Bridging experiments, models and simulations : an integrative approach to validation in computational cardiac electrophysiology

Computational models in physiology often integrate functional and structural information from a large range of spatio-temporal scales from the ionic to the whole organ level. Their sophistication raises both expectations and scepticism concerning how computational methods can improve our understanding of living organisms and also how they can reduce, replace and refine animal experiments. A fundamental requirement to fulfil these expectations and achieve the full potential of computational physiology is a clear understanding of what models represent and how they can be validated. The present study aims at informing strategies for validation by elucidating the complex interrelations between experiments, models and simulations in cardiac electrophysiology. We describe the processes, data and knowledge involved in the construction of whole ventricular multiscale models of cardiac electrophysiology. Our analysis reveals that models, simulations, and experiments are intertwined, in an assemblage that is a system itself, namely the model-simulation-experiment (MSE) system. Validation must therefore take into account the complex interplay between models, simulations and experiments. Key points for developing strategies for validation are: 1) understanding sources of bio-variability is crucial to the comparison between simulation and experimental results; 2) robustness of techniques and tools is a pre-requisite to conducting physiological investigations using the MSE system; 3) definition and adoption of standards facilitates interoperability of experiments, models and simulations; 4) physiological validation must be understood as an iterative process that defines the specific aspects of electrophysiology the MSE system targets, and is driven by advancements in experimental and computational methods and the combination of both.

Models of survivorship care provision in adult patients with haematological cancer : an integrative literature review

Purpose: Increasing numbers of haematology cancer survivors warrants identification of the most effective model of survivorship care to survivors from a diverse range of haematological cancers with aggressive treatment regimens. This review aimed to identify models of survivorship care to support the needs of haematology cancer survivors. Methods: An integrative literature review method utilised a search of electronic databases (CINAHL, Medline, PsycInfo, PubMed, EMBASE, PsycArticles, Cochrane Library) for eligible articles (up to July 2014). Articles were included if they proposed or reported the use of a model of care for haematology cancer survivors. Results: Fourteen articles were included in this review. Eight articles proposed and described models of care and six reported the use of a range of survivorship models of care in haematology cancer survivors. No randomised controlled trials or literature reviews were found to have been undertaken specifically with this cohort of cancer survivors. There was variation in the models described and who provided the survivorship care. Conclusion: Due to the lack of studies evaluating the effectiveness of models of care, it is difficult to determine the best model of care for haematology cancer survivors. Many different models of care are being put into practice before robust research is conducted. Therefore well-designed high quality pragmatic randomised controlled trials are required to inform clinical practice.

Community development and community resilience: An integrative approach

Throughout history, communities and civilizations have sought to enhance the quality of community life and the well-being of its people. However, more recently there has been greater interest in attending to the details of community development by capitalizing on the improved ability to capture community well-being and successes scientifically. That interest invites greater attention to the development of indicators that can quantify those qualities of life that lead to strong and healthy communities. The selection of meaningful indicators is dependent upon several factors including a process that stimulates meaningful involvement of community stakeholders, but the single most important is the identification of an underlying model to guide the work. Indicators do not have meaning in themselves. For these measures to provide a coherent assessment of the community, an integrative approach to understanding what constitutes a healthy and strong community in a dynamic environment is required. A resilience perspective serves that purpose and provides a framework that is broad, neutral, and conceptually strong enough to structure development of significant sets of indicators. Exemplary community indicator processes across the nation, particularly recent efforts in the Phoenix, Arizona region, provide evidence supporting the value of indicator development for community building.

A multi-field bio-economic model of irrigated grain-cotton farming systems.

We present a participatory modelling framework that integrates information from interviews and discussions with farmers and consultants, with dynamic bio-economic models to answer complex questions on the allocation of limited resources at the farm business level. Interviews and discussions with farmers were used to: describe the farm business; identify relevant research questions; identify potential solutions; and discuss and learn from the whole-farm simulations. The simulations are done using a whole-farm, multi-field configuration of APSIM (APSFarm). APSFarm results were validated against farmers' experience. Once the model was accepted by the participating farmers as a fair representation of their farm business, the model was used to explore changes in the tactical or strategic management of the farm and results were then discussed to identify feasible options for improvement. Here we describe the modelling framework and present an example of the application of integrative whole farm system tools to answer relevant questions from an irrigated farm business case study near Dalby (151.27E - 27.17S), Queensland, Australia. Results indicated that even though cotton crops generates more farm income per hectare a more diversified rotation with less cotton would be relatively more profitable, with no increase in risk, as a more cotton dominated traditional rotation. Results are discussed in terms of the benefits and constraints from developing and applying more integrative approaches to represent farm businesses and their management in participatory research projects with the aim of designing more profitable and sustainable irrigated farming systems.

Content Based Integration of Construction Site Images in AEC/FM Model Based Systems

The Architecture, Engineering, Construction and Facilities Management (AEC/FM) industry is rapidly becoming a multidisciplinary, multinational and multi-billion dollar economy, involving large numbers of actors working concurrently at different locations and using heterogeneous software and hardware technologies. Since the beginning of the last decade, a great deal of effort has been spent within the field of construction IT in order to integrate data and information from most computer tools used to carry out engineering projects. For this purpose, a number of integration models have been developed, like web-centric systems and construction project modeling, a useful approach in representing construction projects and integrating data from various civil engineering applications. In the modern, distributed and dynamic construction environment it is important to retrieve and exchange information from different sources and in different data formats in order to improve the processes supported by these systems. Previous research demonstrated that a major hurdle in AEC/FM data integration in such systems is caused by its variety of data types and that a significant part of the data is stored in semi-structured or unstructured formats. Therefore, new integrative approaches are needed to handle non-structured data types like images and text files. This research is focused on the integration of construction site images. These images are a significant part of the construction documentation with thousands stored in site photographs logs of large scale projects. However, locating and identifying such data needed for the important decision making processes is a very hard and time-consuming task, while so far, there are no automated methods for associating them with other related objects. Therefore, automated methods for the integration of construction images are important for construction information management. During this research, processes for retrieval, classification, and integration of construction images in AEC/FM model based systems have been explored. Specifically, a combination of techniques from the areas of image and video processing, computer vision, information retrieval, statistics and content-based image and video retrieval have been deployed in order to develop a methodology for the retrieval of related construction site image data from components of a project model. This method has been tested on available construction site images from a variety of sources like past and current building construction and transportation projects and is able to automatically classify, store, integrate and retrieve image data files in inter-organizational systems so as to allow their usage in project management related tasks.

Gastroprotective potential of Buddleja scordioides Kunth: Effects into the modulation of antioxidant enzymes and inflammation markers in an in vivo model

Ethnopharmacological relevance: A common plant used to treat several gastric disorders is Buddleja scordioides Kunth,commonly known as salvilla. Aim of thes tudy: To detect inflammatory markers,in order to evaluate the gastroprotective potential of salvilla infusions,as this could have beneficial impact on the population exposed to gastric ulcers and colitis. Materials and methods: The present work attempted infusions were prepared with B. scordioides (1% w/w) lyophilized and stored.Total phenolic content and GC–MS analysis were performed. Wistar rats were divided into five groups a negative vehicle control,an indomethacin group,and three experimental groups,named preventive,curative,and suppressive. All rats were sacrificed under deep ether anesthesia(6h)after the last oral administration of indomethacin/infusion.The rat stomachs were promptly excised,weighed,and chilled in ice-cold and 0.9%NaCl.Histological analysis,nitrites quantification and immunodetection assays were done. Results: B.scordioides infusions markedly reduced the visible hemorrhagic lesions induced byindomethacin in rat stomachs,also showed down-regulation of COX2, IL-8 and TNFα and up-regulation of COX-1with a moderate down-regulation of NFkB and lower amount of nitrites.However,this behavior was dependent on the treatment,showing most down-regulation of COX-2,TNFα and IL-8 in the curative treatment;more down-regulation of NF-kB in the preventive treatment;and more up-regulation of COX-1 for the suppressor and preventive treatments. Conclusion: The anti-inflammatory potential of B. scordioides infusions could be related with the presence of polyphenols as quercetin in the infusion and how this one is consumed.

Integrative motivation and global language (English) acquisition in Poland

This study investigated the consistency of a measure of integrative motivation in the prediction of achievement in English as a foreign language in 18 samples of Polish school students. The results are shown to have implications for concerns expressed that integrative motivation might not be appropriate to the acquisition of English because it is a global language and moreover that other factors such as the gender of the student or the environment of the class might also influence its predictability. Results of a hierarchical linear modeling analysis indicated that for the older samples, integrative motivation was a consistent predictor of grades in English, unaffected by either the gender of the student or class environment acting as covariates. Comparable results were obtained for the younger samples except that student gender also contributed to the prediction of grades in English. Examination of the correlations of the elements of the integrative motivation score with English grades demonstrated that the aggregate score is the more consistent correlate from sample to sample than the elements themselves. Such results lead to the hypothesis that integrative motivation is a multi-dimensional construct and different aspects of the motivational complex come into play for each individual. That is, two individuals can hold the same level of integrative motivation and thus attain the same level of achievement but one might be higher in some elements and lower in others than another individual, resulting in consistent correlations of the aggregate but less so for the elements.

Integrative Genomics Reveals a Role for GNA13 in Lymphomagenesis

Lymphomas comprise a diverse group of malignancies derived from immune cells. High throughput sequencing has recently emerged as a powerful and versatile method for analysis of the cancer genome and transcriptome. As these data continue to emerge, the crucial work lies in sorting through the wealth of information to hone in on the critical aspects that will give us a better understanding of biology and new insight for how to treat disease. Finding the important signals within these large data sets is one of the major challenges of next generation sequencing.

In this dissertation, I have developed several complementary strategies to describe the genetic underpinnings of lymphomas. I begin with developing a better method for RNA sequencing that enables strand-specific total RNA sequencing and alternative splicing profiling in the same analysis. I then combine this RNA sequencing technique with whole exome sequencing to better understand the global landscape of aberrations in these diseases. Finally, I use traditional cell and molecular biology techniques to define the consequences of major genetic alterations in lymphoma.

Through this analysis, I find recurrent silencing mutations in the G alpha binding protein GNA13 and associated focal adhesion proteins. I aim to describe how loss-of-function mutations in GNA13 can be oncogenic in the context of germinal center B cell biology. Using in vitro techniques including liquid chromatography-mass spectrometry and knockdown and overexpression of genes in B cell lymphoma cell lines, I determine protein binding partners and downstream effectors of GNA13. I also develop a transgenic mouse model to study the role of GNA13 in the germinal center in vivo to determine effects of GNA13 deletion on germinal center structure and cell migration.

Thus, I have developed complementary approaches that span the spectrum from discovery to context-dependent gene models that afford a better understanding of the biological function of aberrant events and ultimately result in a better understanding of disease.

Challenges in integrative approaches to modelling the marine ecosystems of the North Atlantic: Physics to fish and coasts to ocean

It has long been recognised that there are strong interactions and feedbacks between climate, upper ocean biogeochemistry and marine food webs, and also that food web structure and phytoplankton community distribution are important determinants of variability in carbon production and export from the euphotic zone. Numerical models provide a vital tool to explore these interactions, given their capability to investigate multiple connected components of the system and the sensitivity to multiple drivers, including potential future conditions. A major driver for ecosystem model development is the demand for quantitative tools to support ecosystem-based management initiatives. The purpose of this paper is to review approaches to the modelling of marine ecosystems with a focus on the North Atlantic Ocean and its adjacent shelf seas, and to highlight the challenges they face and suggest ways forward. We consider the state of the art in simulating oceans and shelf sea physics, planktonic and higher trophic level ecosystems, and look towards building an integrative approach with these existing tools. We note how the different approaches have evolved historically and that many of the previous obstacles to harmonisation may no longer be present. We illustrate this with examples from the on-going and planned modelling effort in the Integrative Modelling Work Package of the EURO-BASIN programme.

Speciation in Red Algae: Members of the Ceramiales as Model Organisms

Red algae (Rhodophyta) are an ancient group with unusual morphological, biochemical, and life-history features including a complete absence of flagella. Although the red algae present many opportunities for studying speciation, this has rarely been explicitly addressed. Here, we examine an aspect of paternal gene flow by determining fertilization success of female Neosiphonia harveyi (Ceramiales), which retains a morphological record of all successful and unsuccessful female gametes. High fertilization rates were observed except when there were no males at all within the tidepool, or in a submerged marina environment. Small numbers of reproductive males were able to saturate fertilization rates, suggesting that limited availability of sperm may be less significant in red algae than previously thought. In another member of the Ceramiales, Antithamnion, relatively large chromosomes permit karyological identification of polyploids. The Western Pacific species Antithamnion sparsum is closely related to the diploid species Antithamnion defectum, known only from the Eastern Pacific, and appears to have evolved from it. Molecular evidence suggests that A. sparsum is an autopolyploid, and that the European species known as Antithamnion densum is divergent from the A. sparsum/defectum complex.

Molecular pathology - The value of an integrative approach

Molecular Pathology (MP) is at the heart of modern diagnostics and translational research, but the controversy on how MP is best developed has not abated. The lack of a proper model or trained pathologists to support the diagnostic and research missions makes MP a rare commodity overall. Here we analyse the scientific and technology areas, in research and diagnostics, which are encompassed by MP of solid tumours; we highlight the broad overlap of technologies and analytical capabilities in tissue research and diagnostics; and we describe an integrated model that rationalizes technical know-how and pathology talent for both. The model is based on a single, accredited laboratory providing a single standard of high-quality for biomarker discovery, biomarker validation and molecular diagnostics.

Towards an improved understanding of farmers' behaviour: the integrative agent-centred (IAC) framework

An effective approach to research on farmers' behaviour is based on: i) an explicit and well-motivated behavioural theory; ii) an integrative approach; and iii) understanding feedback processes and dynamics. While current approaches may effectively tackle some of them, they often fail to combine them together. The paper presents the integrative agent-centred (IAC) framework, which aims at filling this gap. It functions in accordance with these three pillars and provides a conceptual structure to understand farmers' behaviour in agricultural systems. The IAC framework is agent-centred and supports the understanding of farmers' behavior consistently with the perspective of agricultural systems as complex social-ecological systems. It combines different behavioural drivers, bridges between micro and macro levels, and depicts a potentially varied model of human agency. The use of the framework in practice is illustrated through two studies on pesticide use among smallholders in Colombia. The examples show how the framework can be implemented to derive policy implications to foster a transition towards more sustainable agricultural practices. The paper finally suggests that the framework can support different research designs for the study of agents' behaviour in agricultural and social-ecological systems.

Simulating human and environmental exposure from hand-held knapsack pesticide application: Be-WetSpa-Pest, an integrative, spatially explicit modeling approach

This paper presents an integrative and spatially explicit modeling approach for analyzing human and environmental exposure from pesticide application of smallholders in the potato producing Andean region in Colombia. The modeling approach fulfills the following criteria: (i) it includes environmental and human compartments; (ii) it contains a behavioral decision-making model for estimating the effect of policies on pesticide flows to humans and the environment; (iii) it is spatially explicit; and (iv) it is modular and easily expandable to include additional modules, crops or technologies. The model was calibrated and validated for the Vereda La Hoya and was used to explore the effect of different policy measures in the region. The model has moderate data requirements and can be adapted relatively easy to other regions in developing countries with similar conditions.

A regionally informed abundance index for supporting integrative analyses across butterfly monitoring schemes

1. The rapid expansion of systematic monitoring schemes necessitates robust methods to reliably assess species' status and trends. Insect monitoring poses a challenge where there are strong seasonal patterns, requiring repeated counts to reliably assess abundance. Butterfly monitoring schemes (BMSs) operate in an increasing number of countries with broadly the same methodology, yet they differ in their observation frequency and in the methods used to compute annual abundance indices. 2. Using simulated and observed data, we performed an extensive comparison of two approaches used to derive abundance indices from count data collected via BMS, under a range of sampling frequencies. Linear interpolation is most commonly used to estimate abundance indices from seasonal count series. A second method, hereafter the regional generalized additive model (GAM), fits a GAM to repeated counts within sites across a climatic region. For the two methods, we estimated bias in abundance indices and the statistical power for detecting trends, given different proportions of missing counts. We also compared the accuracy of trend estimates using systematically degraded observed counts of the Gatekeeper Pyronia tithonus (Linnaeus 1767). 3. The regional GAM method generally outperforms the linear interpolation method. When the proportion of missing counts increased beyond 50%, indices derived via the linear interpolation method showed substantially higher estimation error as well as clear biases, in comparison to the regional GAM method. The regional GAM method also showed higher power to detect trends when the proportion of missing counts was substantial. 4. Synthesis and applications. Monitoring offers invaluable data to support conservation policy and management, but requires robust analysis approaches and guidance for new and expanding schemes. Based on our findings, we recommend the regional generalized additive model approach when conducting integrative analyses across schemes, or when analysing scheme data with reduced sampling efforts. This method enables existing schemes to be expanded or new schemes to be developed with reduced within-year sampling frequency, as well as affording options to adapt protocols to more efficiently assess species status and trends across large geographical scales.

The Dynamics of The Firm : In Search for a General Model

This paper describe a model from system theory that can be used as a base for better understanding of different situations in the firms evolution. This change model is derived from the theory of organic systems and divides the evolution of the system into higher complexity of the system structure in three distinctive phases. These phases are a formative phase, a normative phase and an integrative phase. After a summary of different types of models of the dynamics of the firm the paper makes a theoretical presentation of the model and how this model is adaptable for better understanding of the need for change in strategic orientation, organization form and leadership style over time.