Visuo-motor pathways in humans revealed by event-related fMRI.

Whether different brain networks are involved in generating unimanual responses to a simple visual stimulus presented in the ipsilateral versus contralateral hemifield remains a controversial issue. Visuo-motor routing was investigated with event-related functional magnetic resonance imaging (fMRI) using the Poffenberger reaction time task. A 2 hemifield x 2 response hand design generated the "crossed" and "uncrossed" conditions, describing the spatial relation between these factors. Both conditions, with responses executed by the left or right hand, showed a similar spatial pattern of activated areas, including striate and extrastriate areas bilaterally, SMA, and M1 contralateral to the responding hand. These results demonstrated that visual information is processed bilaterally in striate and extrastriate visual areas, even in the "uncrossed" condition. Additional analyses based on sorting data according to subjects' reaction times revealed differential crossed versus uncrossed activity only for the slowest trials, with response strength in infero-temporal cortices significantly correlating with crossed-uncrossed differences (CUD) in reaction times. Collectively, the data favor a parallel, distributed model of brain activation. The presence of interhemispheric interactions and its consequent bilateral activity is not determined by the crossed anatomic projections of the primary visual and motor pathways. Distinct visuo-motor networks need not be engaged to mediate behavioral responses for the crossed visual field/response hand condition. While anatomical connectivity heavily influences the spatial pattern of activated visuo-motor pathways, behavioral and functional parameters appear to also affect the strength and dynamics of responses within these pathways.

Understanding and Fighting the Medicine Counterfeit Market

Medicine counterfeiting is a serious worldwide issue, involving networks of manufacture and distribution that are an integral part of industrialized organized crime. Despite the potentially devastating health repercussions involved, legal sanctions are often inappropriate or simply not applied. The difficulty in agreeing on a definition of counterfeiting, the huge profits made by the counterfeiters and the complexity of the market are the other main reasons for the extent of the phenomenon. Above all, international cooperation is needed to thwart the spread of counterfeiting. Moreover effort is urgently required on the legal, enforcement and scientific levels. Pharmaceutical companies and agencies have developed measures to protect the medicines and allow fast and reliable analysis of the suspect products. Several means, essentially based on chromatography and spectroscopy, are now at the disposal of the analysts to enable the distinction between genuine and counterfeit products. However the determination of the components and the use of analytical data for forensic purposes still constitute a challenge. The aim of this review article is therefore to point out the intricacy of medicine counterfeiting so that a better understanding can provide solutions to fight more efficiently against it.

The effects of physiologically plausible connectivity structure on local and global dynamics in large scale brain models.

Functionally relevant large scale brain dynamics operates within the framework imposed by anatomical connectivity and time delays due to finite transmission speeds. To gain insight on the reliability and comparability of large scale brain network simulations, we investigate the effects of variations in the anatomical connectivity. Two different sets of detailed global connectivity structures are explored, the first extracted from the CoCoMac database and rescaled to the spatial extent of the human brain, the second derived from white-matter tractography applied to diffusion spectrum imaging (DSI) for a human subject. We use the combination of graph theoretical measures of the connection matrices and numerical simulations to explicate the importance of both connectivity strength and delays in shaping dynamic behaviour. Our results demonstrate that the brain dynamics derived from the CoCoMac database are more complex and biologically more realistic than the one based on the DSI database. We propose that the reason for this difference is the absence of directed weights in the DSI connectivity matrix.

International Standardisation and Local Participatory Dynamics : The INTERNORM Project

This paper presents a pilot project (INTERNORM) funded by the University of Lausanne (2010 - 2013) to support the involvement of civil society organisations (CSO) in international standard setting bodies such as the ISO. It analyses how a distinct participatory mechanism can influence the institutional environment of technical diplomacy in which standards are shaped. The project is an attempt to respond to the democratic deficit attested in the field of international standardisation, formally open to civil society participation, but still largely dominated by expert knowledge and market players. Many international standards have direct implications on society as a whole, but CSOs (consumers and environmental associations, trade unions) are largely under-represented in negotiation arenas. The paper draws upon international relations literature on new institutional forms in global governance and studies of participation in science and technology. It argues that there are significant limitations to the rise of civil society participation in such global governance mechanisms. The INTERNORM project has been designed as a platform of knowledge exchange between CSO and academic experts, with earmarked funding and official membership to a national standardisation body. But INTERNORM cannot substitute for a long- established lack of resources in time, money and expertise of CSOs. Despite high entry costs into technical diplomacy, participation thus appears as less a matter of upstream engagement, or of procedure only, than of dedicated means to shift the geometry of actors and the framing of socio-technical change.

Influence of ionization state on the activation of temocapril by hCES1: a molecular-dynamics study.

Temocapril is a prodrug whose hydrolysis by carboxylesterase 1 (CES1) yields the active ACE inhibitor temocaprilat. This molecular-dynamics (MD) study uses a resolved structure of the human CES1 (hCES1) to investigate some mechanistic details of temocapril hydrolysis. The ionization constants of temocapril (pK1 and pK3) and temocaprilat (pK1, pK2, and pK3) were determined experimentally and computationally using commercial algorithms. The constants so obtained were in good agreement and revealed that temocapril exists mainly in three ionic forms (a cation, a zwitterion, and an anion), whereas temocaprilat exists in four major ionic forms (a cation, a zwitterion, an anion, and a dianion). All these ionic forms were used as ligands in 5-ns MS simulations. While the cationic and zwitterionic forms of temocapril were involved in an ion-pair bond with Glu255 suggestive of an inhibitor behavior, the anionic form remained in a productive interaction with the catalytic center. As for temocaprilat, its cation appeared trapped by Glu255, while its zwitterion and anion made a slow departure from the catalytic site and a partial egress from the protein. Only its dianion was effectively removed from the catalytic site and attracted to the protein surface by Lys residues. A detailed mechanism of product egress emerges from the simulations.

Care complexity, mood, and quality of life in liver pre-transplant patients.

RATIONALE: This study was intended to document the frequency of care complexity in liver transplant candidates, and its association with mood disturbance and poor health-related quality of life (HRQoL). METHODS: Consecutive patients fulfilling inclusion criteria, recruited in three European hospitals, were assessed with INTERMED, a reliable and valid method for the early assessment of bio-psychosocial health risks and needs. Blind to the results, they were also assessed with the Hospital Anxiety and Depression Scale (HADS). HRQoL was documented with the EuroQol and the SF36. Statistical analysis included multivariate and multilevel techniques. RESULTS: Among patients fulfilling inclusion criteria, 60 patients (75.9%) completed the protocol and 38.3% of them were identified as "complex" by INTERMED, but significant between-center differences were found. In support of the working hypothesis, INTERMED scores were significantly associated with all measures of both the SF36 and the EuroQol, and also with the HADS. A one point increase in the INTERMED score results in a reduction in 0.93 points in EuroQol and a 20% increase in HADS score. CONCLUSIONS: INTERMED-measured case complexity is frequent in liver transplant candidates but varies widely between centers. The use of this method captures in one instrument multiple domains of patient status, including mood disturbances and reduced HRQoL.

Resting-state temporal synchronization networks emerge from connectivity topology and heterogeneity.

Spatial patterns of coherent activity across different brain areas have been identified during the resting-state fluctuations of the brain. However, recent studies indicate that resting-state activity is not stationary, but shows complex temporal dynamics. We were interested in the spatiotemporal dynamics of the phase interactions among resting-state fMRI BOLD signals from human subjects. We found that the global phase synchrony of the BOLD signals evolves on a characteristic ultra-slow (<0.01Hz) time scale, and that its temporal variations reflect the transient formation and dissolution of multiple communities of synchronized brain regions. Synchronized communities reoccurred intermittently in time and across scanning sessions. We found that the synchronization communities relate to previously defined functional networks known to be engaged in sensory-motor or cognitive function, called resting-state networks (RSNs), including the default mode network, the somato-motor network, the visual network, the auditory network, the cognitive control networks, the self-referential network, and combinations of these and other RSNs. We studied the mechanism originating the observed spatiotemporal synchronization dynamics by using a network model of phase oscillators connected through the brain's anatomical connectivity estimated using diffusion imaging human data. The model consistently approximates the temporal and spatial synchronization patterns of the empirical data, and reveals that multiple clusters that transiently synchronize and desynchronize emerge from the complex topology of anatomical connections, provided that oscillators are heterogeneous.

Large scale assessment of regulatory evolution and transcriptome complexity in mammals

AbstractIn addition to genetic changes affecting the function of gene products, changes in gene expression have been suggested to underlie many or even most of the phenotypic differences among mammals. However, detailed gene expression comparisons were, until recently, restricted to closely related species, owing to technological limitations. Thus, we took advantage of the latest technologies (RNA-Seq) to generate extensive qualitative and quantitative transcriptome data for a unique collection of somatic and germline tissues from representatives of all major mammalian lineages (placental mammals, marsupials and monotremes) and birds, the evolutionary outgroup.In the first major project of my thesis, we performed global comparative analyses of gene expression levels based on these data. Our analyses provided fundamental insights into the dynamics of transcriptome change during mammalian evolution (e.g., the rate of expression change across species, tissues and chromosomes) and allowed the exploration of the functional relevance and phenotypic implications of transcription changes at a genome-wide scale (e.g., we identified numerous potentially selectively driven expression switches).In a second project of my thesis, which was also based on the unique transcriptome data generated in the context of the first project we focused on the evolution of alternative splicing in mammals. Alternative splicing contributes to transcriptome complexity by generating several transcript isoforms from a single gene, which can, thus, perform various functions. To complete the global comparative analysis of gene expression changes, we explored patterns of alternative splicing evolution. This work uncovered several general and unexpected patterns of alternative splicing evolution (e.g., we found that alternative splicing evolves extremely rapidly) as well as a large number of conserved alternative isoforms that may be crucial for the functioning of mammalian organs.Finally, the third and final project of my PhD consisted in analyzing in detail the unique functional and evolutionary properties of the testis by exploring the extent of its transcriptome complexity. This organ was previously shown to evolve rapidly both at the phenotypic and molecular level, apparently because of the specific pressures that act on this organ and are associated with its reproductive function. Moreover, my analyses of the amniote tissue transcriptome data described above, revealed strikingly widespread transcriptional activity of both functional and nonfunctional genomic elements in the testis compared to the other organs. To elucidate the cellular source and mechanisms underlying this promiscuous transcription in the testis, we generated deep coverage RNA-Seq data for all major testis cell types as well as epigenetic data (DNA and histone methylation) using the mouse as model system. The integration of these complete dataset revealed that meiotic and especially post-meiotic germ cells are the major contributors to the widespread functional and nonfunctional transcriptome complexity of the testis, and that this "promiscuous" spermatogenic transcription is resulting, at least partially, from an overall transcriptionally permissive chromatin state. We hypothesize that this particular open state of the chromatin results from the extensive chromatin remodeling that occurs during spermatogenesis which ultimately leads to the replacement of histones by protamines in the mature spermatozoa. Our results have important functional and evolutionary implications (e.g., regarding new gene birth and testicular gene expression evolution).Generally, these three large-scale projects of my thesis provide complete and massive datasets that constitute valuables resources for further functional and evolutionary analyses of mammalian genomes.

Contribution à la cartographie géomorphologique de la dynamique sédimentaire des petits bassins versants torrentiels

Les laves torrentielles sont l'un des vecteurs majeurs de sédiments en milieu montagneux. Leur comportement hydrogéomorphologique est contrôlé par des facteurs géologique, géomorphologique, topographique, hydrologique, climatique et anthropique. Si, en Europe, la recherche s'est plus focalisée sur les aspects hydrologiques que géomorphologiques de ces phénomènes, l'identification des volumes de sédiments potentiellement mobilisables au sein de petits systèmes torrentiels et des processus responsables de leur transfert est d'une importance très grande en termes d'aménagement du territoire et de gestion des dangers naturels. De plus, une corrélation entre des événements pluviométriques et l'occurrence de laves torrentielles n'est pas toujours établie et de nombreux événements torrentiels semblent se déclencher lorsqu'un seuil géomorphologique intrinsèque (degré de remplissage du chenal) au cours d'eau est atteint.Une méthodologie pragmatique a été développée pour cartographier les stocks sédimentaires constituant une source de matériaux pour les laves torrentielles, comme outil préliminaire à la quantification des volumes transportés par ces phénomènes. La méthode s'appuie sur des données dérivées directement d'analyses en environnement SIG réalisées sur des modèles numériques d'altitude de haute précision, de mesures de terrain et d'interprétation de photographies aériennes. La méthode a été conçue pour évaluer la dynamique des transferts sédimentaires, en prenant en compte le rôle des différents réservoirs sédimentaires, par l'application du concept de cascade sédimentaire sous un angle cartographique.Les processus de transferts sédimentaires ont été étudiés dans deux bassins versants des Alpes suisses (torrent du Bruchi, à Blatten beiNaters et torrent du Meretschibach, à Agarn). La cartographie géomorphologique a été couplée avec des mesures complémentaires permettant d'estimer les flux sédimentaires et les taux d'érosion (traçages de peinture, piquets de dénudation et utilisation du LiDAR terrestre). La méthode proposée se révèle innovatrice en comparaison avec la plupart des systèmes de légendes géomorphologiques existants, qui ne sont souvent pas adaptés pour cartographier de manière satisfaisante les systèmes géomorphologiques complexes et actifs que sont les bassins torrentiels. L'intérêt de cette méthode est qu'elle permet l'établissement d'une cascade sédimentaire, mais uniquement pour des systèmes où l'occurrence d'une lave torrentielle est contrôlé par le degré de remplissage en matériaux du chenal. Par ailleurs, le produit cartographique ne peut être directement utilisé pour la création de cartes de dangers - axées sur les zones de dépôt - mais revêt un intérêt pour la mise en place de mesures de correction et pour l'installation de systèmes de monitoring ou d'alerte.La deuxième partie de ce travail de recherche est consacrée à la cartographie géomorphologique. Une analyse a porté sur un échantillon de 146 cartes ou systèmes de légende datant des années 1950 à 2009 et réalisés dans plus de 40 pays. Cette analyse a permis de mettre en évidence la diversité des applications et des techniques d'élaboration des cartes géomorphologiques. - Debris flows are one of the most important vectors of sediment transfer in mountainous areas. Their hydro-geomorphological behaviour is conditioned by geological, geomorphological, topographical, hydrological, climatic and anthropic factors. European research in torrential systems has focused more on hydrological processes than on geomorphological processes acting as debris flow triggers. Nevertheless, the identification of sediment volumes that have the potential to be mobilised in small torrential systems, as well as the recognition of processes responsible for their mobilisation and transfer within the torrential system, are important in terms of land-use planning and natural hazard management. Moreover, a correlation between rainfall and debris flow occurrence is not always established and a number of debris flows seems to occur when a poorly understood geomorphological threshold is reached.A pragmatic methodology has been developed for mapping sediment storages that may constitute source zone of bed load transport and debris flows as a preliminary tool before quantifying their volumes. It is based on data directly derived from GIS analysis using high resolution DEM's, field measurements and aerial photograph interpretations. It has been conceived to estimate sediment transfer dynamics, taking into account the role of different sediment stores in the torrential system applying the concept of "sediment cascade" in a cartographic point of view.Sediment transfer processes were investigated in two small catchments in the Swiss Alps (Bruchi torrent, Blatten bei Naters and Meretschibach torrent, Agarn). Thorough field geomorphological mapping coupled with complementary measurements were conducted to estimate sediment fluxes and denudation rates, using various methods (reference coloured lines, wooden markers and terrestrial LiDAR). The proposed geomorphological mapping methodology is quite innovative in comparison with most legend systems that are not adequate for mapping active and complex geomorphological systems such as debris flow catchments. The interest of this mapping method is that it allows the concept of sediment cascade to be spatially implemented but only for supply-limited systems. The map cannot be used directly for the creation of hazard maps, focused on the deposition areas, but for the design of correction measures and the implementation of monitoring and warning systems.The second part of this work focuses on geomorphological mapping. An analysis of a sample of 146 (extracts of) maps or legend systems dating from the middle of the 20th century to 2009 - realised in more than 40 different countries - was carried out. Even if this study is not exhaustive, it shows a clear renewed interest for the discipline worldwide. It highlights the diversity of applications, techniques (scale, colours and symbology) used for their conception.

Cost-effective experimental design to support modeling of concentration-response functions

Modeling concentration-response function became extremely popular in ecotoxicology during the last decade. Indeed, modeling allows determining the total response pattern of a given substance. However, reliable modeling is consuming in term of data, which is in contradiction with the current trend in ecotoxicology, which aims to reduce, for cost and ethical reasons, the number of data produced during an experiment. It is therefore crucial to determine experimental design in a cost-effective manner. In this paper, we propose to use the theory of locally D-optimal designs to determine the set of concentrations to be tested so that the parameters of the concentration-response function can be estimated with high precision. We illustrated this approach by determining the locally D-optimal designs to estimate the toxicity of the herbicide dinoseb on daphnids and algae. The results show that the number of concentrations to be tested is often equal to the number of parameters and often related to the their meaning, i.e. they are located close to the parameters. Furthermore, the results show that the locally D-optimal design often has the minimal number of support points and is not much sensitive to small changes in nominal values of the parameters. In order to reduce the experimental cost and the use of test organisms, especially in case of long-term studies, reliable nominal values may therefore be fixed based on prior knowledge and literature research instead of on preliminary experiments

Automatic Mapping and Classification of Spatial Environmental Data

The paper deals with the development and application of the generic methodology for automatic processing (mapping and classification) of environmental data. General Regression Neural Network (GRNN) is considered in detail and is proposed as an efficient tool to solve the problem of spatial data mapping (regression). The Probabilistic Neural Network (PNN) is considered as an automatic tool for spatial classifications. The automatic tuning of isotropic and anisotropic GRNN/PNN models using cross-validation procedure is presented. Results are compared with the k-Nearest-Neighbours (k-NN) interpolation algorithm using independent validation data set. Real case studies are based on decision-oriented mapping and classification of radioactively contaminated territories.

Automatic selection of tidal volume, respiratory frequency and minute ventilation in intubated ICU patients as start up procedure for closed-loop controlled ventilation.

OBJECTIVE: Before a patient can be connected to a mechanical ventilator, the controls of the apparatus need to be set up appropriately. Today, this is done by the intensive care professional. With the advent of closed loop controlled mechanical ventilation, methods will be needed to select appropriate start up settings automatically. The objective of our study was to test such a computerized method which could eventually be used as a start-up procedure (first 5-10 minutes of ventilation) for closed-loop controlled ventilation. DESIGN: Prospective Study. SETTINGS: ICU's in two adult and one children's hospital. PATIENTS: 25 critically ill adult patients (age > or = 15 y) and 17 critically ill children selected at random were studied. INTERVENTIONS: To stimulate 'initial connection', the patients were disconnected from their ventilator and transiently connected to a modified Hamilton AMADEUS ventilator for maximally one minute. During that time they were ventilated with a fixed and standardized breath pattern (Test Breaths) based on pressure controlled synchronized intermittent mandatory ventilation (PCSIMV). MEASUREMENTS AND MAIN RESULTS: Measurements of airway flow, airway pressure and instantaneous CO2 concentration using a mainstream CO2 analyzer were made at the mouth during application of the Test-Breaths. Test-Breaths were analyzed in terms of tidal volume, expiratory time constant and series dead space. Using this data an initial ventilation pattern consisting of respiratory frequency and tidal volume was calculated. This ventilation pattern was compared to the one measured prior to the onset of the study using a two-tailed paired t-test. Additionally, it was compared to a conventional method for setting up ventilators. The computer-proposed ventilation pattern did not differ significantly from the actual pattern (p > 0.05), while the conventional method did. However the scatter was large and in 6 cases deviations in the minute ventilation of more than 50% were observed. CONCLUSIONS: The analysis of standardized Test Breaths allows automatic determination of an initial ventilation pattern for intubated ICU patients. While this pattern does not seem to be superior to the one chosen by the conventional method, it is derived fully automatically and without need for manual patient data entry such as weight or height. This makes the method potentially useful as a start up procedure for closed-loop controlled ventilation.

The rewards of cooperation: The effects of membership in European regulatory networks

Networks famously epitomize the shift from 'government' to 'governance' as governing structures for exercising control and coordination besides hierarchies and markets. Their distinctive features are their horizontality, the interdependence among member actors and an interactive decision-making style. Networks are expected to increase the problem-solving capacity of political systems in a context of growing social complexity, where political authority is increasingly fragmented across territorial and functional levels. However, very little attention has been given so far to another crucial implication of network governance - that is, the effects of networks on their members. To explore this important question, this article examines the effects of membership in European regulatory networks on two crucial attributes of member agencies, which are in charge of regulating finance, energy, telecommunications and competition: organisational growth and their regulatory powers. Panel analysis applied to data on 118 agencies during a ten-year period and semi-structured interviews provide mixed support regarding the expectation of organisational growth while strongly confirming the positive effect of networks on the increase of the regulatory powers attributed to member agencies.

Astrocyte Ca²⁺ signalling: an unexpected complexity.

Astrocyte Ca(2+) signalling has been proposed to link neuronal information in different spatial-temporal dimensions to achieve a higher level of brain integration. However, some discrepancies in the results of recent studies challenge this view and highlight key insufficiencies in our current understanding. In parallel, new experimental approaches that enable the study of astrocyte physiology at higher spatial-temporal resolution in intact brain preparations are beginning to reveal an unexpected level of compartmentalization and sophistication in astrocytic Ca(2+) dynamics. This newly revealed complexity needs to be attentively considered in order to understand how astrocytes may contribute to brain information processing.

Schizotypy and hemispheric asymmetry: results from two Chapman scales, the O-LIFE questionnaire, and two laterality measures

Schizotypy is a multidimensional personality construct representing the extension of psychosis-like traits into the general population. Schizotypy has been associated with attenuated expressions of many of the same neuropsychological abnormalities as schizophrenia, including atypical pattern of functional hemispheric asymmetry. Unfortunately, the previous literature on links between schizotypy and hemispheric asymmetry is inconsistent with some research indicating that elevated schizotypy is associated with relative right over left hemisphere shifts, left over right hemisphere shifts, bilateral impairments, or with no hemispheric differences at all. This inconsistency may result from different methodologies, scales, and / or sex proportions between studies. In a within-participant design, we tested for the four possible links between laterality and schizotypy by comparing the relationship between two common self-report measures of multidimensional schizotypy (the O-LIFE questionnaire, and two Chapman scales, magical ideation and physical anhedonia) and performance in two computerized lateralised hemifield paradigms (lexical decision, chimeric face processing) in 80 men and 79 women. Results for the two scales and two tasks did not unequivocally support any of the four possible links. We discuss the possibilities that a link between schizotypy and laterality 1) exists, but is subtle, probably fluctuating, unable to be assessed by traditional methodologies used here; 2) does not exist, or 3) is indirect, mediated by other factors (e.g. stress-responsiveness, handedness, drug use) whose influences need further exploration.