Multi-level models and infrastructures for simulating biological system development

The hierarchical organisation of biological systems plays a crucial role in the pattern formation of gene expression resulting from the morphogenetic processes, where autonomous internal dynamics of cells, as well as cell-to-cell interactions through membranes, are responsible for the emergent peculiar structures of the individual phenotype. Being able to reproduce the systems dynamics at different levels of such a hierarchy might be very useful for studying such a complex phenomenon of self-organisation. The idea is to model the phenomenon in terms of a large and dynamic network of compartments, where the interplay between inter-compartment and intra-compartment events determines the emergent behaviour resulting in the formation of spatial patterns. According to these premises the thesis proposes a review of the different approaches already developed in modelling developmental biology problems, as well as the main models and infrastructures available in literature for modelling biological systems, analysing their capabilities in tackling multi-compartment / multi-level models. The thesis then introduces a practical framework, MS-BioNET, for modelling and simulating these scenarios exploiting the potential of multi-level dynamics. This is based on (i) a computational model featuring networks of compartments and an enhanced model of chemical reaction addressing molecule transfer, (ii) a logic-oriented language to flexibly specify complex simulation scenarios, and (iii) a simulation engine based on the many-species/many-channels optimised version of Gillespie’s direct method. The thesis finally proposes the adoption of the agent-based model as an approach capable of capture multi-level dynamics. To overcome the problem of parameter tuning in the model, the simulators are supplied with a module for parameter optimisation. The task is defined as an optimisation problem over the parameter space in which the objective function to be minimised is the distance between the output of the simulator and a target one. The problem is tackled with a metaheuristic algorithm. As an example of application of the MS-BioNET framework and of the agent-based model, a model of the first stages of Drosophila Melanogaster development is realised. The model goal is to generate the early spatial pattern of gap gene expression. The correctness of the models is shown comparing the simulation results with real data of gene expression with spatial and temporal resolution, acquired in free on-line sources.

Development of a multi-species method by GC-coupling with inductively coupled plasma isotope dilution mass spectrometry for the simultaneous determination of alkylated lead, mercury and tin compounds

An accurate and sensitive species-specific GC-ICP-IDMS (gas chromatography inductively coupled plasma isotope dilution mass spectrometry) method for the determination of trimethyllead and a multi-species-specific GC-ICP-IDMS method for the simultaneous determination of trimethyllead, methylmercury, and butyltins in biological and environmental samples were developed. They allow the determination of corresponding elemental species down to the low ng g-1 range. The developed synthesis scheme for the formation of isotopically labeled Me3206Pb+ can be used for future production of this spike. The novel extraction technique, stir bar sorptive extraction (SBSE), was applied for the first time in connection with species-specific isotope dilution GC-ICP-MS for the determination of trimethyllead, methylmercury and butyltins. The results were compared with liquid-liquid extraction. The developed methods were validated by the analysis of certified reference materials. The liquid-liquid extraction GC-ICP-IDMS method was applied to seafood samples purchased from a supermarket. The methylated lead fraction in these samples, correlated to total lead, varied in a broad range of 0.01-7.6 %. On the contrary, the fraction of methylmercury is much higher, normally in the range of 80-98 %. The highest methylmercury content of up to 12 µg g-1 has been determined in shark samples, an animal which is at the end of the marine food chain, whereas in other seafood samples a MeHg+ content of less than 0.2 µg g-1 was found. Butyltin species could only be determined in samples, where anthropogenic contaminations must be assumed. This explains the observed broad variation of the butylated tin fraction in the range of <0.3-49 % in different seafood samples. Because all isotope-labelled spike compounds, except trimethyllead, are commercially available, the developed multi-species-specific GC-ICP-IDMS method has a high potential in future for routine analysis.

Modelling and simulating in systems biology: an approach based on multi-agent systems

Systems Biology is an innovative way of doing biology recently raised in bio-informatics contexts, characterised by the study of biological systems as complex systems with a strong focus on the system level and on the interaction dimension. In other words, the objective is to understand biological systems as a whole, putting on the foreground not only the study of the individual parts as standalone parts, but also of their interaction and of the global properties that emerge at the system level by means of the interaction among the parts. This thesis focuses on the adoption of multi-agent systems (MAS) as a suitable paradigm for Systems Biology, for developing models and simulation of complex biological systems. Multi-agent system have been recently introduced in informatics context as a suitabe paradigm for modelling and engineering complex systems. Roughly speaking, a MAS can be conceived as a set of autonomous and interacting entities, called agents, situated in some kind of nvironment, where they fruitfully interact and coordinate so as to obtain a coherent global system behaviour. The claim of this work is that the general properties of MAS make them an effective approach for modelling and building simulations of complex biological systems, following the methodological principles identified by Systems Biology. In particular, the thesis focuses on cell populations as biological systems. In order to support the claim, the thesis introduces and describes (i) a MAS-based model conceived for modelling the dynamics of systems of cells interacting inside cell environment called niches. (ii) a computational tool, developed for implementing the models and executing the simulations. The tool is meant to work as a kind of virtual laboratory, on top of which kinds of virtual experiments can be performed, characterised by the definition and execution of specific models implemented as MASs, so as to support the validation, falsification and improvement of the models through the observation and analysis of the simulations. A hematopoietic stem cell system is taken as reference case study for formulating a specific model and executing virtual experiments.

Early non-invasive cardiac output monitoring in hemodynamically unstable intensive care patients: A multi-center randomized controlled trial

Introduction Acute hemodynamic instability increases morbidity and mortality. We investigated whether early non-invasive cardiac output monitoring enhances hemodynamic stabilization and improves outcome. Methods A multicenter, randomized controlled trial was conducted in three European university hospital intensive care units in 2006 and 2007. A total of 388 hemodynamically unstable patients identified during their first six hours in the intensive care unit (ICU) were randomized to receive either non-invasive cardiac output monitoring for 24 hrs (minimally invasive cardiac output/MICO group; n = 201) or usual care (control group; n = 187). The main outcome measure was the proportion of patients achieving hemodynamic stability within six hours of starting the study. Results The number of hemodynamic instability criteria at baseline (MICO group mean 2.0 (SD 1.0), control group 1.8 (1.0); P = .06) and severity of illness (SAPS II score; MICO group 48 (18), control group 48 (15); P = .86)) were similar. At 6 hrs, 45 patients (22%) in the MICO group and 52 patients (28%) in the control group were hemodynamically stable (mean difference 5%; 95% confidence interval of the difference -3 to 14%; P = .24). Hemodynamic support with fluids and vasoactive drugs, and pulmonary artery catheter use (MICO group: 19%, control group: 26%; P = .11) were similar in the two groups. The median length of ICU stay was 2.0 (interquartile range 1.2 to 4.6) days in the MICO group and 2.5 (1.1 to 5.0) days in the control group (P = .38). The hospital mortality was 26% in the MICO group and 21% in the control group (P = .34). Conclusions Minimally-invasive cardiac output monitoring added to usual care does not facilitate early hemodynamic stabilization in the ICU, nor does it alter the hemodynamic support or outcome. Our results emphasize the need to evaluate technologies used to measure stroke volume and cardiac output--especially their impact on the process of care--before any large-scale outcome studies are attempted.

Measurement Properties of the Short Multi-Dimensional Observation Scale for Elderly Subjects (MOSES)

This study evaluated the five-factor measurement model of the abbreviated Multidimensional Observation Scale for Elderly Subjects (MOSES), originally proposed by Pruchno, Kleban, and Resch in 1988. Modifications of the five-factor model were examined and evaluated with regard to their practical significance. A confirmatory second-order factor analysis was performed to examine whether the correlations among the first-order factors were adequately accounted for by a global dysfunction factor. Findings indicated that the proposed measurement model was replicated adequately. Although post hoc modifications resulted in significant improvements in overall model fit, the minor parameters had only a trivial influence on the major parameters of the baseline model. Results from the second-order factor analysis showed that a global dysfunc tion factor accounted adequately for the intercorrelations among the first-order factors.

Multi-node TOA-DOA cooperative LOS-NLOS localization : enabling high accuracy and reliability

This dissertation investigates high performance cooperative localization in wireless environments based on multi-node time-of-arrival (TOA) and direction-of-arrival (DOA) estimations in line-of-sight (LOS) and non-LOS (NLOS) scenarios. Here, two categories of nodes are assumed: base nodes (BNs) and target nodes (TNs). BNs are equipped with antenna arrays and capable of estimating TOA (range) and DOA (angle). TNs are equipped with Omni-directional antennas and communicate with BNs to allow BNs to localize TNs; thus, the proposed localization is maintained by BNs and TNs cooperation. First, a LOS localization method is proposed, which is based on semi-distributed multi-node TOA-DOA fusion. The proposed technique is applicable to mobile ad-hoc networks (MANETs). We assume LOS is available between BNs and TNs. One BN is selected as the reference BN, and other nodes are localized in the coordinates of the reference BN. Each BN can localize TNs located in its coverage area independently. In addition, a TN might be localized by multiple BNs. High performance localization is attainable via multi-node TOA-DOA fusion. The complexity of the semi-distributed multi-node TOA-DOA fusion is low because the total computational load is distributed across all BNs. To evaluate the localization accuracy of the proposed method, we compare the proposed method with global positioning system (GPS) aided TOA (DOA) fusion, which are applicable to MANETs. The comparison criterion is the localization circular error probability (CEP). The results confirm that the proposed method is suitable for moderate scale MANETs, while GPS-aided TOA fusion is suitable for large scale MANETs. Usually, TOA and DOA of TNs are periodically estimated by BNs. Thus, Kalman filter (KF) is integrated with multi-node TOA-DOA fusion to further improve its performance. The integration of KF and multi-node TOA-DOA fusion is compared with extended-KF (EKF) when it is applied to multiple TOA-DOA estimations made by multiple BNs. The comparison depicts that it is stable (no divergence takes place) and its accuracy is slightly lower than that of the EKF, if the EKF converges. However, the EKF may diverge while the integration of KF and multi-node TOA-DOA fusion does not; thus, the reliability of the proposed method is higher. In addition, the computational complexity of the integration of KF and multi-node TOA-DOA fusion is much lower than that of EKF. In wireless environments, LOS might be obstructed. This degrades the localization reliability. Antenna arrays installed at each BN is incorporated to allow each BN to identify NLOS scenarios independently. Here, a single BN measures the phase difference across two antenna elements using a synchronized bi-receiver system, and maps it into wireless channel’s K-factor. The larger K is, the more likely the channel would be a LOS one. Next, the K-factor is incorporated to identify NLOS scenarios. The performance of this system is characterized in terms of probability of LOS and NLOS identification. The latency of the method is small. Finally, a multi-node NLOS identification and localization method is proposed to improve localization reliability. In this case, multiple BNs engage in the process of NLOS identification, shared reflectors determination and localization, and NLOS TN localization. In NLOS scenarios, when there are three or more shared reflectors, those reflectors are localized via DOA fusion, and then a TN is localized via TOA fusion based on the localization of shared reflectors.

Critical issues in managing protected areas by multi-stakeholder participation - analysis of a process in the Swiss Alps

Balancing the frequently conflicting priorities of conservation and economic development poses a challenge to management of the Swiss Alps Jungfrau-Aletsch World Heritage Site (WHS). This is a complex societal problem that calls for a knowledge-based solution. This in turn requires a transdisciplinary research framework in which problems are defined and solved cooperatively by actors from the scientific community and the life-world. In this article we re-examine studies carried out in the region of the Swiss Alps Jungfrau-Aletsch WHS, covering three key issues prevalent in transdisciplinary settings: integration of stakeholders into participatory processes; perceptions and positions; and negotiability and implementation. In the case of the Swiss Alps Jungfrau-Aletsch WHS the transdisciplinary setting created a situation of mutual learning among stakeholders from different levels and backgrounds. However, the studies showed that the benefits of such processes of mutual learning are continuously at risk of being diminished by the power play inherent in participatory approaches.

Collision Detection: Broad Phase Adaptation from Multi-Core to Multi-GPU Architecture

We present in this paper several contributions on the collision detection optimization centered on hardware performance. We focus on the broad phase which is the first step of the collision detection process and propose three new ways of parallelization of the well-known Sweep and Prune algorithm. We first developed a multi-core model takes into account the number of available cores. Multi-core architecture enables us to distribute geometric computations with use of multi-threading. Critical writing section and threads idling have been minimized by introducing new data structures for each thread. Programming with directives, like OpenMP, appears to be a good compromise for code portability. We then proposed a new GPU-based algorithm also based on the "Sweep and Prune" that has been adapted to multi-GPU architectures. Our technique is based on a spatial subdivision method used to distribute computations among GPUs. Results show that significant speed-up can be obtained by passing from 1 to 4 GPUs in a large-scale environment.

The cobblers stick to their lasts: pollinators prefer native over alien plant species in a multi-species experiment

The majority of plant species rely, at least partly, on animals for pollination. Our knowledge on whether pollinator visitation differs between native and alien plant species, and between invasive and non-invasive alien species is still limited. Additionally, because numerous invasive plant species are escapees from horticulture, the transition from human-assisted occurrence in urbanized habitats to unassisted persistence and spread in (semi-)natural habitats requires study. To address whether pollinator visitation differs between native, invasive alien and non-invasive alien species, we did pollinator observations for a total of 17 plant species representing five plant families. To test whether pollinator visitation to the three groups of species during the initial stage of invasion depends on habitat type, we did the study in three urbanized habitats and three semi-natural grasslands, using single potted plants. Native plants had more but smaller flower units than alien plants, and invasive alien plants had more but smaller flowers than non-invasive alien plants. After accounting for these differences in floral display, pollinator visitation was higher for native than for alien plant species, but did not differ between invasive and non-invasive alien plant species. Pollinator visitation was on average higher in semi-natural than in urbanized habitats, irrespective of origin or status of the plant species. This might suggest that once an alien species has managed to escape from urbanized into more natural habitats, pollinator limitation will not be a major barrier to establishment and invasion.

The more the merrier: Multi-species experiments in ecology

A major objective in ecology is to find general patterns, and to establish the rules and underlying mechanisms that generate those patterns. Nevertheless, most of our current insights in ecology are based on case studies of a single or few species, whereas multi-species experimental studies remain rare. We underline the power of the multi-species experimental approach for addressing general ecological questions, e. g. on species environmental responses or on patterns of among-and within-species variation. We present simulations that show that the accuracy of estimates of between-group differences is increased by maximizing the number of species rather than the number of populations or individuals per species. Thus, the more species a multi-species experiment includes, the more powerful it is. In addition, we discuss some inevitable methodological challenges of multi-species experiments. While we acknowledge the value of single-or few-species experiments, we strongly advocate the use of multi-species experiments for addressing ecological questions at a more general level.