Del prestatge a la web: la transformació de la formació de les col·leccions a les biblioteques universitàries

L’existència d’una xarxa mundial de comunicacions ubiqua i barata que cada vegada més permet obtenir documents de manera fàcil i gratuïta requerirà una transformació de les pràctiques de la formació de col·leccions a les biblioteques universitàries. Això estarà impulsat per una sèrie d’avenços específics, que inclouen la digitalització de continguts; el desenvolupament de repositoris d’impresos; el desenvolupament de lectors de llibres electrònics i de l’edició mitjançant la impressió sota demanda; el creixement de l’accés obert; els reptes per establir estructures d’edició acadèmica; i el creixement de noves formes d’activitats acadèmiques basades en l’obertura i la productivitat social. Si les biblioteques universitàries volen tenir èxit, hauran de desmuntar les col·leccions impreses patrimonials; passar de la selecció de llibres ítem a ítem a la compra sota demanda i a les subscripcions; gestionar la transició cap a revistes d’accés obert; centrar-se en conservar ítems únics; i desenvolupar nous mecanismes per finançar una infraestructura nacional.

Quantitative analysis of crystal/grain sizes and their distributions in 2D and 3D

We review methods to estimate the average crystal (grain) size and the crystal (grain) size distribution in solid rocks. Average grain sizes often provide the base for stress estimates or rheological calculations requiring the quantification of grain sizes in a rock's microstructure. The primary data for grain size data are either 1D (i.e. line intercept methods), 2D (area analysis) or 3D (e.g., computed tomography, serial sectioning). These data have been used for different data treatments over the years, whereas several studies assume a certain probability function (e.g., logarithm, square root) to calculate statistical parameters as the mean, median, mode or the skewness of a crystal size distribution. The finally calculated average grain sizes have to be compatible between the different grain size estimation approaches in order to be properly applied, for example, in paleo-piezometers or grain size sensitive flow laws. Such compatibility is tested for different data treatments using one- and two-dimensional measurements. We propose an empirical conversion matrix for different datasets. These conversion factors provide the option to make different datasets compatible with each other, although the primary calculations were obtained in different ways. In order to present an average grain size, we propose to use the area-weighted and volume-weighted mean in the case of unimodal grain size distributions, respectively, for 2D and 3D measurements. The shape of the crystal size distribution is important for studies of nucleation and growth of minerals. The shape of the crystal size distribution of garnet populations is compared between different 2D and 3D measurements, which are serial sectioning and computed tomography. The comparison of different direct measured 3D data; stereological data and direct presented 20 data show the problems of the quality of the smallest grain sizes and the overestimation of small grain sizes in stereological tools, depending on the type of CSD. (C) 2011 Published by Elsevier Ltd.

AssociationViewer: a scalable and integrated software tool for visualization of large-scale variation data in genomic context.

SUMMARY: We present a tool designed for visualization of large-scale genetic and genomic data exemplified by results from genome-wide association studies. This software provides an integrated framework to facilitate the interpretation of SNP association studies in genomic context. Gene annotations can be retrieved from Ensembl, linkage disequilibrium data downloaded from HapMap and custom data imported in BED or WIG format. AssociationViewer integrates functionalities that enable the aggregation or intersection of data tracks. It implements an efficient cache system and allows the display of several, very large-scale genomic datasets. AVAILABILITY: The Java code for AssociationViewer is distributed under the GNU General Public Licence and has been tested on Microsoft Windows XP, MacOSX and GNU/Linux operating systems. It is available from the SourceForge repository. This also includes Java webstart, documentation and example datafiles.

Decoding stimulus-related information from single-trial EEG responses based on voltage topographies

Neuroimaging studies typically compare experimental conditions using average brain responses, thereby overlooking the stimulus-related information conveyed by distributed spatio-temporal patterns of single-trial responses. Here, we take advantage of this rich information at a single-trial level to decode stimulus-related signals in two event-related potential (ERP) studies. Our method models the statistical distribution of the voltage topographies with a Gaussian Mixture Model (GMM), which reduces the dataset to a number of representative voltage topographies. The degree of presence of these topographies across trials at specific latencies is then used to classify experimental conditions. We tested the algorithm using a cross-validation procedure in two independent EEG datasets. In the first ERP study, we classified left- versus right-hemifield checkerboard stimuli for upper and lower visual hemifields. In a second ERP study, when functional differences cannot be assumed, we classified initial versus repeated presentations of visual objects. With minimal a priori information, the GMM model provides neurophysiologically interpretable features - vis à vis voltage topographies - as well as dynamic information about brain function. This method can in principle be applied to any ERP dataset testing the functional relevance of specific time periods for stimulus processing, the predictability of subject's behavior and cognitive states, and the discrimination between healthy and clinical populations.

Microvascular burden and Alzheimer-type lesions across the age spectrum.

The occurrence of microvascular and small macrovascular lesions and Alzheimer's disease (AD)-related pathology in the aging human brain is a well-described phenomenon. Although there is a wide consensus about the relationship between macroscopic vascular lesions and incident dementia, the cognitive consequences of the progressive accumulation of these small vascular lesions in the human brain are still a matter of debate. Among the vast group of small vessel-related forms of ischemic brain injuries, the present review discusses the cognitive impact of cortical microinfarcts, subcortical gray matter and deep white matter lacunes, periventricular and diffuse white matter demyelinations, and focal or diffuse gliosis in old age. A special focus will be on the sub-types of microvascular lesions not detected by currently available neuroimaging studies in routine clinical settings. After providing a critical overview of in vivo data on white matter demyelinations and lacunes, we summarize the clinicopathological studies performed by our center in large cohorts of individuals with microvascular lesions and concomitant AD-related pathology across two age ranges (the younger old, 65-85 years old, versus the oldest old, nonagenarians and centenarians). In conjunction with other autopsy datasets, these observations fully support the idea that cortical microinfarcts are the only consistent determinant of cognitive decline across the entire spectrum from pure vascular cases to cases with combined vascular and AD lesion burden.

Statistical analysis and modelling of weather radar beam propagation conditions in the Po Valley (Italy)

Ground clutter caused by anomalous propagation (anaprop) can affect seriously radar rain rate estimates, particularly in fully automatic radar processing systems, and, if not filtered, can produce frequent false alarms. A statistical study of anomalous propagation detected from two operational C-band radars in the northern Italian region of Emilia Romagna is discussed, paying particular attention to its diurnal and seasonal variability. The analysis shows a high incidence of anaprop in summer, mainly in the morning and evening, due to the humid and hot summer climate of the Po Valley, particularly in the coastal zone. Thereafter, a comparison between different techniques and datasets to retrieve the vertical profile of the refractive index gradient in the boundary layer is also presented. In particular, their capability to detect anomalous propagation conditions is compared. Furthermore, beam path trajectories are simulated using a multilayer ray-tracing model and the influence of the propagation conditions on the beam trajectory and shape is examined. High resolution radiosounding data are identified as the best available dataset to reproduce accurately the local propagation conditions, while lower resolution standard TEMP data suffers from interpolation degradation and Numerical Weather Prediction model data (Lokal Model) are able to retrieve a tendency to superrefraction but not to detect ducting conditions. Observing the ray tracing of the centre, lower and upper limits of the radar antenna 3-dB half-power main beam lobe it is concluded that ducting layers produce a change in the measured volume and in the power distribution that can lead to an additional error in the reflectivity estimate and, subsequently, in the estimated rainfall rate.

The Coordinated Radio and Infrared Survey for High-Mass Star Formation (The CORNISH Survey). I. Survey Design

We describe the motivation, design, and implementation of the CORNISH survey, an arcsecondresolution radio continuum survey of the inner galactic plane at 5 GHz using the Very Large Array (VLA). It is a blind survey coordinated with the northern SpitzerGLIMPSE I region covering 10° legacy applications beyond star formation, including evolved stars, active stars and binaries, and extragalactic sources. The CORNISH survey for compact ionized sources complements other Galactic plane surveys that target diffuse and nonthermal sources, as well as atomic and molecular phases to build up a complete picture of the interstellar medium in the Galaxy.

Panoràmica dels sistemes de gestió de biblioteques al segle XXI

In the past decade, a number of trends have come together in the general sphere of computing that have profoundly affected libraries. The popularisation of the Internet, the appearance of open and interoperable systems, the improvements within graphics and multimedia, and the generalised installation of LANs are some of the events of the period. Taken together, the result has been that libraries have undergone an important functional change, representing the switch from simple information depositories to information disseminators. Integrated library management systems have not remained unaffected by this transformation and those that have not adapted to the new technological surroundings are now referred to as legacy systems. The article describes the characteristics of systems existing in today's market and outlines future trends that, according to various authors, include the disappearance of the integrated library management systems that have traditionally been sold.

2011 - 2015 Iowa Transportation Improvement Program

The Iowa Transportation Improvement Program (Program) is published to inform Iowans of planned investments in our state’s transportation system. The Iowa Transportation Commission (Commission) and Iowa Department of Transportation (Iowa DOT) are committed to programming those investments in a fiscally responsible manner. This document serves as the Iowa DOT's annual report as required by Iowa Code section 7A.9. This document reflects Iowa’s multimodal transportation system by the inclusion of investments in aviation, transit, railroads, trails, and highways. A major component of this program is the highway section that documents programmed investments on the primary highway system for the next five years. A large part of funding available for highway programming comes from the federal government. Accurately estimating future funding levels of this federal funding is dependent on having a current enacted multi-year federal transportation authorization. The most recent authorization, Safe, Accountable, Flexible, Efficient Transportation Equity Act: A Legacy for Users (SAFETEA-LU), expired September 30, 2009, and to date it has been extended five times because a new authorization has not yet been enacted. The current extension expires December 31, 2010. While Iowa law does not require the adoption of a Program when federal transportation funding is being reauthorized, the Commission believes it is important to adopt a Program in order to continue on-going planning and project development efforts and to be well positioned when a new authorization is adopted. However, it is important to recognize that, absent a federal authorization bill, there is significant uncertainty in the forecast of federal revenues. The Commission and the Iowa DOT will continue to monitor federal revenues and will adjust future investments as needed to maintain a fiscally responsible Program. In developing the highway section of the program, the Commission’s primary investment objective remains stewardship (i.e. safety, maintenance and preservation) of Iowa’s existing highway system. In fact, over $1.2 billion is programmed in FY2011 through FY2015 for preservation of Iowa’s existing highway system and for enhanced highway safety features. The highway section also includes significant investments for interstate modernization on I-29 inSioux City, on I-29/80/480 in Council Bluffs, and on I-74 in Bettendorf/ Davenport. Another highway programming objective reflected in this Program is maintaining the scheduled completion of capacity and economic development projects that were identified in the previous Program. Finally, with the limited remaining funds the Commission has furthered the investment in capacity and economic development by adding a few projects to the Program. The Iowa DOT and Commission appreciate the public’s involvement in the state’s transportation planning process. Comments received personally, by letter or through participation in the Commission’s regular meetings or public input meetings held around the state each year, are invaluable in providing guidance for the future of Iowa’s transportation system.

2012-2016 Iowa Transportation Improvement Program

The Iowa Transportation Improvement Program (Program) is published to inform Iowans of planned investments in our state’s transportation system. The Iowa Transportation Commission (Commission) and Iowa Department of Transportation (Iowa DOT) are committed to programming those investments in a fiscally responsible manner. This document reflects Iowa’s multimodal transportation system by the inclusion of investments in aviation, transit, railroads, trails, and highways. A major component of this program is the highway section that documents programmed investments on the primary highway system for the next five years. A large part of funding available for highway programming comes from the federal government. Accurately estimating future federal funding levels is dependent on having a current enacted multi-year federal transportation authorization. The most recent authorization, Safe, Accountable, Flexible, Efficient Transportation Equity Act: A Legacy for Users (SAFETEA-LU), expired September 30, 2009, and to date it has been extended seven times because a new authorization has not yet been enacted. The current extension will expire September 30, 2011. This leads to significant uncertainty in federal funding; however, it is becoming evident that, in Federal Fiscal Year 2012 and beyond, federal funding revenue will likely be reduced by 25 percent from current levels in order to match revenue that flows into the Highway Trust Fund. This Program reflects this anticipated reduction in federal funding. While Iowa law does not require the adoption of a Program when federal transportation funding is being reauthorized, the Commission believes it is important to adopt a Program in order to continue on-going planning and project development efforts so that Iowa will be well positioned when a new authorization is adopted. However, it is important to recognize that, absent a federal authorization bill, there is significant uncertainty in the forecast of federal revenues. The Commission and the Iowa DOT will continue to monitor federal revenues and will adjust future investments as needed to maintain a fiscally responsible Program. For 2012-2016, approximately $2.3 billion is forecast to be available for highway right of way and construction. In developing the highway section of the Program, the Commission’s primary investment objective remains stewardship (i.e. safety, maintenance and preservation) of Iowa’s existing highway system. Over $1.3 billion is programmed in FY2012 through FY2016 for preservation of Iowa’s existing highway system and for enhanced highway safety features. The highway section also includes significant interstate investments on I-29 in Sioux City, I-29/80/480 in Council Bluffs, and I-74 in Bettendorf/Davenport. The FY2016 programming for construction on I-74 in Bettendorf/Davenport is the first of several years of significant investments that will be monitored for available funding. Approximately $200 million of the investments on these three major urban interstate projects address preservation needs. In total, approximately $1.5 billion is programmed for highway preservation activities for 2012- 2016. Another highway programming objective is maintaining the scheduled completion of capacity and economic development projects. Projects that were previously scheduled to be completed within the previous Program continue on their current schedule. However, due to the reduction of projected federal revenues, the Commission has delayed by one year the initiation of construction of all multi-year non-Interstate capacity and economic development projects that cannot be completed within this Program. These projects are U.S. 20 in Woodbury County, U.S. 30 in Benton County, U.S. 61 in Louisa County, and Iowa 100 in Linn County. The Iowa DOT and Commission appreciate the public’s involvement in the state’s transportation planning process. Comments received personally, by letter or through participation in the Commission’s regular meetings or public input meetings held around the state each year, are invaluable in providing guidance for the future of Iowa’s transportation system. It should be noted that this document is a planning guide. It does not represent a binding commitment or obligation of the Commission or Iowa DOT, and is subject to change.

BIO-INSPIRED COMPUTATIONAL TECHNIQUES APPLIED TO THE CLUSTERING AND VISUALIZATION OF SPATIO-TEMPORAL GEOSPATIAL DATA

The coverage and volume of geo-referenced datasets are extensive and incessantly¦growing. The systematic capture of geo-referenced information generates large volumes¦of spatio-temporal data to be analyzed. Clustering and visualization play a key¦role in the exploratory data analysis and the extraction of knowledge embedded in¦these data. However, new challenges in visualization and clustering are posed when¦dealing with the special characteristics of this data. For instance, its complex structures,¦large quantity of samples, variables involved in a temporal context, high dimensionality¦and large variability in cluster shapes.¦The central aim of my thesis is to propose new algorithms and methodologies for¦clustering and visualization, in order to assist the knowledge extraction from spatiotemporal¦geo-referenced data, thus improving making decision processes.¦I present two original algorithms, one for clustering: the Fuzzy Growing Hierarchical¦Self-Organizing Networks (FGHSON), and the second for exploratory visual data analysis:¦the Tree-structured Self-organizing Maps Component Planes. In addition, I present¦methodologies that combined with FGHSON and the Tree-structured SOM Component¦Planes allow the integration of space and time seamlessly and simultaneously in¦order to extract knowledge embedded in a temporal context.¦The originality of the FGHSON lies in its capability to reflect the underlying structure¦of a dataset in a hierarchical fuzzy way. A hierarchical fuzzy representation of¦clusters is crucial when data include complex structures with large variability of cluster¦shapes, variances, densities and number of clusters. The most important characteristics¦of the FGHSON include: (1) It does not require an a-priori setup of the number¦of clusters. (2) The algorithm executes several self-organizing processes in parallel.¦Hence, when dealing with large datasets the processes can be distributed reducing the¦computational cost. (3) Only three parameters are necessary to set up the algorithm.¦In the case of the Tree-structured SOM Component Planes, the novelty of this algorithm¦lies in its ability to create a structure that allows the visual exploratory data analysis¦of large high-dimensional datasets. This algorithm creates a hierarchical structure¦of Self-Organizing Map Component Planes, arranging similar variables' projections in¦the same branches of the tree. Hence, similarities on variables' behavior can be easily¦detected (e.g. local correlations, maximal and minimal values and outliers).¦Both FGHSON and the Tree-structured SOM Component Planes were applied in¦several agroecological problems proving to be very efficient in the exploratory analysis¦and clustering of spatio-temporal datasets.¦In this thesis I also tested three soft competitive learning algorithms. Two of them¦well-known non supervised soft competitive algorithms, namely the Self-Organizing¦Maps (SOMs) and the Growing Hierarchical Self-Organizing Maps (GHSOMs); and the¦third was our original contribution, the FGHSON. Although the algorithms presented¦here have been used in several areas, to my knowledge there is not any work applying¦and comparing the performance of those techniques when dealing with spatiotemporal¦geospatial data, as it is presented in this thesis.¦I propose original methodologies to explore spatio-temporal geo-referenced datasets¦through time. Our approach uses time windows to capture temporal similarities and¦variations by using the FGHSON clustering algorithm. The developed methodologies¦are used in two case studies. In the first, the objective was to find similar agroecozones¦through time and in the second one it was to find similar environmental patterns¦shifted in time.¦Several results presented in this thesis have led to new contributions to agroecological¦knowledge, for instance, in sugar cane, and blackberry production.¦Finally, in the framework of this thesis we developed several software tools: (1)¦a Matlab toolbox that implements the FGHSON algorithm, and (2) a program called¦BIS (Bio-inspired Identification of Similar agroecozones) an interactive graphical user¦interface tool which integrates the FGHSON algorithm with Google Earth in order to¦show zones with similar agroecological characteristics.

Occupational respiratory exposures to irritating and sensitizing volatile compounds deriving from cleaning products

Recent findings suggest an association between exposure to cleaning products and respiratory dysfunctions including asthma. However, little information is available about quantitative airborne exposures of professional cleaners to volatile organic compounds deriving from cleaning products. During the first phases of the study, a systematic review of cleaning products was performed. Safety data sheets were reviewed to assess the most frequently added volatile organic compounds. It was found that professional cleaning products are complex mixtures of different components (compounds in cleaning products: 3.5 ± 2.8), and more than 130 chemical substances listed in the safety data sheets were identified in 105 products. The main groups of chemicals were fragrances, glycol ethers, surfactants, solvents; and to a lesser extent phosphates, salts, detergents, pH-stabilizers, acids, and bases. Up to 75% of products contained irritant (Xi), 64% harmful (Xn) and 28% corrosive (C) labeled substances. Hazards for eyes (59%), skin (50%) and by ingestion (60%) were the most reported. Monoethanolamine, a strong irritant and known to be involved in sensitizing mechanisms as well as allergic reactions, is frequently added to cleaning products. Monoethanolamine determination in air has traditionally been difficult and air sampling and analysis methods available were little adapted for personal occupational air concentration assessments. A convenient method was developed with air sampling on impregnated glass fiber filters followed by one step desorption, gas chromatography and nitrogen phosphorous selective detection. An exposure assessment was conducted in the cleaning sector, to determine airborne concentrations of monoethanolamine, glycol ethers, and benzyl alcohol during different cleaning tasks performed by professional cleaning workers in different companies, and to determine background air concentrations of formaldehyde, a known indoor air contaminant. The occupational exposure study was carried out in 12 cleaning companies, and personal air samples were collected for monoethanolamine (n=68), glycol ethers (n=79), benzyl alcohol (n=15) and formaldehyde (n=45). All but ethylene glycol mono-n-butyl ether air concentrations measured were far below (<1/10) of the Swiss eight hours occupational exposure limits, except for butoxypropanol and benzyl alcohol, where no occupational exposure limits were available. Although only detected once, ethylene glycol mono-n-butyl ether air concentrations (n=4) were high (49.5 mg/m3 to 58.7 mg/m3), hovering at the Swiss occupational exposure limit (49 mg/m3). Background air concentrations showed no presence of monoethanolamine, while the glycol ethers were often present, and formaldehyde was universally detected. Exposures were influenced by the amount of monoethanolamine in the cleaning product, cross ventilation and spraying. The collected data was used to test an already existing exposure modeling tool during the last phases of the study. The exposure estimation of the so called Bayesian tool converged with the measured range of exposure the more air concentrations of measured exposure were added. This was best described by an inverse 2nd order equation. The results suggest that the Bayesian tool is not adapted to predict low exposures. The Bayesian tool should be tested also with other datasets describing higher exposures. Low exposures to different chemical sensitizers and irritants should be further investigated to better understand the development of respiratory disorders in cleaning workers. Prevention measures should especially focus on incorrect use of cleaning products, to avoid high air concentrations at the exposure limits. - De récentes études montrent l'existence d'un lien entre l'exposition aux produits de nettoyages et les maladies respiratoires telles que l'asthme. En revanche, encore peu d'informations sont disponibles concernant la quantité d'exposition des professionnels du secteur du nettoyage aux composants organiques volatiles provenant des produits qu'ils utilisent. Pendant la première phase de cette étude, un recueil systématique des produits professionnels utilisés dans le secteur du nettoyage a été effectué. Les fiches de données de sécurité de ces produits ont ensuite été analysées, afin de répertorier les composés organiques volatiles les plus souvent utilisés. Il a été mis en évidence que les produits de nettoyage professionnels sont des mélanges complexes de composants chimiques (composants chimiques dans les produits de nettoyage : 3.5 ± 2.8). Ainsi, plus de 130 substances listées dans les fiches de données de sécurité ont été retrouvées dans les 105 produits répertoriés. Les principales classes de substances chimiques identifiées étaient les parfums, les éthers de glycol, les agents de surface et les solvants; dans une moindre mesure, les phosphates, les sels, les détergents, les régulateurs de pH, les acides et les bases ont été identifiés. Plus de 75% des produits répertoriés contenaient des substances décrites comme irritantes (Xi), 64% nuisibles (Xn) et 28% corrosives (C). Les risques pour les yeux (59%), la peau (50%) et par ingestion (60%) était les plus mentionnés. La monoéthanolamine, un fort irritant connu pour être impliqué dans les mécanismes de sensibilisation tels que les réactions allergiques, est fréquemment ajouté aux produits de nettoyage. L'analyse de la monoéthanolamine dans l'air a été habituellement difficile et les échantillons d'air ainsi que les méthodes d'analyse déjà disponibles étaient peu adaptées à l'évaluation de la concentration individuelle d'air aux postes de travail. Une nouvelle méthode plus efficace a donc été développée en captant les échantillons d'air sur des filtres de fibre de verre imprégnés, suivi par une étape de désorption, puis une Chromatographie des gaz et enfin une détection sélective des composants d'azote. Une évaluation de l'exposition des professionnels a été réalisée dans le secteur du nettoyage afin de déterminer la concentration atmosphérique en monoéthanolamine, en éthers de glycol et en alcool benzylique au cours des différentes tâches de nettoyage effectuées par les professionnels du nettoyage dans différentes entreprises, ainsi que pour déterminer les concentrations atmosphériques de fond en formaldéhyde, un polluant de l'air intérieur bien connu. L'étude de l'exposition professionnelle a été effectuée dans 12 compagnies de nettoyage et les échantillons d'air individuels ont été collectés pour l'éthanolamine (n=68), les éthers de glycol (n=79), l'alcool benzylique (n=15) et le formaldéhyde (n=45). Toutes les substances mesurées dans l'air, excepté le 2-butoxyéthanol, étaient en-dessous (<1/10) de la valeur moyenne d'exposition aux postes de travail en Suisse (8 heures), excepté pour le butoxypropanol et l'alcool benzylique, pour lesquels aucune valeur limite d'exposition n'était disponible. Bien que détecté qu'une seule fois, les concentrations d'air de 2-butoxyéthanol (n=4) étaient élevées (49,5 mg/m3 à 58,7 mg/m3), se situant au-dessus de la frontière des valeurs limites d'exposition aux postes de travail en Suisse (49 mg/m3). Les concentrations d'air de fond n'ont montré aucune présence de monoéthanolamine, alors que les éthers de glycol étaient souvent présents et les formaldéhydes quasiment toujours détectés. L'exposition des professionnels a été influencée par la quantité de monoéthanolamine présente dans les produits de nettoyage utilisés, par la ventilation extérieure et par l'emploie de sprays. Durant la dernière phase de l'étude, les informations collectées ont été utilisées pour tester un outil de modélisation de l'exposition déjà existant, l'outil de Bayesian. L'estimation de l'exposition de cet outil convergeait avec l'exposition mesurée. Cela a été le mieux décrit par une équation du second degré inversée. Les résultats suggèrent que l'outil de Bayesian n'est pas adapté pour mettre en évidence les taux d'expositions faibles. Cet outil devrait également être testé avec d'autres ensembles de données décrivant des taux d'expositions plus élevés. L'exposition répétée à des substances chimiques ayant des propriétés irritatives et sensibilisantes devrait être investiguée d'avantage, afin de mieux comprendre l'apparition de maladies respiratoires chez les professionnels du nettoyage. Des mesures de prévention devraient tout particulièrement être orientées sur l'utilisation correcte des produits de nettoyage, afin d'éviter les concentrations d'air élevées se situant à la valeur limite d'exposition acceptée.

Estudi de l'estat de Salut autopercebut: Modelització de l'índex d'utilitat EQ-5D mitjançant un model tobit

Objective: Health status measures usually have an asymmetric distribution and present a highpercentage of respondents with the best possible score (ceiling effect), specially when they areassessed in the overall population. Different methods to model this type of variables have beenproposed that take into account the ceiling effect: the tobit models, the Censored Least AbsoluteDeviations (CLAD) models or the two-part models, among others. The objective of this workwas to describe the tobit model, and compare it with the Ordinary Least Squares (OLS) model,that ignores the ceiling effect.Methods: Two different data sets have been used in order to compare both models: a) real datacomming from the European Study of Mental Disorders (ESEMeD), in order to model theEQ5D index, one of the measures of utilities most commonly used for the evaluation of healthstatus; and b) data obtained from simulation. Cross-validation was used to compare thepredicted values of the tobit model and the OLS models. The following estimators werecompared: the percentage of absolute error (R1), the percentage of squared error (R2), the MeanSquared Error (MSE) and the Mean Absolute Prediction Error (MAPE). Different datasets werecreated for different values of the error variance and different percentages of individuals withceiling effect. The estimations of the coefficients, the percentage of explained variance and theplots of residuals versus predicted values obtained under each model were compared.Results: With regard to the results of the ESEMeD study, the predicted values obtained with theOLS model and those obtained with the tobit models were very similar. The regressioncoefficients of the linear model were consistently smaller than those from the tobit model. In thesimulation study, we observed that when the error variance was small (s=1), the tobit modelpresented unbiased estimations of the coefficients and accurate predicted values, specially whenthe percentage of individuals wiht the highest possible score was small. However, when theerrror variance was greater (s=10 or s=20), the percentage of explained variance for the tobitmodel and the predicted values were more similar to those obtained with an OLS model.Conclusions: The proportion of variability accounted for the models and the percentage ofindividuals with the highest possible score have an important effect in the performance of thetobit model in comparison with the linear model.

Cheminformatic studies of molecular properties and their influence on bioactivity in the context of drug discovery

Molecular shape has long been known to be an important property for the process of molecular recognition. Previous studies postulated the existence of a drug-like shape space that could be used to artificially bias the composition of screening libraries, with the aim to increase the chance of success in Hit Identification. In this work, it was analysed to which extend this assumption holds true. Normalized Principal Moments of Inertia Ratios (NPRs) have been used to describe the molecular shape of small molecules. It was investigated, whether active molecules of diverse targets are located in preferred subspaces of the NPR shape space. Results illustrated a significantly stronger clustering than could be expected by chance, with parts of the space unlikely to be occupied by active compounds. Furthermore, a strong enrichment of elongated, rather flat shapes could be observed, while globular compounds were highly underrepresented. This was confirmed for a wide range of small molecule datasets from different origins. Active compounds exhibited a high overlap in their shape distributions across different targets, making a purely shape­ based discrimination very difficult. An additional perspective was provided by comparing the shapes of protein binding pockets with those of their respective ligands. Although more globular than their ligands, it was observed that binding sites shapes exhibited a similarly skewed distribution in shape space: spherical shapes were highly underrepresented. This was different for unoccupied binding pockets of smaller size. These were on the contrary identified to possess a more globular shape. The relation between shape complementarity and exhibited bioactivity was analysed; a moderate correlation between bioactivity and parameters including pocket coverage, distance in shape space, and others could be identified, which reflects the importance of shape complementarity. However, this also suggests that other aspects are of relevance for molecular recognition. A subsequent analysis assessed if and how shape and volume information retrieved from pocket or respective reference ligands could be used as a pre-filter in a virtual screening approach. ln Lead Optimization compounds need to get optimized with respect to a variety of pararneters. Here, the availability of past success stories is very valuable, as they can guide medicinal chemists during their analogue synthesis plans. However, although of tremendous interest for the public domain, so far only large corporations had the ability to mine historical knowledge in their proprietary databases. With the aim to provide such information, the SwissBioisostere database was developed and released during this thesis. This database contains information on 21,293,355 performed substructural exchanges, corresponding to 5,586,462 unique replacements that have been measured in 35,039 assays against 1,948 molecular targets representing 30 target classes, and on their impact on bioactivity . A user-friendly interface was developed that provides facile access to these data and is accessible at http//www.swissbioisostere.ch. The ChEMBL database was used as primary data source of bioactivity information. Matched molecular pairs have been identified in the extracted and cleaned data. Success-based scores were developed and integrated into the database to allow re-ranking of proposed replacements by their past outcomes. It was analysed to which degree these scores correlate with chemical similarity of the underlying fragments. An unexpectedly weak relationship was detected and further investigated. Use cases of this database were envisioned, and functionalities implemented accordingly: replacement outcomes are aggregatable at the assay level, and it was shawn that an aggregation at the target or target class level could also be performed, but should be accompanied by a careful case-by-case assessment. It was furthermore observed that replacement success depends on the activity of the starting compound A within a matched molecular pair A-B. With increasing potency the probability to lose bioactivity through any substructural exchange was significantly higher than in low affine binders. A potential existence of a publication bias could be refuted. Furthermore, often performed medicinal chemistry strategies for structure-activity-relationship exploration were analysed using the acquired data. Finally, data originating from pharmaceutical companies were compared with those reported in the literature. It could be seen that industrial medicinal chemistry can access replacement information not available in the public domain. In contrast, a large amount of often-performed replacements within companies could also be identified in literature data. Preferences for particular replacements differed between these two sources. The value of combining different endpoints in an evaluation of molecular replacements was investigated. The performed studies highlighted furthermore that there seem to exist no universal substructural replacement that always retains bioactivity irrespective of the biological environment. A generalization of bioisosteric replacements seems therefore not possible. - La forme tridimensionnelle des molécules a depuis longtemps été reconnue comme une propriété importante pour le processus de reconnaissance moléculaire. Des études antérieures ont postulé que les médicaments occupent préférentiellement un sous-ensemble de l'espace des formes des molécules. Ce sous-ensemble pourrait être utilisé pour biaiser la composition de chimiothèques à cribler, dans le but d'augmenter les chances d'identifier des Hits. L'analyse et la validation de cette assertion fait l'objet de cette première partie. Les Ratios de Moments Principaux d'Inertie Normalisés (RPN) ont été utilisés pour décrire la forme tridimensionnelle de petites molécules de type médicament. Il a été étudié si les molécules actives sur des cibles différentes se co-localisaient dans des sous-espaces privilégiés de l'espace des formes. Les résultats montrent des regroupements de molécules incompatibles avec une répartition aléatoire, avec certaines parties de l'espace peu susceptibles d'être occupées par des composés actifs. Par ailleurs, un fort enrichissement en formes allongées et plutôt plates a pu être observé, tandis que les composés globulaires étaient fortement sous-représentés. Cela a été confirmé pour un large ensemble de compilations de molécules d'origines différentes. Les distributions de forme des molécules actives sur des cibles différentes se recoupent largement, rendant une discrimination fondée uniquement sur la forme très difficile. Une perspective supplémentaire a été ajoutée par la comparaison des formes des ligands avec celles de leurs sites de liaison (poches) dans leurs protéines respectives. Bien que plus globulaires que leurs ligands, il a été observé que les formes des poches présentent une distribution dans l'espace des formes avec le même type d'asymétrie que celle observée pour les ligands: les formes sphériques sont fortement sous­ représentées. Un résultat différent a été obtenu pour les poches de plus petite taille et cristallisées sans ligand: elles possédaient une forme plus globulaire. La relation entre complémentarité de forme et bioactivité a été également analysée; une corrélation modérée entre bioactivité et des paramètres tels que remplissage de poche, distance dans l'espace des formes, ainsi que d'autres, a pu être identifiée. Ceci reflète l'importance de la complémentarité des formes, mais aussi l'implication d'autres facteurs. Une analyse ultérieure a évalué si et comment la forme et le volume d'une poche ou de ses ligands de référence pouvaient être utilisés comme un pré-filtre dans une approche de criblage virtuel. Durant l'optimisation d'un Lead, de nombreux paramètres doivent être optimisés simultanément. Dans ce contexte, la disponibilité d'exemples d'optimisations réussies est précieuse, car ils peuvent orienter les chimistes médicinaux dans leurs plans de synthèse par analogie. Cependant, bien que d'un extrême intérêt pour les chercheurs dans le domaine public, seules les grandes sociétés pharmaceutiques avaient jusqu'à présent la capacité d'exploiter de telles connaissances au sein de leurs bases de données internes. Dans le but de remédier à cette limitation, la base de données SwissBioisostere a été élaborée et publiée dans le domaine public au cours de cette thèse. Cette base de données contient des informations sur 21 293 355 échanges sous-structuraux observés, correspondant à 5 586 462 remplacements uniques mesurés dans 35 039 tests contre 1948 cibles représentant 30 familles, ainsi que sur leur impact sur la bioactivité. Une interface a été développée pour permettre un accès facile à ces données, accessible à http:/ /www.swissbioisostere.ch. La base de données ChEMBL a été utilisée comme source de données de bioactivité. Une version modifiée de l'algorithme de Hussain et Rea a été implémentée pour identifier les Matched Molecular Pairs (MMP) dans les données préparées au préalable. Des scores de succès ont été développés et intégrés dans la base de données pour permettre un reclassement des remplacements proposés selon leurs résultats précédemment observés. La corrélation entre ces scores et la similarité chimique des fragments correspondants a été étudiée. Une corrélation plus faible qu'attendue a été détectée et analysée. Différents cas d'utilisation de cette base de données ont été envisagés, et les fonctionnalités correspondantes implémentées: l'agrégation des résultats de remplacement est effectuée au niveau de chaque test, et il a été montré qu'elle pourrait également être effectuée au niveau de la cible ou de la classe de cible, sous réserve d'une analyse au cas par cas. Il a en outre été constaté que le succès d'un remplacement dépend de l'activité du composé A au sein d'une paire A-B. Il a été montré que la probabilité de perdre la bioactivité à la suite d'un remplacement moléculaire quelconque est plus importante au sein des molécules les plus actives que chez les molécules de plus faible activité. L'existence potentielle d'un biais lié au processus de publication par articles a pu être réfutée. En outre, les stratégies fréquentes de chimie médicinale pour l'exploration des relations structure-activité ont été analysées à l'aide des données acquises. Enfin, les données provenant des compagnies pharmaceutiques ont été comparées à celles reportées dans la littérature. Il a pu être constaté que les chimistes médicinaux dans l'industrie peuvent accéder à des remplacements qui ne sont pas disponibles dans le domaine public. Par contre, un grand nombre de remplacements fréquemment observés dans les données de l'industrie ont également pu être identifiés dans les données de la littérature. Les préférences pour certains remplacements particuliers diffèrent entre ces deux sources. L'intérêt d'évaluer les remplacements moléculaires simultanément selon plusieurs paramètres (bioactivité et stabilité métabolique par ex.) a aussi été étudié. Les études réalisées ont souligné qu'il semble n'exister aucun remplacement sous-structural universel qui conserve toujours la bioactivité quel que soit le contexte biologique. Une généralisation des remplacements bioisostériques ne semble donc pas possible.

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.