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.

Superfícies geomórficas e atributos de Latossolos em uma seqüência Arenítico-Basáltica da região de Jaboticabal (SP)

Em um segmento de vertente com substrato de arenito em contato com basalto, regionalmente muito freqüente, pretendeu-se não só relacionar as superfícies geomórficas com os atributos físicos, químicos e mineralógicos dos Latossolos nelas encontrados, mas também testar métodos geoestatísticos para localização de limites dessas superfícies. Usando critérios geomorfológicos, três superfícies foram identificadas e topograficamente caracterizadas. Os solos foram amostrados, a intervalos regulares de 25 m, na profundidade de 0,6 a 0,8 m (topo do horizonte B), em uma transeção de 1.700 m perfazendo 109 pontos. Nas amostras, foram analisados: densidade de partículas, granulometria, CTC do solo, CTC da argila, Fe total da argila (ataque por H2SO4) e óxidos de Fe "livres" (por dissolução seletiva). A fração argila desferrificada foi analisada por difração de raios X. Com base na estratigrafia e variações do relevo local, foram identificadas e diferenciadas, no campo, três superfícies geomórficas. Analisaram-se também o perfil altimétrico e o modelo de elevação digital do terreno. Observou-se que as três diferentes superfícies estão bem relacionadas com os atributos físicos, químicos e mineralógicos dos seus respectivos solos. Na parte inferior desta vertente, superfície mais recente e sobre basalto, em Latossolo Vermelho eutroférrico típico, foram encontradas as maiores variabilidades da declividade, da argila e de Fe. As variações da inclinação do terreno, quando analisadas sistematicamente pelo "split moving windows dissimilarity analysis" (análise estatística de dissimilaridade, em segmentos móveis), mostraram que este método estatístico pode ser usado para ajudar a localizar os limites entre superfícies geomórficas. As variações dos solos da transeção, e arredores, mostraram-se relacionadas com idade, inclinação do terreno e litologia. O trabalho geomórfico detalhado forneceu importantes informações para subsidiar os trabalhos de levantamento de solos e de pedogênese.

Trends in indices of daily precipitation extremes in Catalonia (NE Spain), 1951-2003

The aim of this paper is to quantitatively characterize the climatology of daily precipitation indices in Catalonia (northeastern Iberian Peninsula) from 1951 to 2003. This work has been performed analyzing a subset of the ETCCDI (Expert Team on Climate Change Detection and Indices) precipitation indices calculated from a new interpolated dataset of daily precipitation, namely SPAIN02, regular at 0.2° horizontal resolution (around 20 km) and from two high-quality stations: the Ebro and Fabra observatories. Using a jack-knife technique, we have found that the sampling error of the SPAIN02 regional averaged is relatively low. The trend analysis has been implemented using a Circular Block Bootstrap procedure applicable to non-normal distributions and autocorrelated series. A running trend analysis has been applied to analyze the trend persistence. No general trends at a regional scale are observed, considering the annual or the seasonal regional averaged series of all the indices for all the time windows considered. Only the consecutive dry days index (CDD) at annual scale shows a locally coherent spatial trend pattern; around 30% of the Catalonia area has experienced an increase of around 2¿3 days decade¿1. The Ebro and Fabra observatories show a similar CDD trend, mainly due to the summer contribution. Besides this, a significant decrease in total precipitation (around ¿10 mm decade¿1) and in the index "highest precipitation amount in five-day period" (RX5DAY, around ¿5 mm decade¿1), have been found in summer for the Ebro observatory.

Tecnologies de la informació (barates) aplicades a les persones amb necessitats especials

As a consequence of the lack of adequate support, many people with physical or sensorial difficulties frequently encounter obstacles to using information technologies. Today equipment and programmes exist for overcoming these barriers, but frequently they are too expensive for the economic limitations of our smaller libraries, document centres, archives, museums, etc. An inexpensive alternative can be found in the accessibility options incorporated into Windows. While these probably do not offer the best or the most adequate solutions, it can be argued that, they are an acceptable alternative, considering existing budget restrictions. This text describes the functionalities of Windows XP, grouping them according to the type of difficulty addressed (visual, motor or auditory) in order to facilitate access to the application.

Modelagem de atributos físico-hídricos do solo numa bacia hidrográfica da região do Alto Rio Grande, MG

O presente trabalho objetivou desenvolver modelos para estimativa dos atributos físico-hídricos do solo porosidade drenável (PD) e capacidade total de retenção de água (CTA), com base em atributos físicos de fácil e rápida obtenção (textura, argila dispersa em água, volume total de poros, densidade do solo e densidade de partícula) e a determinação de matéria orgânica. Os atributos foram coletados na bacia hidrográfica do Ribeirão Marcela, na camada de 0 a 15 cm, obedecendo aos grids de 240 x 240 e 60 x 60 m, totalizando 165 pontos amostrados. Trabalhou-se com regressão múltipla linear, constituindo-se variáveis por meio da combinação dos diferentes atributos entre si e estimando os respectivos coeficientes pelo método dos mínimos quadrados, utilizando-se o programa SAS for Windows. Os modelos gerados para CTA e PD apresentaram boa qualidade estatística, com elevados coeficientes de determinação, baixos erros de estimativa e variáveis significativas, o que permitiu sua aplicação na estimativa desses atributos na bacia hidrográfica do Ribeirão Marcela, representativa do domínio dos Latossolos na região do Alto Rio Grande, fornecendo assim subsídios para implantação de projetos agrícolas e ambientais, especialmente no auxílio à parametrização de modelos de simulação hidrossedimentológica, os quais estão em desenvolvimento para aplicação na região.

Tough adults, frail babies: an analysis of stress sensitivity across early life-history stages of widely introduced marine invertebrates

All ontogenetic stages of a life cycle are exposed to environmental conditions so that population persistence depends on the performance of both adults and offspring. Most studies analysing the influence of abiotic conditions on species performance have focussed on adults, while studies covering early life-history stages remain rare. We investigated the responses of early stages of two widely introduced ascidians, Styela plicata and Microcosmus squamiger, to different abiotic conditions. Stressors mimicked conditions in the habitats where both species can be found in their distributional ranges and responses were related to the selection potential of their populations by analysing their genetic diversity. Four developmental stages (egg fertilisation, larval development, settlement, metamorphosis) were studied after exposure to high temperature (30°C), low salinities (26 and 22 ) and high copper concentrations (25, 50 and 100 µg/L). Although most stressors effectively led to failure of complete development (fertilisation through metamorphosis), fertilisation and larval development were the most sensitive stages. All the studied stressors affected the development of both species, though responses differed with stage and stressor. S. plicata was overall more resistant to copper, and some stages of M. squamiger to low salinities. No relationship was found between parental genetic composition and responses to stressors. We conclude that successful development can be prevented at several life-history stages, and therefore, it is essential to consider multiple stages when assessing species' abilities to tolerate stress. Moreover, we found that early development of these species cannot be completed under conditions prevailing where adults live. These populations must therefore recruit from elsewhere or reproduce during temporal windows of more benign conditions. Alternatively, novel strategies or behaviours that increase overall reproductive success might be responsible for ensuring population survival.

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.

Linking Real Time and Location in Scheduling Demand-Responsive Transit, September 1996

The role of rural demand-responsive transit is changing, and with that change is coming an increasing need for technology. As long as rural transit was limited to a type of social service transportation for a specific set of clients who primarily traveled in groups to common meal sites, work centers for the disabled, or clinics in larger communities, a preset calendar augmented by notes on a yellow legal pad was sufficient to develop schedules. Any individual trips were arranged at least 24 to 48 hours ahead of time and were carefully scheduled the night before in half-hour or twenty-minute windows by a dispatcher who knew every lane in the service area. Since it took hours to build the schedule, any last-minute changes could wreak havoc with the plans and raise the stress level in the dispatch office. Nevertheless, given these parameters, a manual scheduling system worked for a small demand-responsive operation.

Symmetry breaking in small rotating clouds of trapped ultracold Bose atoms

We study the signatures of rotational and phase symmetry breaking in small rotating clouds of trapped ultracold Bose atoms by looking at rigorously defined condensate wave function. Rotational symmetry breaking occurs in narrow frequency windows, where energy degeneracy between the lowest energy states of different total angular momentum takes place. This leads to a complex condensate wave function that exhibits vortices clearly seen as holes in the density, as well as characteristic local phase patterns, reflecting the appearance of vorticities. Phase symmetry (or gauge symmetry) breaking, on the other hand, is clearly manifested in the interference of two independent rotating clouds.

Blood pressure and LDL-cholesterol targets for prevention of recurrent strokes and cognitive decline in the hypertensive patient: design of the European Society of Hypertension-Chinese Hypertension League Stroke in Hypertension Optimal Treatment randomized trial.

BACKGROUND AND OBJECTIVES: The SBP values to be achieved by antihypertensive therapy in order to maximize reduction of cardiovascular outcomes are unknown; neither is it clear whether in patients with a previous cardiovascular event, the optimal values are lower than in the low-to-moderate risk hypertensive patients, or a more cautious blood pressure (BP) reduction should be obtained. Because of the uncertainty whether 'the lower the better' or the 'J-curve' hypothesis is correct, the European Society of Hypertension and the Chinese Hypertension League have promoted a randomized trial comparing antihypertensive treatment strategies aiming at three different SBP targets in hypertensive patients with a recent stroke or transient ischaemic attack. As the optimal level of low-density lipoprotein cholesterol (LDL-C) level is also unknown in these patients, LDL-C-lowering has been included in the design. PROTOCOL DESIGN: The European Society of Hypertension-Chinese Hypertension League Stroke in Hypertension Optimal Treatment trial is a prospective multinational, randomized trial with a 3 × 2 factorial design comparing: three different SBP targets (1, <145-135; 2, <135-125; 3, <125 mmHg); two different LDL-C targets (target A, 2.8-1.8; target B, <1.8 mmol/l). The trial is to be conducted on 7500 patients aged at least 65 years (2500 in Europe, 5000 in China) with hypertension and a stroke or transient ischaemic attack 1-6 months before randomization. Antihypertensive and statin treatments will be initiated or modified using suitable registered agents chosen by the investigators, in order to maintain patients within the randomized SBP and LDL-C windows. All patients will be followed up every 3 months for BP and every 6 months for LDL-C. Ambulatory BP will be measured yearly. OUTCOMES: Primary outcome is time to stroke (fatal and non-fatal). Important secondary outcomes are: time to first major cardiovascular event; cognitive decline (Montreal Cognitive Assessment) and dementia. All major outcomes will be adjudicated by committees blind to randomized allocation. A Data and Safety Monitoring Board has open access to data and can recommend trial interruption for safety. SAMPLE SIZE CALCULATION: It has been calculated that 925 patients would reach the primary outcome after a mean 4-year follow-up, and this should provide at least 80% power to detect a 25% stroke difference between SBP targets and a 20% difference between LDL-C targets.

FERRAMENTAS MATEMÁTICAS, SUSCETIBILIDADE MAGNÉTICA E MODELOS DE PAISAGEM APLICADOS NA DELIMITAÇÃO DE ÁREAS DE MANEJO ESPECÍFICO

A identificação de padrões de variabilidade dos atributos do solo permite o uso e a ocupação do solo de maneira sustentável. O objetivo deste trabalho foi delimitar áreas de manejo específico utilizando ferramentas matemáticas, suscetibilidade magnética e modelos de paisagem. A área de estudo localiza-se no município de Guariba, SP. Escolheu-se uma área de 110 ha, onde foram identificadas e mapeadas três superfícies geomórficas (I, II e III). Na área, foram coletadas 204 amostras de solo em uma transeção, nas profundidades de 0,00-0,20 e 0,60-0,80 m. Foram determinados o pH em CaCl2, os teores de areia, argila, matéria orgânica, P, Ca, Mg, K, H+Al, e calculados SB, CTC e V. A suscetibilidade magnética (SM) foi medida com o auxílio de uma balança analítica. Os limites matemáticos da técnica Split Moving Windows Dissimilarity Analysis (SMWDA) utilizando as informações da suscetibilidade magnética ficaram próximos aos limites de campo identificados com base nos modelos de paisagem. A utilização conjunta da suscetibilidade magnética, dos modelos matemáticos e de paisagem permitiu identificar diferentes áreas de manejo, locais com diferentes teores de argila e níveis de fertilidade do solo. A susceptibilidade magnética pode ser adotada como alternativa para identificar e mapear unidades de manejo.

Therapeutic drug monitoring in cancer - Are we missing a trick?

Therapeutic drug monitoring (TDM) can be defined as the measurement of drug in biological samples to individualise treatment by adapting drug dose to improve efficacy and/or reduce toxicity. The cytotoxic drugs are characterised by steep dose-response relationships and narrow therapeutic windows. Inter-individual pharmacokinetic (PK) variability is often substantial. There are, however, a multitude of reasons why TDM has never been fully implemented in daily oncology practice. These include difficulties in establishing appropriate concentration target, common use of combination chemotherapies and the paucity of published data from pharmacological trials. The situation is different with targeted therapies. The large interindividual PK variability is influenced by the pharmacogenetic background of the patient (e.g. cytochrome P450 and ABC transporters polymorphisms), patient characteristics such as adherence to treatment and environmental factors (drug-drug interactions). Retrospective studies have shown that targeted drug exposure correlates with treatment response in various cancers. Evidence for imatinib currently exists, others are emerging for compounds including nilotinib, dasatinib, erlotinib, sunitinib, sorafenib and mammalian target of rapamycin (mTOR) inhibitors. Applications for TDM during oral targeted therapies may best be reserved for particular situations including lack of therapeutic response, severe or unexpected toxicities, anticipated drug-drug interactions and concerns over adherence treatment. There are still few data with monoclonal antibodies (mAbs) in favour of TDM approaches, even if data showed encouraging results with rituximab and cetuximab. TDM of mAbs is not yet supported by scientific evidence. Considerable effort should be made for targeted therapies to better define concentration-effect relationships and to perform comparative randomised trials of classic dosing versus pharmacokinetically-guided adaptive dosing.

Ectodysplasin A (EDA)-EDA receptor signalling and its pharmacological modulation

L'ectodysplasine Al (EDA1 ou EDA), un ligand de la famille du TNF, et son récepteur EDAR favorisent le développement des poils, des dents et de plusieurs types de glandes. Chez l'humain, une déficience en EDA cause une dysplasie ectodermique liée à l'X, caractérisée par la genèse défectueuse des phanères. Les souris Tabby, déficientes en Eda, présentent des symptômes similaires. Nous démontrons que les souris Tabby sont en moyenne 7% plus légères que les contrôles au moment du sevrage. Ce phénotype ne dépend pas du génotype des petits, mais exclusivement de celui de la mère, suggérant que l'absence d'EDA perturbe la fonction mammaire. La glande mammaire se développe en plusieurs étapes, principalement à la puberté et pendant la grossesse. Nous avons généré des anticorps pour activer ou inhiber la signalisation d'EDAR. Les anticorps agonistes corrigent le développement de souris ou de chiens déficients en EDA, alors que les antagonistes provoquent une dysplasie ectodermique chez les souris saines. L'exposition répétée de souris Tabby aux anticorps agonistes après le sevrage accroît la taille et la fonction des glandes sébacées, démonstration pharmacologique qu'EDA contrôle l'homéostasie de la glande sébacée adulte. Ces outils seront utiles pour étudier la fonction d'EDA aux diverses étapes du développement de la glande mammaire. Fc-EDAl, un stimulateur d'EDAR, est en phase d'évaluation clinique. Nous avons montré que les structures dépendantes d'EDA qui se forment à différentes étapes du développement répondent à l'action du Fc-EDAl dans des fenêtres temporelles étroites ou larges. De plus, certaines structures peuvent être induites plusieurs jours après le début naturel de leur formation. Alors que la plupart des structures se forment suite à un seul jour d'activation d'EDAR, d'autre demandent un temps de stimulation plus long. La formation des dents est régulée par des signaux activateurs et inhibiteurs. Une forte stimulation d'EDAR spécifiquement appliquée aux deux premières molaires induit des signaux négatifs qui avortent la formation de la troisième molaire, alors qu'une forte stimulation donnée à la troisième molaire la rend hypertrophique tout en induisant parfois une quatrième molaire jamais observée chez les souris de type sauvage ou Tabby. EDA est donc un activateur important de la formation dentaire. Pris dans leur ensemble, ces résultats ont des implications pour la thérapie des dysplasies ectodermiques. - The TNF family ligand Ectodysplasin Al (EDA1 or EDA) and its receptor ED AR regulate embryonic development of hair, teeth and several types of glands. In humans, EDA mutations cause X-linked hypohidrotic ectodermal dysplasia (XLHED), a condition characterized by defective development of skin appendages. £da-deficient (Tabby) mice suffer from similar defects. We observed that Tabby pups at weaning were on average 7% smaller than WT controls, a phenotype that was curiously not linked to the genotype of pups, but to that of mothers, suggesting decreased mammary gland function in the absence of EDA. Mammary glands develop in several steps, most of which are post-natal. We generated monoclonal antibodies to block or activate EDAR signaling. Agonist antibodies rescued developmental defects when administered timely in £cfo-deficient mice and dogs, whereas blocking antibodies induced ectodermal dysplasia in WT mice. Agonist antibodies administered after weaning in £da-deficient mice for several months markedly increased both size and function of sebaceous glands, providing the first demonstration that pharmacological activation of the EDAR pathway in adults can correct important aspects of the dry skin phenotype. This also highlights a role for EDA1 in the homeostasis of adult sebaceous glands. These tools will be useful to study the function of EDA 1 at different stages of mammary gland development. Another EDAR agonist, Fc-EDAl, is currently evaluated in clinical trials. We found that EDA 1-dependent structures forming at different time points during development can respond to Fc-EDAl during time response windows that are narrow or wide. Also, some structures can be triggered up to several days after their normal time of induction. While most structures could be rescued by a single day of EDAR signaling, others required longer exposure times to form. Tooth formation is regulated by activating and inhibitory signals that impact one on the other. When strong EDAR signals were specifically given to the first two molars, overwhelming inhibitory signals completely inhibited formation of the third molar. In contrast, strong signals specifically given to the third molar induced hypertrophy of the later with occasional appearance of a fourth molar never observed in WT or £da-deficient mice. This clearly positions EDA as an important activating signal in tooth formation. Taken together, these results have implications for the therapy of ectodermal dysplasias.

What makes for peaceful post-conflict elections?

Elections play a crucial role in post-conflict peace and democratization processes as, among other factors, they provide an answer to the question of who is to legitimately rule the country. However, because of the competitiveness arising from their central role in allocating power they can also represent windows of vulnerability where deeply rooted societal conflicts can come to the surface. This working paper focuses on two post-conflict elections (Sierra Leone 2007; Nepal 2008) which, despite perceived high risks, did not result in widespread violence or a return to armed conflict. The aim of these case studies is to identify the factors and measures that may have played an important role in contributing to this outcome. Each of the two case studies first outlines the risks associated with the elections and then analyzes the violence and conflict preventing factors. The paper shows that that the context greatly influences the type of measures that can be taken in such situations, but that there are also some similarities in the two cases studied. In particular, it appears that that the credibility of the elections, largely attributable to a good electoral administration, was an important factor in both Nepal and Sierra Leone. Furthermore, the inclusion of all key stakeholders in decisions regarding key electoral institutions helped to diffuse potential conflict. The study also shows that in both cases the international community played an important role by providing financial, logistical and technical support and by pressuring certain important actors to comply with the rules.