaviour and brain activity interdependencies at both single-subject and at group levels. In basic neurophysiology, it provides a new representation of ERPs and promises to cast light on the mechanisms of its generation and inter-individual variability.

Contact metamorphism and emplacement of the western Adamello tonalite

The geodynamic forces acting in the Earth's interior manifest themselves in a variety of ways. Volcanoes are amongst the most impressive examples in this respect, but like with an iceberg, they only represent the tip of a more extensive system hidden underground. This system consists of a source region where melt forms and accumulates, feeder connections in which magma is transported towards the surface, and different reservoirs where it is stored before it eventually erupts to form a volcano. A magma represents a mixture of melt and crystals. The latter can be extracted from the source region, or form anywhere along the path towards their final crystallization place. They will retain information of the overall plumbing system. The host rocks of an intrusion, in contrast, provide information at the emplacement level. They record the effects of thermal and mechanical forces imposed by the magma. For a better understanding of the system, both parts - magmatic and metamorphic petrology - have to be integrated. I will demonstrate in my thesis that information from both is complementary. It is an iterative process, using constraints from one field to better constrain the other. Reading the history of the host rocks is not always straightforward. This is shown in chapter two, where a model for the formation of clustered garnets observed in the contact aureole is proposed. Fragments of garnets, older than the intrusive rocks are overgrown by garnet crystallizing due to the reheating during emplacement of the adjacent pluton. The formation of the clusters is therefore not a single event as generally assumed but the result of a two-stage process, namely the alteration of the old grains and the overgrowth and amalgamation of new garnet rims. This makes an important difference when applying petrological methods such as thermobarometry, geochronology or grain size distributions. The thermal conditions in the aureole are a strong function of the emplacement style of the pluton. therefore it is necessary to understand the pluton before drawing conclusions about its aureole. A study investigating the intrusive rocks by means of field, geochemical, geochronologi- cal and structural methods is presented in chapter three. This provided important information about the assembly of the intrusion, but also new insights on the nature of large, homogeneous plutons and the structure of the plumbing system in general. The incremental nature of the emplacement of the Western Adamello tonalité is documented, and the existence of an intermediate reservoir beneath homogeneous plutons is proposed. In chapter four it is demonstrated that information extracted from the host rock provides further constraints on the emplacement process of the intrusion. The temperatures obtain by combining field observations with phase petrology modeling are used together with thermal models to constrain the magmatic activity in the immediate intrusion. Instead of using the thermal models to control the petrology result, the inverse is done. The model parameters were changed until a match with the aureole temperatures was obtained. It is shown, that only a few combinations give a positive match and that temperature estimates from the aureole can constrain the frequency of ancient magmatic systems. In the fifth chapter, the Anisotropy of Magnetic Susceptibility of intrusive rocks is compared to 3D tomography. The obtained signal is a function of the shape and distribution of ferromagnetic grains, and is often used to infer flow directions of magma. It turns out that the signal is dominated by the shape of the magnetic crystals, and where they form tight clusters, also by their distribution. This is in good agreement with the predictions made in the theoretical and experimental literature. In the sixth chapter arguments for partial melting of host rock carbonates are presented. While at first very surprising, this is to be expected when considering the prior results from the intrusive study and experiments from the literature. Partial melting is documented by compelling microstructures, geochemical and structural data. The necessary conditions are far from extreme and this process might be more frequent than previously thought. The carbonate melt is highly mobile and can move along grain boundaries, infiltrating other rocks and ultimately alter the existing mineral assemblage. Finally, a mineralogical curiosity is presented in chapter seven. The mineral assemblage magne§site and calcite is in apparent equilibrium. It is well known that these two carbonates are not stable together in the system Ca0-Mg0-Fe0-C02. Indeed, magnesite and calcite should react to dolomite during metamorphism. The presented explanation for this '"forbidden" assemblage is, that a calcite melt infiltrated the magnesite bearing rock along grain boundaries and caused the peculiar microstructure. This is supported by isotopie disequilibrium between calcite and magnesite. A further implication of partially molten carbonates is, that the host rock drastically looses its strength so that its physical properties may be comparable to the ones of the intrusive rocks. This contrasting behavior of the host rock may ease the emplacement of the intrusion. We see that the circle closes and the iterative process of better constraining the emplacement could start again. - La Terre est en perpétuel mouvement et les forces tectoniques associées à ces mouvements se manifestent sous différentes formes. Les volcans en sont l'un des exemples les plus impressionnants, mais comme les icebergs, les laves émises en surfaces ne représentent que la pointe d'un vaste système caché dans les profondeurs. Ce système est constitué d'une région source, région où la roche source fond et produit le magma ; ce magma peut s'accumuler dans cette région source ou être transporté à travers différents conduits dans des réservoirs où le magma est stocké. Ce magma peut cristalliser in situ et produire des roches plutoniques ou alors être émis en surface. Un magma représente un mélange entre un liquide et des cristaux. Ces cristaux peuvent être extraits de la source ou se former tout au long du chemin jusqu'à l'endroit final de cristallisation. L'étude de ces cristaux peut ainsi donner des informations sur l'ensemble du système magmatique. Au contraire, les roches encaissantes fournissent des informations sur le niveau d'emplacement de l'intrusion. En effet ces roches enregistrent les effets thermiques et mécaniques imposés par le magma. Pour une meilleure compréhension du système, les deux parties, magmatique et métamorphique, doivent être intégrées. Cette thèse a pour but de montrer que les informations issues de l'étude des roches magmatiques et des roches encaissantes sont complémentaires. C'est un processus itératif qui utilise les contraintes d'un domaine pour améliorer la compréhension de l'autre. Comprendre l'histoire des roches encaissantes n'est pas toujours aisé. Ceci est démontré dans le chapitre deux, où un modèle de formation des grenats observés sous forme d'agrégats dans l'auréole de contact est proposé. Des fragments de grenats plus vieux que les roches intru- sives montrent une zone de surcroissance générée par l'apport thermique produit par la mise en place du pluton adjacent. La formation des agrégats de grenats n'est donc pas le résultat d'un seul événement, comme on le décrit habituellement, mais d'un processus en deux phases, soit l'altération de vieux grains engendrant une fracturation de ces grenats, puis la formation de zone de surcroissance autour de ces différents fragments expliquant la texture en agrégats observée. Cette interprétation en deux phases est importante, car elle engendre des différences notables lorsque l'on applique des méthodes pétrologiques comme la thermobarométrie, la géochronologie ou encore lorsque l'on étudie la distribution relative de la taille des grains. Les conditions thermales dans l'auréole de contact dépendent fortement du mode d'emplacement de l'intrusion et c'est pourquoi il est nécessaire de d'abord comprendre le pluton avant de faire des conclusions sur son auréole de contact. Une étude de terrain des roches intrusives ainsi qu'une étude géochimique, géochronologique et structurale est présente dans le troisième chapitre. Cette étude apporte des informations importantes sur la formation de l'intrusion mais également de nouvelles connaissances sur la nature de grands plutons homogènes et la structure de système magmatique en général. L'emplacement incrémental est mis en évidence et l'existence d'un réservoir intermédiaire en-dessous des plutons homogènes est proposé. Le quatrième chapitre de cette thèse illustre comment utiliser l'information extraite des roches encaissantes pour expliquer la mise en place de l'intrusion. Les températures obtenues par la combinaison des observations de terrain et l'assemblage métamorphique sont utilisées avec des modèles thermiques pour contraindre l'activité magmatique au contact directe de cette auréole. Au lieu d'utiliser le modèle thermique pour vérifier le résultat pétrologique, une approche inverse a été choisie. Les paramètres du modèle ont été changés jusqu'à ce qu'on obtienne une correspondance avec les températures observées dans l'auréole de contact. Ceci montre qu'il y a peu de combinaison qui peuvent expliquer les températures et qu'on peut contraindre la fréquence de l'activité magmatique d'un ancien système magmatique de cette manière. Dans le cinquième chapitre, les processus contrôlant l'anisotropie de la susceptibilité magnétique des roches intrusives sont expliqués à l'aide d'images de la distribution des minéraux dans les roches obtenues par tomographie 3D. Le signal associé à l'anisotropie de la susceptibilité magnétique est une fonction de la forme et de la distribution des grains ferromagnétiques. Ce signal est fréquemment utilisé pour déterminer la direction de mouvement d'un magma. En accord avec d'autres études de la littérature, les résultats montrent que le signal est dominé par la forme des cristaux magnétiques, ainsi que par la distribution des agglomérats de ces minéraux dans la roche. Dans le sixième chapitre, une étude associée à la fusion partielle de carbonates dans les roches encaissantes est présentée. Si la présence de liquides carbonatés dans les auréoles de contact a été proposée sur la base d'expériences de laboratoire, notre étude démontre clairement leur existence dans la nature. La fusion partielle est documentée par des microstructures caractéristiques pour la présence de liquides ainsi que par des données géochimiques et structurales. Les conditions nécessaires sont loin d'être extrêmes et ce processus pourrait être plus fréquent qu'attendu. Les liquides carbonatés sont très mobiles et peuvent circuler le long des limites de grain avant d'infiltrer d'autres roches en produisant une modification de leurs assemblages minéralogiques. Finalement, une curiosité minéralogique est présentée dans le chapitre sept. L'assemblage de minéraux de magnésite et de calcite en équilibre apparent est observé. Il est bien connu que ces deux carbonates ne sont pas stables ensemble dans le système CaO-MgO-FeO-CO.,. En effet, la magnésite et la calcite devraient réagir et produire de la dolomite pendant le métamorphisme. L'explication présentée pour cet assemblage à priori « interdit » est que un liquide carbonaté provenant des roches adjacentes infiltre cette roche et est responsable pour cette microstructure. Une autre implication associée à la présence de carbonates fondus est que la roche encaissante montre une diminution drastique de sa résistance et que les propriétés physiques de cette roche deviennent comparables à celles de la roche intrusive. Cette modification des propriétés rhéologiques des roches encaissantes peut faciliter la mise en place des roches intrusives. Ces différentes études démontrent bien le processus itératif utilisé et l'intérêt d'étudier aussi bien les roches intrusives que les roches encaissantes pour la compréhension des mécanismes de mise en place des magmas au sein de la croûte terrestre.

Substitution of (R,S)-methadone by (R)-methadone: Impact on QTc interval.

Methadone is administered as a chiral mixture of (R,S)-methadone. The opioid effect is mainly mediated by (R)-methadone, whereas (S)-methadone blocks the human ether-à-go-go-related gene (hERG) voltage-gated potassium channel more potently, which can cause drug-induced long QT syndrome, leading to potentially lethal ventricular tachyarrhythmias. To investigate whether substitution of (R,S)-methadone by (R)-methadone could reduce the corrected QT (QTc) interval, (R,S)-methadone was replaced by (R)-methadone (half-dose) in 39 opioid-dependent patients receiving maintenance treatment for 14 days. (R)-methadone was then replaced by the initial dose of (R,S)-methadone for 14 days (n = 29). Trough (R)-methadone and (S)-methadone plasma levels and electrocardiogram measurements were taken. The Fridericia-corrected QT (QTcF) interval decreased when (R,S)-methadone was replaced by a half-dose of (R)-methadone; the median (interquartile range [IQR]) values were 423 (398-440) milliseconds (ms) and 412 (395-431) ms (P = .06) at days 0 and 14, respectively. Using a univariate mixed-effect linear model, the QTcF value decreased by a mean of -3.9 ms (95% confidence interval [CI], -7.7 to -0.2) per week (P = .04). The QTcF value increased when (R)-methadone was replaced by the initial dose of (R,S)-methadone for 14 days; median (IQR) values were 424 (398-436) ms and 424 (412-443) ms (P = .01) at days 14 and 28, respectively. The univariate model showed that the QTcF value increased by a mean of 4.7 ms (95% CI, 1.3-8.1) per week (P = .006). Substitution of (R,S)-methadone by (R)-methadone reduces the QTc interval value. A safer cardiac profile of (R)-methadone is in agreement with previous in vitro and pharmacogenetic studies. If the present results are confirmed by larger studies, (R)-methadone should be prescribed instead of (R,S)-methadone to reduce the risk of cardiac toxic effects and sudden death.

Structure of the glycosyl-phosphatidylinositol membrane anchor of the Leishmania major promastigote surface protease.

In common with many other plasma membrane glycoproteins of eukaryotic origin, the promastigote surface protease (PSP) of the protozoan parasite Leishmania contains a glycosyl-phosphatidylinositol (GPI) membrane anchor. The GPI anchor of Leishmania major PSP was purified following proteolysis of the PSP and analyzed by two-dimensional 1H-1H NMR, compositional and methylation linkage analyses, chemical and enzymatic modifications, and amino acid sequencing. From these results, the structure of the GPI-containing peptide was found to be Asp-Gly-Gly-Asn-ethanolamine-PO4-6Man alpha 1-6Man alpha 1-4GlcN alpha 1-6myo-inositol-1-PO4-(1-alkyl-2-acyl-glycerol). The glycan structure is identical to the conserved glycan core regions of the GPI anchor of Trypanosoma brucei variant surface glycoprotein and rat brain Thy-1 antigen, supporting the notion that this portion of GPIs are highly conserved. The phosphatidylinositol moiety of the PSP anchor is unusual, containing a fully saturated, unbranched 1-O-alkyl chain (mainly C24:0) and a mixture of fully saturated unbranched 2-O-acyl chains (C12:0, C14:0, C16:0, and C18:0). This lipid composition differs significantly from those of the GPIs of T. brucei variant surface glycoprotein and mammalian erythrocyte acetylcholinesterase but is similar to that of a family of glycosylated phosphoinositides found uniquely in Leishmania.

Immunogenicity of dimorphic and C-terminal fragments of Plasmodium falciparum MSP2 formulated with different adjuvants in mice.

BACKGROUND: Plasmodium falciparum MSP2 is a blood stage protein that is associated with protection against malaria. It was shown that the MSP2 dimorphic (D) and constant (C) regions were well recognized by immune human antibodies, and were characterized by major conserved epitopes in different endemic areas and age groups. These Abs recognized merozoite-derived proteins in WB and IFA. Here, the goal was to determine in mice the immunogenicity of the two allelic MSP2 D and C domains formulated with different adjuvants, for their possible use in future clinical studies. METHOD: Female A/J, C3H, and ICR mice were immunized subcutaneously 3 times at 3-week interval with a mixture of allelic and conserved MSP2 long synthetic peptides formulated with different adjuvants. One week after the third injection, sera from each group were obtained and stored at -20°C for subsequent testing. RESULTS: Both domains of the two MSP2 families are immunogenic and the fine specificity and intensity of the Ab responses are dependent on mouse strains and adjuvants. The major epitopes were restricted to the 20-mer peptide sequences comprising the last 8aa of D and first 12aa of C of the two allelic families and the first 20aa of the C region, this for most strains and adjuvants. Strong immune responses were associated with GLA-SE adjuvant and its combination with other TLR agonists (CpG or GDQ) compared to alhydrogel and Montanide. Further, the elicited Abs were also capable of recognizing Plasmodium-derived MSP2 and inhibiting parasite growth in ADCI. CONCLUSION: The data provide a valuable opportunity to evaluate in mice different adjuvant and antigen formulations of a candidate vaccine containing both MSP2 D and C fragments. The formulations with GLA-SE seem to be a promising option to be compared with the alhydrogel one in human clinical trials.