A modular approach for integrative analysis of large-scale gene-expression and drug-response data

High-throughput technologies are now used to generate more than one type of data from the same biological samples. To properly integrate such data, we propose using co-modules, which describe coherent patterns across paired data sets, and conceive several modular methods for their identification. We first test these methods using in silico data, demonstrating that the integrative scheme of our Ping-Pong Algorithm uncovers drug-gene associations more accurately when considering noisy or complex data. Second, we provide an extensive comparative study using the gene-expression and drug-response data from the NCI-60 cell lines. Using information from the DrugBank and the Connectivity Map databases we show that the Ping-Pong Algorithm predicts drug-gene associations significantly better than other methods. Co-modules provide insights into possible mechanisms of action for a wide range of drugs and suggest new targets for therapy

Aerotropolis: an aviation-linked space

This paper examines the conditions allowing the formation of aeropolitan areas as large industrial areas with a high concentration of commercial activities in the proximity of selected airports. We assume that firms deliver their production by plane and land competition takes place among service operators, firms and farmers. Service operators supply facilities that firms can absorb. Our framework identifies a unique land equilibrium characterized by the spatial sequence Airport - Industrial park - Rural area (A-I-R). Aerotropolis-type configurations are associated with the level of transport costs and the degree of intensity of facilities. Keywords: aerotropolis; facilities; bid-rent function. JEL Classification Numbers: L29; L90; R14.

New pre-dual space of Morrey space

In this paper we give new characterization of the classical Morrey space. Complementary global Morrey-type spaces are introduced. It is proved that for particular values of parameters these spaces give new pre-dual space of the classical Morrey space. We also show that our new pre-dual space of the Morrey space coincides with known pre-dual spaces.

Quantitative integration of geophysical and hydraulic data : from the local towards the regional scale range

Des progrès significatifs ont été réalisés dans le domaine de l'intégration quantitative des données géophysique et hydrologique l'échelle locale. Cependant, l'extension à de plus grandes échelles des approches correspondantes constitue encore un défi majeur. Il est néanmoins extrêmement important de relever ce défi pour développer des modèles fiables de flux des eaux souterraines et de transport de contaminant. Pour résoudre ce problème, j'ai développé une technique d'intégration des données hydrogéophysiques basée sur une procédure bayésienne de simulation séquentielle en deux étapes. Cette procédure vise des problèmes à plus grande échelle. L'objectif est de simuler la distribution d'un paramètre hydraulique cible à partir, d'une part, de mesures d'un paramètre géophysique pertinent qui couvrent l'espace de manière exhaustive, mais avec une faible résolution (spatiale) et, d'autre part, de mesures locales de très haute résolution des mêmes paramètres géophysique et hydraulique. Pour cela, mon algorithme lie dans un premier temps les données géophysiques de faible et de haute résolution à travers une procédure de réduction déchelle. Les données géophysiques régionales réduites sont ensuite reliées au champ du paramètre hydraulique à haute résolution. J'illustre d'abord l'application de cette nouvelle approche dintégration des données à une base de données synthétiques réaliste. Celle-ci est constituée de mesures de conductivité hydraulique et électrique de haute résolution réalisées dans les mêmes forages ainsi que destimations des conductivités électriques obtenues à partir de mesures de tomographic de résistivité électrique (ERT) sur l'ensemble de l'espace. Ces dernières mesures ont une faible résolution spatiale. La viabilité globale de cette méthode est testée en effectuant les simulations de flux et de transport au travers du modèle original du champ de conductivité hydraulique ainsi que du modèle simulé. Les simulations sont alors comparées. Les résultats obtenus indiquent que la procédure dintégration des données proposée permet d'obtenir des estimations de la conductivité en adéquation avec la structure à grande échelle ainsi que des predictions fiables des caractéristiques de transports sur des distances de moyenne à grande échelle. Les résultats correspondant au scénario de terrain indiquent que l'approche d'intégration des données nouvellement mise au point est capable d'appréhender correctement les hétérogénéitées à petite échelle aussi bien que les tendances à gande échelle du champ hydraulique prévalent. Les résultats montrent également une flexibilté remarquable et une robustesse de cette nouvelle approche dintégration des données. De ce fait, elle est susceptible d'être appliquée à un large éventail de données géophysiques et hydrologiques, à toutes les gammes déchelles. Dans la deuxième partie de ma thèse, j'évalue en détail la viabilité du réechantillonnage geostatique séquentiel comme mécanisme de proposition pour les méthodes Markov Chain Monte Carlo (MCMC) appliquées à des probmes inverses géophysiques et hydrologiques de grande dimension . L'objectif est de permettre une quantification plus précise et plus réaliste des incertitudes associées aux modèles obtenus. En considérant une série dexemples de tomographic radar puits à puits, j'étudie deux classes de stratégies de rééchantillonnage spatial en considérant leur habilité à générer efficacement et précisément des réalisations de la distribution postérieure bayésienne. Les résultats obtenus montrent que, malgré sa popularité, le réechantillonnage séquentiel est plutôt inefficace à générer des échantillons postérieurs indépendants pour des études de cas synthétiques réalistes, notamment pour le cas assez communs et importants où il existe de fortes corrélations spatiales entre le modèle et les paramètres. Pour résoudre ce problème, j'ai développé un nouvelle approche de perturbation basée sur une déformation progressive. Cette approche est flexible en ce qui concerne le nombre de paramètres du modèle et lintensité de la perturbation. Par rapport au rééchantillonage séquentiel, cette nouvelle approche s'avère être très efficace pour diminuer le nombre requis d'itérations pour générer des échantillons indépendants à partir de la distribution postérieure bayésienne. - Significant progress has been made with regard to the quantitative integration of geophysical and hydrological data at the local scale. However, extending corresponding approaches beyond the local scale still represents a major challenge, yet is critically important for the development of reliable groundwater flow and contaminant transport models. To address this issue, I have developed a hydrogeophysical data integration technique based on a two-step Bayesian sequential simulation procedure that is specifically targeted towards larger-scale problems. The objective is to simulate the distribution of a target hydraulic parameter based on spatially exhaustive, but poorly resolved, measurements of a pertinent geophysical parameter and locally highly resolved, but spatially sparse, measurements of the considered geophysical and hydraulic parameters. To this end, my algorithm links the low- and high-resolution geophysical data via a downscaling procedure before relating the downscaled regional-scale geophysical data to the high-resolution hydraulic parameter field. I first illustrate the application of this novel data integration approach to a realistic synthetic database consisting of collocated high-resolution borehole measurements of the hydraulic and electrical conductivities and spatially exhaustive, low-resolution electrical conductivity estimates obtained from electrical resistivity tomography (ERT). The overall viability of this method is tested and verified by performing and comparing flow and transport simulations through the original and simulated hydraulic conductivity fields. The corresponding results indicate that the proposed data integration procedure does indeed allow for obtaining faithful estimates of the larger-scale hydraulic conductivity structure and reliable predictions of the transport characteristics over medium- to regional-scale distances. The approach is then applied to a corresponding field scenario consisting of collocated high- resolution measurements of the electrical conductivity, as measured using a cone penetrometer testing (CPT) system, and the hydraulic conductivity, as estimated from electromagnetic flowmeter and slug test measurements, in combination with spatially exhaustive low-resolution electrical conductivity estimates obtained from surface-based electrical resistivity tomography (ERT). The corresponding results indicate that the newly developed data integration approach is indeed capable of adequately capturing both the small-scale heterogeneity as well as the larger-scale trend of the prevailing hydraulic conductivity field. The results also indicate that this novel data integration approach is remarkably flexible and robust and hence can be expected to be applicable to a wide range of geophysical and hydrological data at all scale ranges. In the second part of my thesis, I evaluate in detail the viability of sequential geostatistical resampling as a proposal mechanism for Markov Chain Monte Carlo (MCMC) methods applied to high-dimensional geophysical and hydrological inverse problems in order to allow for a more accurate and realistic quantification of the uncertainty associated with the thus inferred models. Focusing on a series of pertinent crosshole georadar tomographic examples, I investigated two classes of geostatistical resampling strategies with regard to their ability to efficiently and accurately generate independent realizations from the Bayesian posterior distribution. The corresponding results indicate that, despite its popularity, sequential resampling is rather inefficient at drawing independent posterior samples for realistic synthetic case studies, notably for the practically common and important scenario of pronounced spatial correlation between model parameters. To address this issue, I have developed a new gradual-deformation-based perturbation approach, which is flexible with regard to the number of model parameters as well as the perturbation strength. Compared to sequential resampling, this newly proposed approach was proven to be highly effective in decreasing the number of iterations required for drawing independent samples from the Bayesian posterior distribution.

Sound objects in time, space and action

SOUND OBJECTS IN TIME, SPACE AND ACTIONThe term "sound object" describes an auditory experience that is associated with an acoustic event produced by a sound source. At cortical level, sound objects are represented by temporo-spatial activity patterns within distributed neural networks. This investigation concerns temporal, spatial and action aspects as assessed in normal subjects using electrical imaging or measurement of motor activity induced by transcranial magnetic stimulation (TMS).Hearing the same sound again has been shown to facilitate behavioral responses (repetition priming) and to modulate neural activity (repetition suppression). In natural settings the same source is often heard again and again, with variations in spectro-temporal and spatial characteristics. I have investigated how such repeats influence response times in a living vs. non-living categorization task and the associated spatio-temporal patterns of brain activity in humans. Dynamic analysis of distributed source estimations revealed differential sound object representations within the auditory cortex as a function of the temporal history of exposure to these objects. Often heard sounds are coded by a modulation in a bilateral network. Recently heard sounds, independently of the number of previous exposures, are coded by a modulation of a left-sided network.With sound objects which carry spatial information, I have investigated how spatial aspects of the repeats influence neural representations. Dynamics analyses of distributed source estimations revealed an ultra rapid discrimination of sound objects which are characterized by spatial cues. This discrimination involved two temporo-spatially distinct cortical representations, one associated with position-independent and the other with position-linked representations within the auditory ventral/what stream.Action-related sounds were shown to increase the excitability of motoneurons within the primary motor cortex, possibly via an input from the mirror neuron system. The role of motor representations remains unclear. I have investigated repetition priming-induced plasticity of the motor representations of action sounds with the measurement of motor activity induced by TMS pulses applied on the hand motor cortex. TMS delivered to the hand area within the primary motor cortex yielded larger magnetic evoked potentials (MEPs) while the subject was listening to sounds associated with manual than non- manual actions. Repetition suppression was observed at motoneuron level, since during a repeated exposure to the same manual action sound the MEPs were smaller. I discuss these results in terms of specialized neural network involved in sound processing, which is characterized by repetition-induced plasticity.Thus, neural networks which underlie sound object representations are characterized by modulations which keep track of the temporal and spatial history of the sound and, in case of action related sounds, also of the way in which the sound is produced.LES OBJETS SONORES AU TRAVERS DU TEMPS, DE L'ESPACE ET DES ACTIONSLe terme "objet sonore" décrit une expérience auditive associée avec un événement acoustique produit par une source sonore. Au niveau cortical, les objets sonores sont représentés par des patterns d'activités dans des réseaux neuronaux distribués. Ce travail traite les aspects temporels, spatiaux et liés aux actions, évalués à l'aide de l'imagerie électrique ou par des mesures de l'activité motrice induite par stimulation magnétique trans-crânienne (SMT) chez des sujets sains. Entendre le même son de façon répétitive facilite la réponse comportementale (amorçage de répétition) et module l'activité neuronale (suppression liée à la répétition). Dans un cadre naturel, la même source est souvent entendue plusieurs fois, avec des variations spectro-temporelles et de ses caractéristiques spatiales. J'ai étudié la façon dont ces répétitions influencent le temps de réponse lors d'une tâche de catégorisation vivant vs. non-vivant, et les patterns d'activité cérébrale qui lui sont associés. Des analyses dynamiques d'estimations de sources ont révélé des représentations différenciées des objets sonores au niveau du cortex auditif en fonction de l'historique d'exposition à ces objets. Les sons souvent entendus sont codés par des modulations d'un réseau bilatéral. Les sons récemment entendus sont codé par des modulations d'un réseau du côté gauche, indépendamment du nombre d'expositions. Avec des objets sonores véhiculant de l'information spatiale, j'ai étudié la façon dont les aspects spatiaux des sons répétés influencent les représentations neuronales. Des analyses dynamiques d'estimations de sources ont révélé une discrimination ultra rapide des objets sonores caractérisés par des indices spatiaux. Cette discrimination implique deux représentations corticales temporellement et spatialement distinctes, l'une associée à des représentations indépendantes de la position et l'autre à des représentations liées à la position. Ces représentations sont localisées dans la voie auditive ventrale du "quoi".Des sons d'actions augmentent l'excitabilité des motoneurones dans le cortex moteur primaire, possiblement par une afférence du system des neurones miroir. Le rôle des représentations motrices des sons d'actions reste peu clair. J'ai étudié la plasticité des représentations motrices induites par l'amorçage de répétition à l'aide de mesures de potentiels moteurs évoqués (PMEs) induits par des pulsations de SMT sur le cortex moteur de la main. La SMT appliquée sur le cortex moteur primaire de la main produit de plus grands PMEs alors que les sujets écoutent des sons associée à des actions manuelles en comparaison avec des sons d'actions non manuelles. Une suppression liée à la répétition a été observée au niveau des motoneurones, étant donné que lors de l'exposition répétée au son de la même action manuelle les PMEs étaient plus petits. Ces résultats sont discuté en termes de réseaux neuronaux spécialisés impliqués dans le traitement des sons et caractérisés par de la plasticité induite par la répétition. Ainsi, les réseaux neuronaux qui sous-tendent les représentations des objets sonores sont caractérisés par des modulations qui gardent une trace de l'histoire temporelle et spatiale du son ainsi que de la manière dont le son a été produit, en cas de sons d'actions.

Multiple-scale hydrological and geophysical data integration through non-linear Bayesian sequential simulation

Significant progress has been made with regard to the quantitative integration of geophysical and hydrological data at the local scale. However, extending the corresponding approaches to the scale of a field site represents a major, and as-of-yet largely unresolved, challenge. To address this problem, we have developed downscaling procedure based on a non-linear Bayesian sequential simulation approach. The main objective of this algorithm is to estimate the value of the sparsely sampled hydraulic conductivity at non-sampled locations based on its relation to the electrical conductivity logged at collocated wells and surface resistivity measurements, which are available throughout the studied site. The in situ relationship between the hydraulic and electrical conductivities is described through a non-parametric multivariatekernel density function. Then a stochastic integration of low-resolution, large-scale electrical resistivity tomography (ERT) data in combination with high-resolution, local-scale downhole measurements of the hydraulic and electrical conductivities is applied. The overall viability of this downscaling approach is tested and validated by comparing flow and transport simulation through the original and the upscaled hydraulic conductivity fields. Our results indicate that the proposed procedure allows obtaining remarkably faithful estimates of the regional-scale hydraulic conductivity structure and correspondingly reliable predictions of the transport characteristics over relatively long distances.

Control of optical fields and single photon emitters by advanced nanoantenna structures

The control of optical fields on the nanometre scale is becoming an increasingly important tool in many fields, ranging from channelling light delivery in photovoltaics and light emitting diodes to increasing the sensitivity of chemical sensors to single molecule levels. The ability to design and manipulate light fields with specific frequency and space characteristics is explored in this project. We present an alternative realisation of Extraordinary Optical Transmission (EOT) that requires only a single aperture and a coupled waveguide. We show how this waveguide-resonant EOT improves the transmissivity of single apertures. An important technique in imaging is Near-Field Scanning Optical Microscopy (NSOM); we show how waveguide-resonant EOT and the novel probe design assist in improving the efficiency of NSOM probes by two orders of magnitude, and allow the imaging of single molecules with an optical resolution of as good as 50 nm. We show how optical antennas are fabricated into the apex of sharp tips and can be used in a near-field configuration.

On separation of a degenerate differential operator in Hilbert space

A coercive estimate for a solution of a degenerate second order di fferential equation is installed, and its applications to spectral problems for the corresponding dif ferential operator is demonstrated. The suffi cient conditions for existence of the solutions of one class of the nonlinear second order diff erential equations on the real axis are obtained.

Mesurer la stigmatisaion perçue chez les personnes souffrant de troubles psychiques : traduction française, validation et adaptation de la Stigma Scale

L'objectif de l'étude présentée est d'adapter et de valider une version française de la Stigma Scale (King, 2007) auprès d'une population de personnes souffrant de troubles psychiques. Dans une première phase, la stabilité temporelle (fidélité test-retest), la cohérence interne et la validité convergente de l'instrument original à 28 items traduit en français ont été évaluées auprès d'un échantillon de 183 patients. Les résultats d'analyses factorielles confirmatoires ne nous ont pas permis de confirmer la structure originale de l'instrument. Nous avons donc proposé, sur la base des résultats d'une analyse factorielle exploratoire, une version courte de l'échelle de stigmatisation (9 items) qui conserve la structure en trois facteurs du modèle original. Dans une deuxième phase, nous avons examiné les qualités psychométriques et validé cette version abrégée de l'échelle de stigmatisation auprès d'un second échantillon de 234 patients. Les indices d'ajustements de notre analyse factorielle confirmatoire confirme la structure en trois facteurs de la version abrégée de la Stigma Scale. Les résultats suggèrent que la version française abrégée de l'échelle de stigmatisation constitue un instrument utile, fiable et valide dans l'autoévaluation de la stigmatisation perçue par des personnes souffrant de troubles psychiques. - Aim People suffering from mental illness are exposed to stigma. However, only few tools are available to assess stigmatization as perceived from the patient's perspective. The aim of this study is to adapt and validate a French version of the Stigma Scale (King, 2007). This self-report questionnaire has a three-factor structure: discrimination, disclosure and positive aspects of mental illness. Discrimination subscale refers to perceived negative reactions by others. Disclosure subscale refers mainly to managing disclosure to avoid discrimination and finally positive aspects subscale taps into how patients are becoming more accepting, more understanding toward their illness. Method In the first step, internal consistency, convergent validity and test-retest reliability of the French adaptation of the 28-item scale have been assessed on a sample of 183 patients. Results of confirmatory factor analyses (CFA) did not confirm the hypothesized structure. In light of the failed attempts to validate the original version, an alternative 9-item short-form version of the Stigma Scale, maintaining the integrity of the original model, was developed based on results of exploratory factor analyses in the first sample and cross- validated in a new sample of 234 patients. Results Results of CFA did not confirm that the data fitted well to the three-factor model of the 28-item Stigma Scale (χ2/άί=2.02, GFI=0.77, AGFI=0.73, RMSEA=0.07, CFI=0.77 et NNFI=0.75). Cronbach's α are excellent for discrimination (0.84) and disclosure (0.83) subscales but poor for potential positive aspects (0.46). External validity is satisfactory. Overall Stigma Scale total score is negatively correlated with score on Rosenberg's Self-Esteem Scale (r = -0.49), and each sub-scale is significantly correlated with a visual analogue scale that refers to the specific aspect of stigma (0.43 < |r| < 0.60). Intraclass correlation coefficients between 0.68 and 0.89 indicate good test- retest reliability. Results of CFA demonstrate that the items chosen for the short version of the Stigma Scale have the expected fit properties fa2/df=1.02, GFI=0.98, AGFI=0.98, RMSEA=0.01, CFI=1.0 et NNFI=1.0). Considering the small number (3 items) of items in each subscales of the short version of the Stigma Scale, a coefficients for the discrimination (0.57), disclosure (0.80) and potential positive aspects subscales (0.62) are considered as good. Conclusion Our results suggest that the 9-item French short-version of the Stigma Scale is a useful, reliable and valid self-report questionnaire to assess perceived stigmatization in people suffering from mental illness. The time of completion is really short and questions are well understood and accepted by the patients.

Validation of an adapted falls efficacy scale in older rehabilitation patients.

OBJECTIVE: To determine the psychometric properties of an adapted version of the Falls Efficacy Scale (FES) in older rehabilitation patients. DESIGN: Cross-sectional survey. SETTING: Postacute rehabilitation facility in Switzerland. PARTICIPANTS: Seventy elderly persons aged 65 years and older receiving postacute, inpatient rehabilitation. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: FES questions asked about subject's confidence (range, 0 [none]-10 [full]) in performing 12 activities of daily living (ADLs) without falling. Construct validity was assessed using correlation with measures of physical (basic ADLs [BADLs]), cognitive (Mini-Mental State Examination [MMSE]), affective (15-item Geriatric Depression Scale [GDS]), and mobility (Performance Oriented Mobility Assessment [POMA]) performance. Predictive validity was assessed using the length of rehabilitation stay as the outcome. To determine test-retest reliability, FES administration was repeated in a random subsample (n=20) within 72 hours. RESULTS: FES scores ranged from 10 to 120 (mean, 88.7+/-26.5). Internal consistency was optimal (Cronbach alpha=.90), and item-to-total correlations were all significant, ranging from .56 (toilet use) to .82 (reaching into closets). Test-retest reliability was high (intraclass correlation coefficient, .97; 95% confidence interval, .95-.99; P<.001). Subjects reporting a fall in the previous year had lower FES scores than nonfallers (85.0+/-25.2 vs 94.4+/-27.9, P=.054). The FES correlated with POMA (Spearman rho=.40, P<.001), MMSE (rho=.37, P=.001), BADL (rho=.43, P<.001), and GDS (rho=-.53, P<.001) scores. These relationships remained significant in multivariable analysis for BADLs and GDS, confirming FES construct validity. There was a significant inverse relationship between FES score and the length of rehabilitation stay, independent of sociodemographic, functional, cognitive, and fall status. CONCLUSIONS: This adapted FES is reliable and valid in older patients undergoing postacute rehabilitation. The independent association between poor falls efficacy and increased length of stay has not been previously described and needs further investigations.