Assembling models of embryo development: Image analysis and the construction of digital atlases

Digital atlases of animal development provide a quantitative description of morphogenesis, opening the path toward processes modeling. Prototypic atlases offer a data integration framework where to gather information from cohorts of individuals with phenotypic variability. Relevant information for further theoretical reconstruction includes measurements in time and space for cell behaviors and gene expression. The latter as well as data integration in a prototypic model, rely on image processing strategies. Developing the tools to integrate and analyze biological multidimensional data are highly relevant for assessing chemical toxicity or performing drugs preclinical testing. This article surveys some of the most prominent efforts to assemble these prototypes, categorizes them according to salient criteria and discusses the key questions in the field and the future challenges toward the reconstruction of multiscale dynamics in model organisms.

Effect of misorientation on the compression of highly anisotropic single-crystal micropillars

The effect of crystal misorientation, geometrical tilt, and contact misalignment on the compression of highly anisotropic single crystal micropillars was assessed by means of crystal plasticity finite element simulations. The investigation was focused in single crystals with the NaCl structure, like MgO or LiF, which present a marked plastic anisotropy as a result of the large difference in the critical resolved shear stress between the “soft” {110}〈110〉 and the “hard” {100}〈110〉 active slip systems. It was found that contact misalignment led to a large reduction in the initial stiffness of the micropillar in crystals oriented in the soft and hard direction. The crystallographic tilt did not modify, however, the initial crystal stiffness. From the viewpoint of the plastic response, none of the effects analyzed led to significant differences in the flow stress when the single crystals were oriented along the “soft” [100] direction. Large differences were found, however, if the single crystal was oriented in the “hard” [111] direction as a result of the activation of the soft slip system. Numerical simulations were in very good agreement with experimental literature data.

INFOBIOMED: European Network of Excellence on Biomedical Informatics to support individualised healthcare

INFOBIOMED is an European Network of Excellence (NoE) funded by the Information Society Directorate-General of the European Commission (EC). A consortium of European organizations from ten different countries is involved within the network. Four pilots, all related to linking clinical and genomic information, are being carried out. From an informatics perspective, various challenges, related to data integration and mining, are included.

A novel motion tracking system for evaluation of functional rehabilitation of the upper limbs

Upper limb function impairment is one of the most common sequelae of central nervous system injury, especially in stroke patients and when spinal cord injury produces tetraplegia. Conventional assessment methods cannot provide objective evaluation of patient performance and the tiveness of therapies. The most common assessment tools are based on rating scales, which are inefficient when measuring small changes and can yield subjective bias. In this study, we designed an inertial sensor-based monitoring system composed of five sensors to measure and analyze the complex movements of the upper limbs, which are common in activities of daily living. We developed a kinematic model with nine degrees of freedom to analyze upper limb and head movements in three dimensions. This system was then validated using a commercial optoelectronic system. These findings suggest that an inertial sensor-based motion tracking system can be used in patients who have upper limb impairment through data integration with a virtual reality-based neuroretation system.

Sistema para integrar automáticamente datos públicos del NCBI en la plataforma de medicina personalizada p-medicine

En los últimos años ha habido un gran aumento de fuentes de datos biomédicos. La aparición de nuevas técnicas de extracción de datos genómicos y generación de bases de datos que contienen esta información ha creado la necesidad de guardarla para poder acceder a ella y trabajar con los datos que esta contiene. La información contenida en las investigaciones del campo biomédico se guarda en bases de datos. Esto se debe a que las bases de datos permiten almacenar y manejar datos de una manera simple y rápida. Dentro de las bases de datos existen una gran variedad de formatos, como pueden ser bases de datos en Excel, CSV o RDF entre otros. Actualmente, estas investigaciones se basan en el análisis de datos, para a partir de ellos, buscar correlaciones que permitan inferir, por ejemplo, tratamientos nuevos o terapias más efectivas para una determinada enfermedad o dolencia. El volumen de datos que se maneja en ellas es muy grande y dispar, lo que hace que sea necesario el desarrollo de métodos automáticos de integración y homogeneización de los datos heterogéneos. El proyecto europeo p-medicine (FP7-ICT-2009-270089) tiene como objetivo asistir a los investigadores médicos, en este caso de investigaciones relacionadas con el cáncer, proveyéndoles con nuevas herramientas para el manejo de datos y generación de nuevo conocimiento a partir del análisis de los datos gestionados. La ingestión de datos en la plataforma de p-medicine, y el procesamiento de los mismos con los métodos proporcionados, buscan generar nuevos modelos para la toma de decisiones clínicas. Dentro de este proyecto existen diversas herramientas para integración de datos heterogéneos, diseño y gestión de ensayos clínicos, simulación y visualización de tumores y análisis estadístico de datos. Precisamente en el ámbito de la integración de datos heterogéneos surge la necesidad de añadir información externa al sistema proveniente de bases de datos públicas, así como relacionarla con la ya existente mediante técnicas de integración semántica. Para resolver esta necesidad se ha creado una herramienta, llamada Term Searcher, que permite hacer este proceso de una manera semiautomática. En el trabajo aquí expuesto se describe el desarrollo y los algoritmos creados para su correcto funcionamiento. Esta herramienta ofrece nuevas funcionalidades que no existían dentro del proyecto para la adición de nuevos datos provenientes de fuentes públicas y su integración semántica con datos privados.---ABSTRACT---Over the last few years, there has been a huge growth of biomedical data sources. The emergence of new techniques of genomic data generation and data base generation that contain this information, has created the need of storing it in order to access and work with its data. The information employed in the biomedical research field is stored in databases. This is due to the capability of databases to allow storing and managing data in a quick and simple way. Within databases there is a variety of formats, such as Excel, CSV or RDF. Currently, these biomedical investigations are based on data analysis, which lead to the discovery of correlations that allow inferring, for example, new treatments or more effective therapies for a specific disease or ailment. The volume of data handled in them is very large and dissimilar, which leads to the need of developing new methods for automatically integrating and homogenizing the heterogeneous data. The p-medicine (FP7-ICT-2009-270089) European project aims to assist medical researchers, in this case related to cancer research, providing them with new tools for managing and creating new knowledge from the analysis of the managed data. The ingestion of data into the platform and its subsequent processing with the provided tools aims to enable the generation of new models to assist in clinical decision support processes. Inside this project, there exist different tools related to areas such as the integration of heterogeneous data, the design and management of clinical trials, simulation and visualization of tumors and statistical data analysis. Particularly in the field of heterogeneous data integration, there is a need to add external information from public databases, and relate it to the existing ones through semantic integration methods. To solve this need a tool has been created: the term Searcher. This tool aims to make this process in a semiautomatic way. This work describes the development of this tool and the algorithms employed in its operation. This new tool provides new functionalities that did not exist inside the p-medicine project for adding new data from public databases and semantically integrate them with private data.

Direct evidence for a predominantly exolytic processive mechanism for depolymerization of heparin-like glycosaminoglycans by heparinase I

Heparinase I from Flavobacterium heparinum has important uses for elucidating the complex sequence heterogeneity of heparin-like glycosaminoglycans (HLGAGs). Understanding the biological function of HLGAGs has been impaired by the limited methods for analysis of pure or mixed oligosaccharide fragments. Here, we use methodologies involving MS and capillary electrophoresis to investigate the sequence of events during heparinase I depolymerization of HLGAGs. In an initial step, heparinase I preferentially cleaves exolytically at the nonreducing terminal linkage of the HLGAG chain, although it also cleaves internal linkages at a detectable rate. In a second step, heparinase I has a strong preference for cleaving the same substrate molecule processively, i.e., to cleave the next site toward the reducing end of the HLGAG chain. Computer simulation showed that the experimental results presented here from analysis of oligosaccharide degradation were consistent with literature data for degradation of polymeric HLGAG by heparinase I. This study presents direct evidence for a predominantly exolytic and processive mechanism of depolymerization of HLGAG by heparinase I.

Expressão dos genes da via mTORC1 e seu envolvimento nas Neoplasias Mieloproliferativas

As Neoplasias Mieloproliferativas (NMPs) se caracterizam por apresentarem acúmulo de eritrócitos, leucócitos e plaquetas morfologicamente normais e seus precursores. Nos últimos anos vários estudos buscaram conhecer os mecanismos celulares e moleculares envolvidos na fisiopatologia e evolução dessas desordens, com o intuito de encontrar marcadores de diagnóstico, prognóstico e terapias eficazes. A mutação pontual no gene que codifica a enzima Janus Kinase 2 (JAK2 V617F), presente em aproximadamente 90% dos pacientes com PV e em 50% dos pacientes com TE e MF, foi o principal achado genético anormal associado a essas doenças. Essa mutação resulta na ativação constitutiva da enzima JAK2 e na desregulação da proliferação celular e resistência à apoptose. Nosso grupo de pesquisa descreveu em PV, TE e MF a expressão alterada de genes reguladores da apoptose e dados da literatura indicam que a desregulação do ciclo celular contribui para a fisiopatologia das NMPs. Nesse projeto o intuito foi investigar a associação da via de sinalização m-TOR com as alterações do ciclo celular e via JAK/STAT nas NMPs. A via de sinalização m-TOR participa dos processos celulares de sobrevivência e proliferação. A estratégia experimental foi avaliar a expressão de genes e proteínas, reguladores da via m-TOR, em leucócitos de pacientes com NPMC e linhagens celulares JAK2+ tratadas com inibidores de JAK2 e AKT. Para determinar a relação da via m-TOR nas NMPs foi escolhido o gene eIF4E, alterado nessas doenças, para observar sua modulação diante da inibição farmacológica nas linhagens celulares JAK2 positivas. Os resultados desse estudo contribuem para a descrição de novos alvos terapêuticos dependentes e indepentendes da atividade quinase JAK2 e para o melhor conhecimento da participação da via de sinalização m-TOR na fisiopatologia das NMPs.

Fotofísica de enodionas

Em 1906, Albrecht obteve a primeira enodiona conhecida, ao reagir benzoquinona com ciclopentadieno. A estrutura desta enodiona somente foi elucidada em 1928, por Diels e Alder que, entretanto, perceberam ser possív.el existirem dois diferentes isômeros para o composto em questão: endo e exo. A descoberta, em 1958, da reação de fotocilização deste aduto de Diels-Alder, por Cookson e colaboradores, demonstrou que se tratava do isômero endo e esta reação passou a ser utilizada para se comprovar a configuração endo de vários compostos de estrutura análoga. Porém, apesar de sua importância histórica como método para comprovar a configuração dos adutos de Diels-Alder, os dados disponíveis até hoje são insuficientes para o esclarecimento dos processos subjacentes à fotociclização desses compostos, especialmente porque hoje sabemos que existem adutos de configuração endo que não fotociclizam. Visando aumentar o conhecimento sobre o comportamento destes adutos frente à reação de fotociclização, determinaram-se seus espectros de absorção (na região do UVNisível) e de emissão de luminescência e concluiu-se, com base em nossos resultados e daqueles relatados na literatura, que o fato de não ocorrer a fotociclização de alguns adutos de configuração endo não depende exclusivamente da estabilidade dos estados excitados envolvidos, ainda que essa característica e a natureza destes certamente afete os rendimentos quânticos da reação. Antes, parece-nos que estruturas que permitam deslocalizar um dos elétrons do birradical intermediariamente formado neste processo propiciam a reversão deste intermediário ao reagente, ao invés de se formar o produto de fotociclização. Alem disso, reinvestigamos a reação de fotoisomerização endo → exo do aduto de benzoquinona e ciclopentadieno, por irradiação em etanol/trietil-amina, relatada por Pandey e colaboradores em 1990, tendo verificado que tal isomerização não ocorre nas condições descritas na literatura, obtendo-se, ao invés disso, principalmente o tautômero aromático da enodiona e seu produto de fotociclização. Por outro lado, descobrimos que, deixar em repouso, no escuro, o aduto de benzoquinona e ciclopentadieno em etanol/trietil-amina conduz,a um dímero deste aduto, não descrito previamente.

Análise da abrangência de modelo modificado para mancais curtos com deformação.

Este trabalho apresenta uma discussão sobre o estudo dos efeitos térmicos e elásticos decorrentes da pressão de sustentação presentes nos mancais. Para tanto, propõe-se um modelo matemático baseado nas equações para mancais curtos considerando a região de cavitação e utilizando o princípio da continuidade de massa. Com isto, deduzem-se as equações para o mancal a partir das equações de Reynolds e da energia, aplicando uma solução modificada para a solução de Ocvirk, sendo as equações resolvidas numericamente pelo Método das Diferenças Finitas. Somado o tratamento de mecânica dos fluidos, o trabalho discute dois modelos térmicos de previsão de temperatura média do fluido e sua influência no campo de pressão, apresentando gráficos representativos do campo de pressão e de temperatura, assim como as diferenças e implicações das diferenças. Para o cálculo de deformação da estrutura, utiliza-se um Modelo de Elementos Finitos para uma dada geometria, fazendo-se uma avaliação da variação do campo de pressão e o quanto essa diferença afeta as demais propriedades do fluido. Por fim, com o modelo completo, calcula-se o quanto esse modelamento para mancais curtos se aproxima de soluções para mancais finitos, com base em resultados da literatura, chegando a desvios quase oito vezes menores que os previstos pela literatura. Além disso, pode-se estabelecer a abrangência do modelo, ou seja, prever as condições em que suas propriedades são válidas e podem ser utilizadas para estudos iniciais.

Thermodynamic, surface and structural properties of liquid Co-Si alloys

The knowledge of thermophysical properties of liquid Co-Si alloys is a key requirement for manufacturing of composite materials by infiltration method. Despite this need, the experimental and predicted property data of the Co-Si system are scarce and often inconsistent between the various sources. In the present work the mixing behaviour of Co-Si melts has been analysed through the study of the concentration dependence of various thermodynamic, surface (surface tension and surface composition) and structural properties (concentration fluctuations in the long-wavelength limit and chemical short-range order parameter) in the framework of the Compound Formation Model (CFM) and Quasi Chemical Approximation for regular solutions (QCA). In addition, the surface tension of the Co22·5Si77.5 (in at%) eutectic alloy, that is proposed to be used as the infiltrant, has been measured by the pendant drop method at temperatures ranging from 1593 to 1773 K. The results obtained were discussed with respect to both, temperature and concentration, and subsequently compared with the model predictions and literature data.

Improved slope adjustment functions for soil erosion prediction

Numerous studies in the last 60 years have investigated the relationship between land slope and soil erosion rates. However, relatively few of these have investigated slope gradient responses: ( a) for steep slopes, (b) for specific erosion processes, and ( c) as a function of soil properties. Simulated rainfall was applied in the laboratory on 16 soils and 16 overburdens at 100 mm/h to 3 replicates of unconsolidated flume plots 3 m long by 0.8 m wide and 0.15 m deep at slopes of 20, 5, 10, 15, and 30% slope in that order. Sediment delivery at each slope was measured to determine the relationship between slope steepness and erosion rate. Data from this study were evaluated alongside data and existing slope adjustment functions from more than 55 other studies from the literature. Data and the literature strongly support a logistic slope adjustment function of the form S = A + B/[1 + exp (C - D sin theta)] where S is the slope adjustment factor and A, B, C, and D are coefficients that depend on the dominant detachment and transport processes. Average coefficient values when interill-only processes are active are A - 1.50, B 6.51, C 0.94, and D 5.30 (r(2) = 0.99). When rill erosion is also potentially active, the average slope response is greater and coefficient values are A - 1.12, B 16.05, C 2.61, and D 8.32 (r(2) = 0.93). The interill-only function predicts increases in sediment delivery rates from 5 to 30% slope that are approximately double the predictions based on existing published interill functions. The rill + interill function is similar to a previously reported value. The above relationships represent a mean slope response for all soils, yet the response of individual soils varied substantially from a 2.5-fold to a 50-fold increase over the range of slopes studied. The magnitude of the slope response was found to be inversely related ( log - log linear) to the dispersed silt and clay content of the soil, and 3 slope adjustment equations are proposed that provide a better estimate of slope response when this soil property is known. Evaluation of the slope adjustment equations proposed in this paper using independent datasets showed that the new equations can improve soil erosion predictions.

Molecular size as the main determinant of solute maximum flux across the skin

One of the most important determinants of dermatological and systemic penetration after topical application is the delivery or flux of solutes into or through the skin. The maximum dose of solute able to be delivered over a given period of time and area of application is defined by its maximum flux (J(max), mol per cm(2) per h) from a given vehicle. In this work, J(max) values from aqueous solution across human skin were acquired or estimated from experimental data and correlated with solute physicochemical properties. Whereas epidermal permeability coefficients (k(p)) are optimally correlated to solute octanol-water partition coefficient (K-ow) and molecular weight (MW) was found to be the dominant determinant of J(max) for this literature data set: log J(max)=-3.90-0.0190MW (n=87, r(2)=0.847, p

Aspergillazines A-E: novel heterocyclic dipeptides from an Australian strain of Aspergillus unilateralis

Biological and chemical pro ling of an Australian strain of the fungus Aspergillus unilateralis (MST-F8675), isolated from a soil sample collected near Mount Isa, Queensland, revealed a complex array of metabolites displaying broad chemotherapeutic properties. Noteworthy among these metabolites were a unique series of highly modified dipeptides aspergillazines A-E, incorporating a selection of unprecedented and yet biosynthetically related heterocyclic systems. Co-occurring with the aspergillazines was the recently described marine-derived fungal metabolite trichodermamide A (cf. penicillazine), whereas re-fermentation of A. unilateralis in NaCl (1%) enriched media resulted in co-production of the only other known example of this structure class, the marine-derived fungal metabolite trichodermamide B. Further investigation of A. unilateralis returned the known terrestrial fungal metabolite viridicatumtoxin as the cytotoxic and antibacterial principle, together with E-2-decenedioic acid, ferulic acid, (7E,7'E)-5,5'-diferulic acid and (7E,7'E)-8,5'-diferulic acid. The aromatic diacids have previously been reported from the chemical and enzymatic (esterase) treatment of plant cell wall material, with their isolation from A. unilateralis being their first apparent reported occurrence as natural products. Structures for all metabolites were determined by detailed spectroscopic analysis and, where appropriate, comparison to literature data and/or authentic samples.

Electrostatically mediated specific adsorption of small molecules in metallo-organic frameworks

We investigate the interaction of ethylene and ethane with a Cu-tricarboxylate complex and show that at low loadings the lighter molecule has a higher binding energy as a result of an increased interaction with the framework Cu and stronger hydrogen bonding with the basic framework oxygens. This leads to selective adsorption of ethylene by a factor of about 2 at low pressure, which is overcome by the stronger van der Waals interaction of ethane at high loadings, explaining recent literature data. The results suggest the possibility of separation of light hydrocarbons at low pressures or in trace amounts.

Phase equilibrium studies at normal pressures

A total pressure apparatus has been developed to measure vapour-liquid equilibrium data on binary mixtures at atmospheric and sub-atmospheric pressures. The method gives isothermal data which can be obtained rapidly. Only measurements of total pressure are made as a direct function of composition of synthetic liquid phase composition, the vapour phase composition being deduced through the Gibbs-Duhem relationship. The need to analyse either of the phases is eliminated. As such the errors introduced by sampling and analysis are removed. The essential requirements are that the pure components be degassed completely since any deficiency in degassing would introduce errors into the measured pressures. A similarly essential requirement was that the central apparatus would have to be absolutely leak-tight as any leakage of air either in or out of the apparatus would introduce erroneous pressure readings. The apparatus was commissioned by measuring the saturated vapour pressures of both degassed water and ethanol as a function of temperature. The pressure-temperature data on degassed water measured were directly compared with data in the literature, with good agreement. Similarly the pressure-temperature data were measured for ethanol, methanol and cyclohexane and where possible a direct comparison made with the literature data. Good agreement between the pure component data of this work and those available in the literature demonstrates firstly that a satisfactory degassing procedure has been achieved and that secondly the measurements of pressure-temperature are consistent for any one component; since this is true for a number of components, the measurements of both temperature and pressure are both self-consistent and of sufficient accuracy, with an observed compatibility between the precision/accuracy of the separate means of measuring pressure and temperature. The liquid mixtures studied were of ethanol-water, methanol-water and ethanol-cyclohexane. The total pressure was measured as the composition inside the equilibrium cell was varied at a set temperature. This gave P-T-x data sets for each mixture at a range of temperatures. A standard fitting-package from the literature was used to reduce the raw data to yield y-values to complete the x-y-P-T data sets. A consistency test could not be applied to the P-T-x data set as no y-values were obtained during the experimental measurements. In general satisfactory agreement was found between the data of this work and those available in the literature. For some runs discrepancies were observed, and further work recommended to eliminate the problems identified.