Multistage model for the action of cytotoxic T lymphocytes in multicellular conjugates

International Nuclear Information System (INIS)

Macken, C.A.; Perelson, A.S.

1984-01-01

The authors propose a multistage stochastic model to explain data on the kinetics of target cell lysis by cytotoxic T lymphocytes in multicellular conjugates. A novel feature of this model is that the authors explicitly consider both the lethal hitting stage and the target cell disintegration stage of the cytolytic process. Further, the authors allow for the possibility that target cell disintegration is itself a complex process composed of many events. The comparison of this model with the data of other investigators suggests that cytotoxic T cells deliver lethal hits at random to undamage target cells. Having received a lethal hit, the target cell disintegrates over a variable length of time. The disintegration times of target cells from different conjugates appear to be randomly distributed and to be consistent with a model in which disintegration occurs by at least two major, sequential, rate-limiting events. For conjugates containing one lymphocyte and multiple target cells, the mean rate at which a lethally hit target cell disintegrates is found to be independent of the total number of target cells in the conjugate. This model predicts that in such multicellular conjugates, individual target cells lyse one by one, on average at approximately 30-min intervals, thus agreeing closely with previously reported experimental observations. 35 references, 3 figures, 2 tables

The origin of multicellularity in cyanobacteria

Science.gov (United States)

2011-01-01

Background Cyanobacteria are one of the oldest and morphologically most diverse prokaryotic phyla on our planet. The early development of an oxygen-containing atmosphere approximately 2.45 - 2.22 billion years ago is attributed to the photosynthetic activity of cyanobacteria. Furthermore, they are one of the few prokaryotic phyla where multicellularity has evolved. Understanding when and how multicellularity evolved in these ancient organisms would provide fundamental information on the early history of life and further our knowledge of complex life forms. Results We conducted and compared phylogenetic analyses of 16S rDNA sequences from a large sample of taxa representing the morphological and genetic diversity of cyanobacteria. We reconstructed ancestral character states on 10,000 phylogenetic trees. The results suggest that the majority of extant cyanobacteria descend from multicellular ancestors. Reversals to unicellularity occurred at least 5 times. Multicellularity was established again at least once within a single-celled clade. Comparison to the fossil record supports an early origin of multicellularity, possibly as early as the "Great Oxygenation Event" that occurred 2.45 - 2.22 billion years ago. Conclusions The results indicate that a multicellular morphotype evolved early in the cyanobacterial lineage and was regained at least once after a previous loss. Most of the morphological diversity exhibited in cyanobacteria today —including the majority of single-celled species— arose from ancient multicellular lineages. Multicellularity could have conferred a considerable advantage for exploring new niches and hence facilitated the diversification of new lineages. PMID:21320320

Multicellular Features of Phytoplankton

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Adi Abada

2018-04-01

Full Text Available Microscopic marine phytoplankton drift freely in the ocean, harvesting sunlight through photosynthesis. These unicellular microorganisms account for half of the primary productivity on Earth and play pivotal roles in the biogeochemistry of our planet (Field et al., 1998. The major groups of microalgae that comprise the phytoplankton community are coccolithophores, diatoms and dinoflagellates. In present oceans, phytoplankton individuals and populations are forced to rapidly adjust, as key chemical and physical parameters defining marine habitats are changing globally. Here we propose that microalgal populations often display the characteristics of a multicellular-like community rather than a random collection of individuals. Evolution of multicellularity entails a continuum of events starting from single cells that go through aggregation or clonal divisions (Brunet and King, 2017. Phytoplankton may be an intermediate state between single cells and aggregates of physically attached cells that communicate and co-operate; perhaps an evolutionary snapshot toward multicellularity. In this opinion article, we journey through several studies conducted in two key phytoplankton groups, coccolithophores and diatoms, to demonstrate how observations in these studies could be interpreted in a multicellular context.

Developing multi-cellular tumor spheroid model (MCTS) in the chitosan/collagen/alginate (CCA) fibrous scaffold for anticancer drug screening

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Wang, Jian-Zheng, E-mail: wppzheng@126.com [Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023 (China); Affiliated General Hospital, Tianguan Group Co., Ltd, Nanyang 473000 (China); Testing Center of Henan Tianguan Group Co., Ltd, Nanyang 473000 (China); Zhu, Yu-Xia [Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023 (China); Affiliated General Hospital, Tianguan Group Co., Ltd, Nanyang 473000 (China); Testing Center of Henan Tianguan Group Co., Ltd, Nanyang 473000 (China); Ma, Hui-Chao; Chen, Si-Nan; Chao, Ji-Ye; Ruan, Wen-Ding; Wang, Duo; Du, Feng-guang [Affiliated General Hospital, Tianguan Group Co., Ltd, Nanyang 473000 (China); Testing Center of Henan Tianguan Group Co., Ltd, Nanyang 473000 (China); Meng, Yue-Zhong [State Key Laboratory of Optoelectronic Materials and Technologies, Sun Yat-sen University, Guangzhou 510275 (China)

2016-05-01

In this work, a 3D MCTS-CCA system was constructed by culturing multi-cellular tumor spheroid (MCTS) in the chitosan/collagen/alginate (CCA) fibrous scaffold for anticancer drug screening. The CCA scaffolds were fabricated by spray-spinning. The interactions between the components of the spray-spun fibers were evidenced by methods of Coomassie Blue stain, X-ray diffraction (XRD) and Fourier transform-infrared spectroscopy (FTIR). Co-culture indicated that MCF-7 cells showed a spatial growth pattern of multi-cellular tumor spheroid (MCTS) in the CCA fibrous scaffold with increased proliferation rate and drug-resistance to MMC, ADM and 5-Aza comparing with the 2D culture cells. Significant increases of total viable cells were found in 3D MCTS groups after drug administration by method of apoptotic analysis. Glucose–lactate analysis indicated that the metabolism of MCTS in CCA scaffold was closer to the tumor issue in vivo than the monolayer cells. In addition, MCTS showed the characteristic of epithelial mesenchymal transition (EMT) which is subverted by carcinoma cells to facilitate metastatic spread. These results demonstrated that MCTS in CCA scaffold possessed a more conservative phenotype of tumor than monolayer cells, and anticancer drug screening in 3D MCTS-CCA system might be superior to the 2D culture system. - Highlights: • Chitosan/collagen/alginate (CCA) scaffolds were fabricated by spray-spinning. • MCF-7 cells presented a multi-cellular tumor spheroid model (MCTS) in CCA scaffold. • MCTS in CCA possessed a more conservative phenotype of tumor than monolayer cells. • Anticancer drug screening in MCTS-CCA system is superior to 2D culture system.

Developing multi-cellular tumor spheroid model (MCTS) in the chitosan/collagen/alginate (CCA) fibrous scaffold for anticancer drug screening

International Nuclear Information System (INIS)

Wang, Jian-Zheng; Zhu, Yu-Xia; Ma, Hui-Chao; Chen, Si-Nan; Chao, Ji-Ye; Ruan, Wen-Ding; Wang, Duo; Du, Feng-guang; Meng, Yue-Zhong

2016-01-01

In this work, a 3D MCTS-CCA system was constructed by culturing multi-cellular tumor spheroid (MCTS) in the chitosan/collagen/alginate (CCA) fibrous scaffold for anticancer drug screening. The CCA scaffolds were fabricated by spray-spinning. The interactions between the components of the spray-spun fibers were evidenced by methods of Coomassie Blue stain, X-ray diffraction (XRD) and Fourier transform-infrared spectroscopy (FTIR). Co-culture indicated that MCF-7 cells showed a spatial growth pattern of multi-cellular tumor spheroid (MCTS) in the CCA fibrous scaffold with increased proliferation rate and drug-resistance to MMC, ADM and 5-Aza comparing with the 2D culture cells. Significant increases of total viable cells were found in 3D MCTS groups after drug administration by method of apoptotic analysis. Glucose–lactate analysis indicated that the metabolism of MCTS in CCA scaffold was closer to the tumor issue in vivo than the monolayer cells. In addition, MCTS showed the characteristic of epithelial mesenchymal transition (EMT) which is subverted by carcinoma cells to facilitate metastatic spread. These results demonstrated that MCTS in CCA scaffold possessed a more conservative phenotype of tumor than monolayer cells, and anticancer drug screening in 3D MCTS-CCA system might be superior to the 2D culture system. - Highlights: • Chitosan/collagen/alginate (CCA) scaffolds were fabricated by spray-spinning. • MCF-7 cells presented a multi-cellular tumor spheroid model (MCTS) in CCA scaffold. • MCTS in CCA possessed a more conservative phenotype of tumor than monolayer cells. • Anticancer drug screening in MCTS-CCA system is superior to 2D culture system.

Multicellularity makes somatic differentiation evolutionarily stable

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Wahl, Mary E.; Murray, Andrew W.

2016-01-01

Many multicellular organisms produce two cell lineages: germ cells, whose descendants produce the next generation, and somatic cells, which support, protect, and disperse the germ cells. This germ-soma demarcation has evolved independently in dozens of multicellular taxa but is absent in unicellular species. A common explanation holds that in these organisms, inefficient intercellular nutrient exchange compels the fitness cost of producing nonreproductive somatic cells to outweigh any potential benefits. We propose instead that the absence of unicellular, soma-producing populations reflects their susceptibility to invasion by nondifferentiating mutants that ultimately eradicate the soma-producing lineage. We argue that multicellularity can prevent the victory of such mutants by giving germ cells preferential access to the benefits conferred by somatic cells. The absence of natural unicellular, soma-producing species previously prevented these hypotheses from being directly tested in vivo: to overcome this obstacle, we engineered strains of the budding yeast Saccharomyces cerevisiae that differ only in the presence or absence of multicellularity and somatic differentiation, permitting direct comparisons between organisms with different lifestyles. Our strains implement the essential features of irreversible conversion from germ line to soma, reproductive division of labor, and clonal multicellularity while maintaining sufficient generality to permit broad extension of our conclusions. Our somatic cells can provide fitness benefits that exceed the reproductive costs of their production, even in unicellular strains. We find that nondifferentiating mutants overtake unicellular populations but are outcompeted by multicellular, soma-producing strains, suggesting that multicellularity confers evolutionary stability to somatic differentiation. PMID:27402737

Multicellular spheroids as an in vitro tumor model

International Nuclear Information System (INIS)

Kozubek, S.; Erzgraber, G.

1982-01-01

Experiments with fractionated irradiation of multicellular spheroids were performed. Our data as well as the data of other works have been evaluated by means of simple mathematical formulae on the basis of several hypothesis. The spheroids are shown to exhibit similar behaviour as in vivo carcinomas. They offer the possibility of investigation of quantitative correlations for practical purposes

Colloquium: Modeling the dynamics of multicellular systems: Application to tissue engineering

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Kosztin, Ioan; Vunjak-Novakovic, Gordana; Forgacs, Gabor

2012-10-01

Tissue engineering is a rapidly evolving discipline that aims at building functional tissues to improve or replace damaged ones. To be successful in such an endeavor, ideally, the engineering of tissues should be based on the principles of developmental biology. Recent progress in developmental biology suggests that the formation of tissues from the composing cells is often guided by physical laws. Here a comprehensive computational-theoretical formalism is presented that is based on experimental input and incorporates biomechanical principles of developmental biology. The formalism is described and it is shown that it correctly reproduces and predicts the quantitative characteristics of the fundamental early developmental process of tissue fusion. Based on this finding, the formalism is then used toward the optimization of the fabrication of tubular multicellular constructs, such as a vascular graft, by bioprinting, a novel tissue engineering technology.

Role of multicellular aggregates in biofilm formation

DEFF Research Database (Denmark)

Kragh, Kasper N.; Hutchison, Jaime B.; Melaugh, Gavin

2016-01-01

In traditional models of in vitro biofilm development, individual bacterial cells seed a surface, multiply, and mature into multicellular, three-dimensional structures. Much research has been devoted to elucidating the mechanisms governing the initial attachment of single cells to surfaces. Howev...

The multicellularity genes of dictyostelid social amoebas

Science.gov (United States)

Glöckner, Gernot; Lawal, Hajara M.; Felder, Marius; Singh, Reema; Singer, Gail; Weijer, Cornelis J.; Schaap, Pauline

2016-01-01

The evolution of multicellularity enabled specialization of cells, but required novel signalling mechanisms for regulating cell differentiation. Early multicellular organisms are mostly extinct and the origins of these mechanisms are unknown. Here using comparative genome and transcriptome analysis across eight uni- and multicellular amoebozoan genomes, we find that 80% of proteins essential for the development of multicellular Dictyostelia are already present in their unicellular relatives. This set is enriched in cytosolic and nuclear proteins, and protein kinases. The remaining 20%, unique to Dictyostelia, mostly consists of extracellularly exposed and secreted proteins, with roles in sensing and recognition, while several genes for synthesis of signals that induce cell-type specialization were acquired by lateral gene transfer. Across Dictyostelia, changes in gene expression correspond more strongly with phenotypic innovation than changes in protein functional domains. We conclude that the transition to multicellularity required novel signals and sensors rather than novel signal processing mechanisms. PMID:27357338

Detecting tree-like multicellular life on extrasolar planets.

Science.gov (United States)

Doughty, Christopher E; Wolf, Adam

2010-11-01

Over the next two decades, NASA and ESA are planning a series of space-based observatories to find Earth-like planets and determine whether life exists on these planets. Previous studies have assessed the likelihood of detecting life through signs of biogenic gases in the atmosphere or a red edge. Biogenic gases and the red edge could be signs of either single-celled or multicellular life. In this study, we propose a technique with which to determine whether tree-like multicellular life exists on extrasolar planets. For multicellular photosynthetic organisms on Earth, competition for light and the need to transport water and nutrients has led to a tree-like body plan characterized by hierarchical branching networks. This design results in a distinct bidirectional reflectance distribution function (BRDF) that causes differing reflectance at different sun/view geometries. BRDF arises from the changing visibility of the shadows cast by objects, and the presence of tree-like structures is clearly distinguishable from flat ground with the same reflectance spectrum. We examined whether the BRDF could detect the existence of tree-like structures on an extrasolar planet by using changes in planetary albedo as a planet orbits its star. We used a semi-empirical BRDF model to simulate vegetation reflectance at different planetary phase angles and both simulated and real cloud cover to calculate disk and rotation-averaged planetary albedo for a vegetated and non-vegetated planet with abundant liquid water. We found that even if the entire planetary albedo were rendered to a single pixel, the rate of increase of albedo as a planet approaches full illumination would be comparatively greater on a vegetated planet than on a non-vegetated planet. Depending on how accurately planetary cloud cover can be resolved and the capabilities of the coronagraph to resolve exoplanets, this technique could theoretically detect tree-like multicellular life on exoplanets in 50 stellar systems.

Bacterial Ventures into Multicellularity: Collectivism through Individuality.

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Simon van Vliet

2015-06-01

Full Text Available Multicellular eukaryotes can perform functions that exceed the possibilities of an individual cell. These functions emerge through interactions between differentiated cells that are precisely arranged in space. Bacteria also form multicellular collectives that consist of differentiated but genetically identical cells. How does the functionality of these collectives depend on the spatial arrangement of the differentiated bacteria? In a previous issue of PLOS Biology, van Gestel and colleagues reported an elegant example of how the spatial arrangement of differentiated cells gives rise to collective behavior in Bacillus subtilus colonies, further demonstrating the similarity of bacterial collectives to higher multicellular organisms.

Analysis of motility in multicellular Chlamydomonas reinhardtii evolved under predation.

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Margrethe Boyd

Full Text Available The advent of multicellularity was a watershed event in the history of life, yet the transition from unicellularity to multicellularity is not well understood. Multicellularity opens up opportunities for innovations in intercellular communication, cooperation, and specialization, which can provide selective advantages under certain ecological conditions. The unicellular alga Chlamydomonas reinhardtii has never had a multicellular ancestor yet it is closely related to the volvocine algae, a clade containing taxa that range from simple unicells to large, specialized multicellular colonies. Simple multicellular structures have been observed to evolve in C. reinhardtii in response to predation or to settling rate-based selection. Structures formed in response to predation consist of individual cells confined within a shared transparent extracellular matrix. Evolved isolates form such structures obligately under culture conditions in which their wild type ancestors do not, indicating that newly-evolved multicellularity is heritable. C. reinhardtii is capable of photosynthesis, and possesses an eyespot and two flagella with which it moves towards or away from light in order to optimize input of radiant energy. Motility contributes to C. reinhardtii fitness because it allows cells or colonies to achieve this optimum. Utilizing phototaxis to assay motility, we determined that newly evolved multicellular strains do not exhibit significant directional movement, even though the flagellae of their constituent unicells are present and active. In C. reinhardtii the first steps towards multicellularity in response to predation appear to result in a trade-off between motility and differential survivorship, a trade-off that must be overcome by further genetic change to ensure long-term success of the new multicellular organism.

A multicellular view of cytokinesis in epithelial tissue.

Science.gov (United States)

Herszterg, Sophie; Pinheiro, Diana; Bellaïche, Yohanns

2014-05-01

The study of cytokinesis in single-cell systems provided a wealth of knowledge on the molecular and biophysical mechanisms controlling daughter cell separation. In this review, we outline recent advances in the understanding of cytokinesis in epithelial tissues. These findings provide evidence for how the cytokinetic machinery adapts to a multicellular context and how the cytokinetic machinery is itself exploited by the tissue for the preservation of tissue function and architecture during proliferation. We propose that cytokinesis in epithelia should be viewed as a multicellular process, whereby the biochemical and mechanical interactions between the dividing cell and its neighbors are essential for successful daughter cell separation while defining epithelial tissue organization and preserving tissue integrity. Copyright © 2013 Elsevier Ltd. All rights reserved.

Resistance of multicellular aggregates to pharmorubicin observed in human hepatocarcinoma cells

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Z. Jianmin

2002-02-01

Full Text Available The objective of the present study was to investigate the multicellular resistance of human hepatocarcinoma cells BEL-7402 to pharmorubicin. Cells (1 x 10(4 and 200 microcarrier Cytodex-3 beads were seeded onto a 24-well plate and cultured in RPMI 1640 medium. After the formation of multicellular aggregates, morphology and cell viability were analyzed by scanning electron microscopy, transmission electron microscopy and flow cytometry, respectively. The IC50 was determined by flow cytometry and MTT assay after the cells cultured in aggregates and monolayers were treated with pharmorubicin. The culture products exhibited structural characteristics somewhat similar to those of trabecular hepatocarcinoma in vivo. Among the microcarriers, cells were organized into several layers. Intercellular spaces were 0.5-2.0 µm wide and filled with many microvilli. The percent of viable cells was 87%. The cells cultured as multicellular aggregates were resistant to pharmorubicin with IC50 4.5-fold and 7.7-fold that of monolayer culture as determined by flow cytometry and MTT assay, respectively. This three-dimensional culture model may be used to investigate the mechanisms of multicellular drug resistance of hepatocarcinoma and to screen new anticancer drugs.

Multicellular stalk-like structures in Saccharomyces cerevisiae

International Nuclear Information System (INIS)

Engelberg, D.; Mimran, A.; Martinetto, H.; Otto, J.; Simchen, G.; Karin, M.; Fink, G.R.

1998-01-01

Stalk formation is a novel pattern of multicellular organization. Yeast cells which survive UV irradiation form colonies that grow vertically to form very long (0.5 to 3.0 cm) and thin (0.5 to 4 mm in diameter) multicellular structures. We describe the conditions required to obtain these stalk-like structures reproducibly in large numbers. Yeast mutants, mutated for control of cell polarity, developmental processes, UV response, and signal transduction cascades were tested and found capable of forming stalk-like structures. We suggest a model that explains the mechanism of stalk formation by mechanical environmental forces. We show that other microorganisms (Candida albicans, Schizosaccharomyces pombe, and Escherichia coli) also form stalks, suggesting that the ability to produce stalks may be a general property of microorganisms. Diploid yeast stalks sporulate at an elevated frequency, raising the possibility that the physiological role of stalks might be disseminating spores

Green Algae and the Origins of Multicellularity in the Plant Kingdom

Science.gov (United States)

Umen, James G.

2014-01-01

The green lineage of chlorophyte algae and streptophytes form a large and diverse clade with multiple independent transitions to produce multicellular and/or macroscopically complex organization. In this review, I focus on two of the best-studied multicellular groups of green algae: charophytes and volvocines. Charophyte algae are the closest relatives of land plants and encompass the transition from unicellularity to simple multicellularity. Many of the innovations present in land plants have their roots in the cell and developmental biology of charophyte algae. Volvocine algae evolved an independent route to multicellularity that is captured by a graded series of increasing cell-type specialization and developmental complexity. The study of volvocine algae has provided unprecedented insights into the innovations required to achieve multicellularity. PMID:25324214

Phylostratigraphic tracking of cancer genes suggests a link to the emergence of multicellularity in metazoa

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Domazet-Lošo Tomislav

2010-05-01

Full Text Available Abstract Background Phylostratigraphy is a method used to correlate the evolutionary origin of founder genes (that is, functional founder protein domains of gene families with particular macroevolutionary transitions. It is based on a model of genome evolution that suggests that the origin of complex phenotypic innovations will be accompanied by the emergence of such founder genes, the descendants of which can still be traced in extant organisms. The origin of multicellularity can be considered to be a macroevolutionary transition, for which new gene functions would have been required. Cancer should be tightly connected to multicellular life since it can be viewed as a malfunction of interaction between cells in a multicellular organism. A phylostratigraphic tracking of the origin of cancer genes should, therefore, also provide insights into the origin of multicellularity. Results We find two strong peaks of the emergence of cancer related protein domains, one at the time of the origin of the first cell and the other around the time of the evolution of the multicellular metazoan organisms. These peaks correlate with two major classes of cancer genes, the 'caretakers', which are involved in general functions that support genome stability and the 'gatekeepers', which are involved in cellular signalling and growth processes. Interestingly, this phylogenetic succession mirrors the ontogenetic succession of tumour progression, where mutations in caretakers are thought to precede mutations in gatekeepers. Conclusions A link between multicellularity and formation of cancer has often been predicted. However, this has not so far been explicitly tested. Although we find that a significant number of protein domains involved in cancer predate the origin of multicellularity, the second peak of cancer protein domain emergence is, indeed, connected to a phylogenetic level where multicellular animals have emerged. The fact that we can find a strong and

Numerical modeling of working of a multicellular proportional counter aimed to individual dosimetry of neutrons

International Nuclear Information System (INIS)

Bordy, J.M.; Barthe, J.; Boutruche, B.

1993-01-01

The use of a personal dosimeter imposes severe constraints, particularly for tension of polarization and tolerable dimensions. That why a numerical modeling of this detector working is an appreciable help for conception. It allows to determine quickly the influence of modification of different parameters (nature and pressure of gas, dimension of electrodes, dimension of channels, tension of polarization,...) without having to make new prototypes. The aim of this report is to give some numerical results got with a multicellular counter with a cylindrical geometry. 6 figs

Semiotic scaffolding of multicellularity

DEFF Research Database (Denmark)

Hoffmeyer, Jesper

2015-01-01

and animals this individuation process poses very different challenges in the three kingdoms of plants, fungi and animals, and the solutions found to these differences are discussed. In the same time as multicellularity ushered life into the epoch of mortality it logically also led to the appearance...

How the evolution of multicellularity set the stage for cancer

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Trigos, Anna S; Pearson, Richard B; Papenfuss, Anthony T; Goode, David L

2018-01-01

Neoplastic growth and many of the hallmark properties of cancer are driven by the disruption of molecular networks established during the emergence of multicellularity. Regulatory pathways and molecules that evolved to impose regulatory constraints upon networks established in earlier unicellular organisms enabled greater communication and coordination between the diverse cell types required for multicellularity, but also created liabilities in the form of points of vulnerability in the network that when mutated or dysregulated facilitate the development of cancer. These factors are usually overlooked in genomic analyses of cancer, but understanding where vulnerabilities to cancer lie in the networks of multicellular species would provide important new insights into how core molecular processes and gene regulation change during tumourigenesis. We describe how the evolutionary origins of genes influence their roles in cancer, and how connections formed between unicellular and multicellular genes that act as key regulatory hubs for normal tissue homeostasis can also contribute to malignant transformation when disrupted. Tumours in general are characterised by increased dependence on unicellular processes for survival, and major dysregulation of the control structures imposed on these processes during the evolution of multicellularity. Mounting molecular evidence suggests altered interactions at the interface between unicellular and multicellular genes play key roles in the initiation and progression of cancer. Furthermore, unicellular network regions activated in cancer show high degrees of robustness and plasticity, conferring increased adaptability to tumour cells by supporting effective responses to environmental pressures such as drug exposure. Examining how the links between multicellular and unicellular regions get disrupted in tumours has great potential to identify novel drivers of cancer, and to guide improvements to cancer treatment by identifying more

Principles of cooperation across systems: from human sharing to multicellularity and cancer.

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Aktipis, Athena

2016-01-01

From cells to societies, several general principles arise again and again that facilitate cooperation and suppress conflict. In this study, I describe three general principles of cooperation and how they operate across systems including human sharing, cooperation in animal and insect societies and the massively large-scale cooperation that occurs in our multicellular bodies. The first principle is that of Walk Away: that cooperation is enhanced when individuals can leave uncooperative partners. The second principle is that resource sharing is often based on the need of the recipient (i.e., need-based transfers) rather than on strict account-keeping. And the last principle is that effective scaling up of cooperation requires increasingly sophisticated and costly cheater suppression mechanisms. By comparing how these principles operate across systems, we can better understand the constraints on cooperation. This can facilitate the discovery of novel ways to enhance cooperation and suppress cheating in its many forms, from social exploitation to cancer.

Geometry, packing, and evolutionary paths to increased multicellular size

Science.gov (United States)

Jacobeen, Shane; Graba, Elyes C.; Brandys, Colin G.; Day, Thomas C.; Ratcliff, William C.; Yunker, Peter J.

2018-05-01

The evolutionary transition to multicellularity transformed life on earth, heralding the evolution of large, complex organisms. Recent experiments demonstrated that laboratory-evolved multicellular "snowflake yeast" readily overcome the physical barriers that limit cluster size by modifying cellular geometry [Jacobeen et al., Nat. Phys. 14, 286 (2018), 10.1038/s41567-017-0002-y]. However, it is unclear why this route to large size is observed, rather than an evolved increase in intercellular bond strength. Here, we use a geometric model of the snowflake yeast growth form to examine the geometric efficiency of increasing size by modifying geometry and bond strength. We find that changing geometry is a far more efficient route to large size than evolving increased intercellular adhesion. In fact, increasing cellular aspect ratio is on average ˜13 times more effective than increasing bond strength at increasing the number of cells in a cluster. Modifying other geometric parameters, such as the geometric arrangement of mother and daughter cells, also had larger effects on cluster size than increasing bond strength. Simulations reveal that as cells reproduce, internal stress in the cluster increases rapidly; thus, increasing bond strength provides diminishing returns in cluster size. Conversely, as cells become more elongated, cellular packing density within the cluster decreases, which substantially decreases the rate of internal stress accumulation. This suggests that geometrically imposed physical constraints may have been a key early selective force guiding the emergence of multicellular complexity.

Experimental evolution of an alternating uni- and multicellular life cycle in Chlamydomonas reinhardtii

Science.gov (United States)

Ratcliff, William C.; Herron, Matthew D.; Howell, Kathryn; Pentz, Jennifer T.; Rosenzweig, Frank; Travisano, Michael

2013-01-01

The transition to multicellularity enabled the evolution of large, complex organisms, but early steps in this transition remain poorly understood. Here we show that multicellular complexity, including development from a single cell, can evolve rapidly in a unicellular organism that has never had a multicellular ancestor. We subject the alga Chlamydomonas reinhardtii to conditions that favour multicellularity, resulting in the evolution of a multicellular life cycle in which clusters reproduce via motile unicellular propagules. While a single-cell genetic bottleneck during ontogeny is widely regarded as an adaptation to limit among-cell conflict, its appearance very early in this transition suggests that it did not evolve for this purpose. Instead, we find that unicellular propagules are adaptive even in the absence of intercellular conflict, maximizing cluster-level fecundity. These results demonstrate that the unicellular bottleneck, a trait essential for evolving multicellular complexity, can arise rapidly via co-option of the ancestral unicellular form. PMID:24193369

Biomaterial Substrate-Mediated Multicellular Spheroid Formation and Their Applications in Tissue Engineering.

Science.gov (United States)

Tseng, Ting-Chen; Wong, Chui-Wei; Hsieh, Fu-Yu; Hsu, Shan-Hui

2017-12-01

Three-dimentional (3D) multicellular aggregates (spheroids), compared to the traditional 2D monolayer cultured cells, are physiologically more similar to the cells in vivo. So far there are various techniques to generate 3D spheroids. Spheroids obtained from different methods have already been applied to regenerative medicine or cancer research. Among the cell spheroids created by different methods, the substrate-derived spheroids and their forming mechanism are unique. This review focuses on the formation of biomaterial substrate-mediated multicellular spheroids and their applications in tissue engineering and tumor models. First, the authors will describe the special chitosan substrate-derived mesenchymal stem cell (MSC) spheroids and their greater regenerative capacities in various tissues. Second, the authors will describe tumor spheroids derived on chitosan and hyaluronan substrates, which serve as a simple in vitro platform to study 3D tumor models or to perform cancer drug screening. Finally, the authors will mention the self-assembly process for substrate-derived multiple cell spheroids (co-spheroids), which may recapitulate the heterotypic cell-cell interaction for co-cultured cells or crosstalk between different types of cells. These unique multicellular mono-spheroids or co-spheroids represent a category of 3D cell culture with advantages of biomimetic cell-cell interaction, better functionalities, and imaging possibilities. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Organism Size Promotes the Evolution of Specialized Cells in Multicellular Digital Organisms

OpenAIRE

Willensdorfer, Martin

2007-01-01

Specialized cells are the essence of complex multicellular life. Fossils allow us to study the modification of specialized, multicellular features such as jaws, scales, and muscular appendages. But it is still unclear what organismal properties contributed to the transition from undifferentiated organisms, which contain only a single cell type, to multicellular organisms with specialized cells. Using digital organisms I study this transition. My simulations show that the transition to special...

Role of Multicellular Aggregates in Biofilm Formation

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Kasper N. Kragh

2016-03-01

Full Text Available In traditional models of in vitro biofilm development, individual bacterial cells seed a surface, multiply, and mature into multicellular, three-dimensional structures. Much research has been devoted to elucidating the mechanisms governing the initial attachment of single cells to surfaces. However, in natural environments and during infection, bacterial cells tend to clump as multicellular aggregates, and biofilms can also slough off aggregates as a part of the dispersal process. This makes it likely that biofilms are often seeded by aggregates and single cells, yet how these aggregates impact biofilm initiation and development is not known. Here we use a combination of experimental and computational approaches to determine the relative fitness of single cells and preformed aggregates during early development of Pseudomonas aeruginosa biofilms. We find that the relative fitness of aggregates depends markedly on the density of surrounding single cells, i.e., the level of competition for growth resources. When competition between aggregates and single cells is low, an aggregate has a growth disadvantage because the aggregate interior has poor access to growth resources. However, if competition is high, aggregates exhibit higher fitness, because extending vertically above the surface gives cells at the top of aggregates better access to growth resources. Other advantages of seeding by aggregates, such as earlier switching to a biofilm-like phenotype and enhanced resilience toward antibiotics and immune response, may add to this ecological benefit. Our findings suggest that current models of biofilm formation should be reconsidered to incorporate the role of aggregates in biofilm initiation.

Developing multi-cellular tumor spheroid model (MCTS) in the chitosan/collagen/alginate (CCA) fibrous scaffold for anticancer drug screening.

Science.gov (United States)

Wang, Jian-Zheng; Zhu, Yu-Xia; Ma, Hui-Chao; Chen, Si-Nan; Chao, Ji-Ye; Ruan, Wen-Ding; Wang, Duo; Du, Feng-guang; Meng, Yue-Zhong

2016-05-01

In this work, a 3D MCTS-CCA system was constructed by culturing multi-cellular tumor spheroid (MCTS) in the chitosan/collagen/alginate (CCA) fibrous scaffold for anticancer drug screening. The CCA scaffolds were fabricated by spray-spinning. The interactions between the components of the spray-spun fibers were evidenced by methods of Coomassie Blue stain, X-ray diffraction (XRD) and Fourier transform-infrared spectroscopy (FTIR). Co-culture indicated that MCF-7 cells showed a spatial growth pattern of multi-cellular tumor spheroid (MCTS) in the CCA fibrous scaffold with increased proliferation rate and drug-resistance to MMC, ADM and 5-Aza comparing with the 2D culture cells. Significant increases of total viable cells were found in 3D MCTS groups after drug administration by method of apoptotic analysis. Glucose-lactate analysis indicated that the metabolism of MCTS in CCA scaffold was closer to the tumor issue in vivo than the monolayer cells. In addition, MCTS showed the characteristic of epithelial mesenchymal transition (EMT) which is subverted by carcinoma cells to facilitate metastatic spread. These results demonstrated that MCTS in CCA scaffold possessed a more conservative phenotype of tumor than monolayer cells, and anticancer drug screening in 3D MCTS-CCA system might be superior to the 2D culture system. Copyright © 2016 Elsevier B.V. All rights reserved.

Asymmetric segregation of damaged cellular components in spatially structured multicellular organisms.

Directory of Open Access Journals (Sweden)

Charlotte Strandkvist

Full Text Available The asymmetric distribution of damaged cellular components has been observed in species ranging from fission yeast to humans. To study the potential advantages of damage segregation, we have developed a mathematical model describing ageing mammalian tissue, that is, a multicellular system of somatic cells that do not rejuvenate at cell division. To illustrate the applicability of the model, we specifically consider damage incurred by mutations to mitochondrial DNA, which are thought to be implicated in the mammalian ageing process. We show analytically that the asymmetric distribution of damaged cellular components reduces the overall damage level and increases the longevity of the cell population. Motivated by the experimental reports of damage segregation in human embryonic stem cells, dividing symmetrically with respect to cell-fate, we extend the model to consider spatially structured systems of cells. Imposing spatial structure reduces, but does not eliminate, the advantage of asymmetric division over symmetric division. The results suggest that damage partitioning could be a common strategy for reducing the accumulation of damage in a wider range of cell types than previously thought.

Bacterial stigmergy: an organising principle of multicellular collective behaviours of bacteria.

Science.gov (United States)

Gloag, Erin S; Turnbull, Lynne; Whitchurch, Cynthia B

2015-01-01

The self-organisation of collective behaviours often manifests as dramatic patterns of emergent large-scale order. This is true for relatively "simple" entities such as microbial communities and robot "swarms," through to more complex self-organised systems such as those displayed by social insects, migrating herds, and many human activities. The principle of stigmergy describes those self-organised phenomena that emerge as a consequence of indirect communication between individuals of the group through the generation of persistent cues in the environment. Interestingly, despite numerous examples of multicellular behaviours of bacteria, the principle of stigmergy has yet to become an accepted theoretical framework that describes how bacterial collectives self-organise. Here we review some examples of multicellular bacterial behaviours in the context of stigmergy with the aim of bringing this powerful and elegant self-organisation principle to the attention of the microbial research community.

X-ray microscopy of living multicellular organisms with the Prague Asterix Iodine Laser System

Czech Academy of Sciences Publication Activity Database

Desai, T.; Batani, D.; Bernadinello, A.; Poletti, G.; Orsini, F.; Ullschmied, Jiří; Juha, Libor; Skála, Jiří; Králiková, Božena; Krouský, Eduard; Pfeifer, Miroslav; Kadlec, Christelle; Mocek, Tomáš; Präg R., Ansgar; Renner, Oldřich; Cotelli, F.; Lamia, C. L.; Zullini, A.

2003-01-01

Roč. 21, č. 4 (2003), s. 511-516 ISSN 0263-0346 R&D Projects: GA MŠk LN00A100 Institutional research plan: CEZ:AV0Z2043910 Keywords : atomic force miscroscopy, laser-produced plasmas, multicellular microorganisms Subject RIV: BH - Optics, Masers, Lasers Impact factor: 0.646, year: 2003

Cellular packing, mechanical stress and the evolution of multicellularity

Science.gov (United States)

Jacobeen, Shane; Pentz, Jennifer T.; Graba, Elyes C.; Brandys, Colin G.; Ratcliff, William C.; Yunker, Peter J.

2018-03-01

The evolution of multicellularity set the stage for sustained increases in organismal complexity1-5. However, a fundamental aspect of this transition remains largely unknown: how do simple clusters of cells evolve increased size when confronted by forces capable of breaking intracellular bonds? Here we show that multicellular snowflake yeast clusters6-8 fracture due to crowding-induced mechanical stress. Over seven weeks ( 291 generations) of daily selection for large size, snowflake clusters evolve to increase their radius 1.7-fold by reducing the accumulation of internal stress. During this period, cells within the clusters evolve to be more elongated, concomitant with a decrease in the cellular volume fraction of the clusters. The associated increase in free space reduces the internal stress caused by cellular growth, thus delaying fracture and increasing cluster size. This work demonstrates how readily natural selection finds simple, physical solutions to spatial constraints that limit the evolution of group size—a fundamental step in the evolution of multicellularity.

A conceptual framework for the evolutionary origins of multicellularity

International Nuclear Information System (INIS)

Libby, Eric; B Rainey, Paul

2013-01-01

The evolution of multicellular organisms from unicellular counterparts involved a transition in Darwinian individuality from single cells to groups. A particular challenge is to understand the nature of the earliest groups, the causes of their evolution, and the opportunities for emergence of Darwinian properties. Here we outline a conceptual framework based on a logical set of possible pathways for evolution of the simplest self-replicating groups. Central to these pathways is the recognition of a finite number of routes by which genetic information can be transmitted between individual cells and groups. We describe the form and organization of each primordial group state and consider factors affecting persistence and evolution of the nascent multicellular forms. Implications arising from our conceptual framework become apparent when attempting to partition fitness effects at individual and group levels. These are discussed with reference to the evolutionary emergence of individuality and its manifestation in extant multicellular life—including those of marginal Darwinian status. (paper)

Bacterial solutions to multicellularity : a tale of biofilms, filaments and fruiting bodies

NARCIS (Netherlands)

Claessen, Dennis; Rozen, Daniel E.; Kuipers, Oscar P.; Søgaard-Andersen, Lotte; Wezel, Gilles P. van

2014-01-01

Although bacteria frequently live as unicellular organisms, many spend at least part of their lives in complex communities, and some have adopted truly multicellular lifestyles and have abandoned unicellular growth. These transitions to multicellularity have occurred independently several times for

Thinking about Bacillus subtilis as a multicellular organism.

Science.gov (United States)

Aguilar, Claudio; Vlamakis, Hera; Losick, Richard; Kolter, Roberto

2007-12-01

Initial attempts to use colony morphogenesis as a tool to investigate bacterial multicellularity were limited by the fact that laboratory strains often have lost many of their developmental properties. Recent advances in elucidating the molecular mechanisms underlying colony morphogenesis have been made possible through the use of undomesticated strains. In particular, Bacillus subtilis has proven to be a remarkable model system to study colony morphogenesis because of its well-characterized developmental features. Genetic screens that analyze mutants defective in colony morphology have led to the discovery of an intricate regulatory network that controls the production of an extracellular matrix. This matrix is essential for the development of complex colony architecture characterized by aerial projections that serve as preferential sites for sporulation. While much progress has been made, the challenge for future studies will be to determine the underlying mechanisms that regulate development such that differentiation occurs in a spatially and temporally organized manner.

Evolution of multicellularity coincided with increased diversification of cyanobacteria and the Great Oxidation Event

Science.gov (United States)

Schirrmeister, Bettina E.; de Vos, Jurriaan M.; Antonelli, Alexandre; Bagheri, Homayoun C.

2013-01-01

Cyanobacteria are among the most diverse prokaryotic phyla, with morphotypes ranging from unicellular to multicellular filamentous forms, including those able to terminally (i.e., irreversibly) differentiate in form and function. It has been suggested that cyanobacteria raised oxygen levels in the atmosphere around 2.45–2.32 billion y ago during the Great Oxidation Event (GOE), hence dramatically changing life on the planet. However, little is known about the temporal evolution of cyanobacterial lineages, and possible interplay between the origin of multicellularity, diversification of cyanobacteria, and the rise of atmospheric oxygen. We estimated divergence times of extant cyanobacterial lineages under Bayesian relaxed clocks for a dataset of 16S rRNA sequences representing the entire known diversity of this phylum. We tested whether the evolution of multicellularity overlaps with the GOE, and whether multicellularity is associated with significant shifts in diversification rates in cyanobacteria. Our results indicate an origin of cyanobacteria before the rise of atmospheric oxygen. The evolution of multicellular forms coincides with the onset of the GOE and an increase in diversification rates. These results suggest that multicellularity could have played a key role in triggering cyanobacterial evolution around the GOE. PMID:23319632

Differences in species richness patterns between unicellular and multicellular organisms.

Science.gov (United States)

Hillebrand, Helmut; Watermann, Frank; Karez, Rolf; Berninger, Ulrike-G

2001-01-01

For unicellular organisms, a lack of effects of local species richness on ecosystem function has been proposed due to their locally high species richness and their ubiquitous distribution. High dispersal ability and high individual numbers may enable unicellular taxa to occur everywhere. Using our own and published data sets on uni- and multicellular organisms, we conducted thorough statistical analyses to test whether (1) unicellular taxa show higher relative local species richness compared to multicellular taxa, (2) unicellular taxa show lower slopes of the species:area relationships and species:individuals relationships, and (3) the species composition of unicellular taxa is less influenced by geographic distance compared to multicellular taxa. We found higher local species richness compared to the global species pool for unicellular organisms than for metazoan taxa. The difference was significant if global species richness was conservatively estimated but not if extrapolated, and therefore higher richness estimates were used. Both microalgae and protozoans showed lower slopes between species richness and sample size (area or individuals) compared to macrozoobenthos, also indicating higher local species richness for unicellular taxa. The similarity of species composition of both benthic diatoms and ciliates decreased with increasing geographic distance. This indicated restricted dispersal ability of protists and the absence of ubiquity. However, a steeper slope between similarity and distance was found for polychaetes and corals, suggesting a stronger effect of distance on the dispersal of metazoans compared to unicellular taxa. In conclusion, we found partly different species richness patterns among uni- and multicellular eukaryotes, but no strict ubiquity of unicellular taxa. Therefore, the effect of local unicellular species richness on ecosystem function has to be reanalyzed. Macroecological patterns suggested for multicellular organisms may differ in

[Self-organization in the ontogeny of multicellular organisms: a computer simulation].

Science.gov (United States)

Markov, M A; Markov, A V

2011-01-01

The progress in understanding the patterns of evolution of ontogeny is hindered by the fact that many features of ontogeny are counterintuitive (as well as the features of other processes related to self-organization, self-assembly, and spontaneous increase in complexity). The basic principle of ontogeny of multicellular organisms is that it is the process of self-assembly of ordered multicellular structures by means of coordinated behavior of many individual modules (cells), each of which follows the same set of"rules" encoded in the genome. These rules are based on the genetic regulatory networks. We hypothesize that many specific features of ontogeny that seem nontrivial or enigmatic are, in fact, the inevitable consequences of this basic principle. If so, they do not need special explanations. In order to verify this hypothesis, we developed the computer program "Evo-Devo" based on the above principle. The program is designed to model the self-assembly of ordered multicellular structures from an aggregation of dividing cells that originate from a single original cell (zygote). Each cell follows a set of rules of behavior ("genotype") that can be specified arbitrarily by the experimenter, and is the same for all cells in the embryo (each cell is programmed in exactly the same way as all other cells). It is not allowed to specify rules for groups of cells or for the whole embryo: only local rules that should be followed at the level of a single cell are possible. The analysis of phenotypic implementation of different genotypes revealed several features which are present in the ontogeny of real organisms and are regularly reproduced in the model. These include: inherent stochasticity; inescapable necessity of development of stabilizing adaptations based on negative feedback in order to decrease this stochasticity; equifinality (noise resistance) resulting from these adaptations; the ability of ontogeny to respond to major perturbations by generating new

How 5000 independent rowers coordinate their strokes in order to row into the sunlight: Phototaxis in the multicellular green alga Volvox

Directory of Open Access Journals (Sweden)

Matsunaga Shigeru

2010-07-01

gravitational forces. Under our conditions, V. rousseletii spheroids showed no negative phototaxis. Conclusions On the basis of our results, we developed a mechanistic model that predicts the phototactic behavior in V. rousseletii. The model involves photoresponses, periodically changing light conditions, morphological polarity, rotation of the spheroid, two modes of flagellar beating, and the impact of gravity. Our results also indicate how recently evolved multicellular organisms adapted the phototactic capabilities of their unicellular ancestors to multicellular life.

Extracellular signaling and multicellularity in Bacillus subtilis.

Science.gov (United States)

Shank, Elizabeth Anne; Kolter, Roberto

2011-12-01

Bacillus subtilis regulates its ability to differentiate into distinct, co-existing cell types in response to extracellular signaling molecules produced either by itself, or present in its environment. The production of molecules by B. subtilis cells, as well as their response to these signals, is not uniform across the population. There is specificity and heterogeneity both within genetically identical populations as well as at the strain-level and species-level. This review will discuss how extracellular signaling compounds influence B. subtilis multicellularity with regard to matrix-producing cannibal differentiation, germination, and swarming behavior, as well as the specificity of the quorum-sensing peptides ComX and CSF. It will also highlight how imaging mass spectrometry can aid in identifying signaling compounds and contribute to our understanding of the functional relationship between such compounds and multicellular behavior. Copyright © 2011 Elsevier Ltd. All rights reserved.

Daunorubicin and doxorubicin but not BCNU have deleterious effects on organotypic multicellular spheroids of gliomas

NARCIS (Netherlands)

Kaaijk, P.; Troost, D.; de Boer, O. J.; van Amstel, P.; Bakker, P. J.; Leenstra, S.; Bosch, D. A.

1996-01-01

In the present study organotypic multicellular spheroids (OMS) were used to study the effects of chemotherapeutic agents on malignant gliomas. Compared with the frequently used cell line models, OMS have several advantages with respect to the preservation of the cellular heterogeneity and the

A 3D printed microfluidic perfusion device for multicellular spheroid cultures.

Science.gov (United States)

Ong, Louis Jun Ye; Islam, Anik; DasGupta, Ramanuj; Iyer, Narayanan Gopalakkrishna; Leo, Hwa Liang; Toh, Yi-Chin

2017-09-11

The advent of 3D printing technologies promises to make microfluidic organ-on-chip technologies more accessible for the biological research community. To date, hydrogel-encapsulated cells have been successfully incorporated into 3D printed microfluidic devices. However, there is currently no 3D printed microfluidic device that can support multicellular spheroid culture, which facilitates extensive cell-cell contacts important for recapitulating many multicellular functional biological structures. Here, we report a first instance of fabricating a 3D printed microfluidic cell culture device capable of directly immobilizing and maintaining the viability and functionality of 3D multicellular spheroids. We evaluated the feasibility of two common 3D printing technologies i.e. stereolithography (SLA) and PolyJet printing, and found that SLA could prototype a device comprising of cell immobilizing micro-structures that were housed within a microfluidic network with higher fidelity. We have also implemented a pump-free perfusion system, relying on gravity-driven flow to perform medium perfusion in order to reduce the complexity and footprint of the device setup, thereby improving its adaptability into a standard biological laboratory. Finally, we demonstrated the biological performance of the 3D printed device by performing pump-free perfusion cultures of patient-derived parental and metastatic oral squamous cell carcinoma tumor and liver cell (HepG2) spheroids with good cell viability and functionality. This paper presents a proof-of-concept in simplifying and integrating the prototyping and operation of a microfluidic spheroid culture device, which will facilitate its applications in various drug efficacy, metabolism and toxicity studies.

Bacterial biofilms: prokaryotic adventures in multicellularity

DEFF Research Database (Denmark)

Webb, J.S.; Givskov, Michael Christian; Kjelleberg, S.

2003-01-01

The development of bacterial biofilms includes both the initial social behavior of undifferentiated cells, as well as cell death and differentiation in the mature biofilm, and displays several striking similarities with higher organisms. Recent advances in the field provide new insight...... into differentiation and cell death events in bacterial biofilm development and propose that biofilms have an unexpected level of multicellularity....

Observation of multicellular spinning behavior of Proteus mirabilis by atomic force microscopy and multifunctional microscopy.

Science.gov (United States)

Liu, Yanxia; Deng, Yuanxin; Luo, Shuxiu; Deng, Yu; Guo, Linming; Xu, Weiwei; Liu, Lei; Liu, Junkang

2014-01-01

This study aimed to observe the multicellular spinning behavior of Proteus mirabilis by atomic force microscopy (AFM) and multifunctional microscopy in order to understand the mechanism underlying this spinning movement and its biological significance. Multifunctional microscopy with charge-coupled device (CCD) and real-time AFM showed changes in cell structure and shape of P. mirabilis during multicellular spinning movement. Specifically, the morphological characteristics of P. mirabilis, multicellular spinning dynamics, and unique movement were observed. Our findings indicate that the multicellular spinning behavior of P. mirabilis may be used to collect nutrients, perform colonization, and squeeze out competitors. The movement characteristics of P. mirabilis are vital to the organism's biological adaptability to the surrounding environment. Copyright © 2013 Elsevier Ltd. All rights reserved.

Bio-electrosprayed multicellular zebrafish embryos are viable and develop normally

International Nuclear Information System (INIS)

Clarke, Jonathan D W; Jayasinghe, Suwan N

2008-01-01

Bio-electrosprays are rapidly emerging as a viable protocol for directly engineering living cells. This communication reports the bio-electrospraying of multicellular organisms, namely zebrafish embryos. The results demonstrate that the bio-electrospray protocol fails to induce any embryological perturbations. In addition to analysing overall embryo morphology, we use transgenic embryos that express green fluorescent protein in specific brain neurons to determine that neuronal numbers and organization are completely normal. These results demonstrate that the bio-electrospraying protocol does not interfere with the complex gene regulation and cell movements required for the development of a multicellular organism. (communication)

From cat's eyes to disjoint multicellular natural convection flow in tall tilted cavities

Energy Technology Data Exchange (ETDEWEB)

Nicolas, Alfredo, E-mail: anc@xanum.uam.mx [Depto. Matematicas, 3er Piso Ed. AT-Diego Bricio, UAM-I, 09340 Mexico D.F. (Mexico); Baez, Elsa [Depto. Matematicas Aplicadas y Sistemas, UAM-C, 01120 Mexico D.F. (Mexico); Bermudez, Blanca [Facultad de C. de la Computacion, BUAP, 72570 Puebla, Pue. (Mexico)

2011-07-11

Numerical results of two-dimensional natural convection problems, in air-filled tall cavities, are reported to study the change of the cat's eyes flow as some parameters vary, the aspect ratio A and the angle of inclination φ of the cavity, with the Rayleigh number Ra mostly fixed; explicitly, the range of the variation is given by 12≤A≤20 and 0{sup o}≤φ≤270{sup o}; about Ra=1.1x10{sup 4}. A novelty contribution of this work is the transition from the cat's eyes changes, as A varies, to a disjoint multicellular flow, as φ varies. These flows may be modeled by the unsteady Boussinesq approximation in stream function and vorticity variables which is solved with a fixed point iterative process applied to the nonlinear elliptic system that results after time discretization. The validation of the results relies on mesh size and time-step independence studies. -- Highlights: → Fixed point iterative method for solving symmetric linear elliptic problems. → Robust method to study effects as aspect ratio and angle of inclination vary. → Interest on the dynamics and evolution of the fluid flow and on heat transfer. → Study of transition from cat's eyes instability to a disjoint multicellular flow.

Rapid formation of size-controllable multicellular spheroids via 3D acoustic tweezers

OpenAIRE

Chen, Kejie; Wu, Mengxi; Guo, Feng; Li, Peng; Chan, Chung-Yu; Mao, Zhangming; Li, Sixing; Ren, Liqiang; Zhang, Rui; Huang, Tony Jun

2016-01-01

The multicellular spheroid is an important 3D cell culture model for drug screening, tissue engineering, and fundamental biological research. Although several spheroid formation methods have been reported, the field still lacks high-throughput and simple fabrication methods to accelerate its adoption in drug development industry. Surface acoustic wave (SAW) based cell manipulation methods, which are known to be non-invasive, flexible, and high-throughput, have not been successfully developed ...

Genome duplication and mutations in ACE2 cause multicellular, fast-sedimenting phenotypes in evolved Saccharomyces cerevisiae.

Science.gov (United States)

Oud, Bart; Guadalupe-Medina, Victor; Nijkamp, Jurgen F; de Ridder, Dick; Pronk, Jack T; van Maris, Antonius J A; Daran, Jean-Marc

2013-11-05

Laboratory evolution of the yeast Saccharomyces cerevisiae in bioreactor batch cultures yielded variants that grow as multicellular, fast-sedimenting clusters. Knowledge of the molecular basis of this phenomenon may contribute to the understanding of natural evolution of multicellularity and to manipulating cell sedimentation in laboratory and industrial applications of S. cerevisiae. Multicellular, fast-sedimenting lineages obtained from a haploid S. cerevisiae strain in two independent evolution experiments were analyzed by whole genome resequencing. The two evolved cell lines showed different frameshift mutations in a stretch of eight adenosines in ACE2, which encodes a transcriptional regulator involved in cell cycle control and mother-daughter cell separation. Introduction of the two ace2 mutant alleles into the haploid parental strain led to slow-sedimenting cell clusters that consisted of just a few cells, thus representing only a partial reconstruction of the evolved phenotype. In addition to single-nucleotide mutations, a whole-genome duplication event had occurred in both evolved multicellular strains. Construction of a diploid reference strain with two mutant ace2 alleles led to complete reconstruction of the multicellular-fast sedimenting phenotype. This study shows that whole-genome duplication and a frameshift mutation in ACE2 are sufficient to generate a fast-sedimenting, multicellular phenotype in S. cerevisiae. The nature of the ace2 mutations and their occurrence in two independent evolution experiments encompassing fewer than 500 generations of selective growth suggest that switching between unicellular and multicellular phenotypes may be relevant for competitiveness of S. cerevisiae in natural environments.

Cytolytic effects of autologous lymphokine-activated killer cells on organotypic multicellular spheroids of gliomas in vitro

NARCIS (Netherlands)

Kaaijk, P.; Troost, D.; Dast, P. K.; van den Berg, F.; Leenstra, S.; Bosch, D. A.

1995-01-01

Knowledge about lymphokine-activated killer (LAK) cell infiltration and LAK cell cytotoxicity is essential to improve the effectiveness of LAK cell therapy against gliomas. In the present study, organotypic multicellular spheroids (OMS) of glioma tissue were used as a culture model to study the

Real-time viability and apoptosis kinetic detection method of 3D multicellular tumor spheroids using the Celigo Image Cytometer.

Science.gov (United States)

Kessel, Sarah; Cribbes, Scott; Bonasu, Surekha; Rice, William; Qiu, Jean; Chan, Leo Li-Ying

2017-09-01

The development of three-dimensional (3D) multicellular tumor spheroid models for cancer drug discovery research has increased in the recent years. The use of 3D tumor spheroid models may be more representative of the complex in vivo tumor microenvironments in comparison to two-dimensional (2D) assays. Currently, viability of 3D multicellular tumor spheroids has been commonly measured on standard plate-readers using metabolic reagents such as CellTiter-Glo® for end point analysis. Alternatively, high content image cytometers have been used to measure drug effects on spheroid size and viability. Previously, we have demonstrated a novel end point drug screening method for 3D multicellular tumor spheroids using the Celigo Image Cytometer. To better characterize the cancer drug effects, it is important to also measure the kinetic cytotoxic and apoptotic effects on 3D multicellular tumor spheroids. In this work, we demonstrate the use of PI and caspase 3/7 stains to measure viability and apoptosis for 3D multicellular tumor spheroids in real-time. The method was first validated by staining different types of tumor spheroids with PI and caspase 3/7 and monitoring the fluorescent intensities for 16 and 21 days. Next, PI-stained and nonstained control tumor spheroids were digested into single cell suspension to directly measure viability in a 2D assay to determine the potential toxicity of PI. Finally, extensive data analysis was performed on correlating the time-dependent PI and caspase 3/7 fluorescent intensities to the spheroid size and necrotic core formation to determine an optimal starting time point for cancer drug testing. The ability to measure real-time viability and apoptosis is highly important for developing a proper 3D model for screening tumor spheroids, which can allow researchers to determine time-dependent drug effects that usually are not captured by end point assays. This would improve the current tumor spheroid analysis method to potentially better

Cryopreservation of organotypic multicellular spheroids from human gliomas

NARCIS (Netherlands)

Kaaijk, P.; van den Berg, F.; van Amstel, P.; Troost, D.

1996-01-01

Fresh human glioma tissue can be cultured on agarose to form organotypic multicellular spheroids (OMS). The major advantage of OMS is the preservation of the cellular heterogeneity and the tumour architecture, which is lost in conventional monolayer cultures. The present study was undertaken to

The green seaweed Ulva: A model system to study morphogenesis

Directory of Open Access Journals (Sweden)

Thomas eWichard

2015-02-01

Full Text Available Green macroalgae, mostly represented by the Ulvophyceae, the main multicellular branch of the Chlorophyceae, constitute important primary producers of marine and brackish coastal ecosystems. Ulva or sea lettuce species are some of the most abundant representatives, being ubiquitous in coastal benthic communities around the world. Nonetheless the genus also remains largely understudied. This review highlights Ulva as an exciting novel model organism for studies of algal growth, development and morphogenesis as well as mutualistic interactions. The key reasons that Ulva is potentially such a good model system are: (i patterns of Ulva development can drive ecologically important events, such as the increasing number of green tides observed worldwide as a result of eutrophication of coastal waters, (ii Ulva growth is symbiotic, with proper development requiring close association with bacterial epiphytes, (iii Ulva is extremely developmentally plastic, which can shed light on the transition from simple to complex multicellularity and (iv Ulva will provide additional information about the evolution of the green lineage.

The green seaweed Ulva: a model system to study morphogenesis.

Science.gov (United States)

Wichard, Thomas; Charrier, Bénédicte; Mineur, Frédéric; Bothwell, John H; Clerck, Olivier De; Coates, Juliet C

2015-01-01

Green macroalgae, mostly represented by the Ulvophyceae, the main multicellular branch of the Chlorophyceae, constitute important primary producers of marine and brackish coastal ecosystems. Ulva or sea lettuce species are some of the most abundant representatives, being ubiquitous in coastal benthic communities around the world. Nonetheless the genus also remains largely understudied. This review highlights Ulva as an exciting novel model organism for studies of algal growth, development and morphogenesis as well as mutualistic interactions. The key reasons that Ulva is potentially such a good model system are: (i) patterns of Ulva development can drive ecologically important events, such as the increasing number of green tides observed worldwide as a result of eutrophication of coastal waters, (ii) Ulva growth is symbiotic, with proper development requiring close association with bacterial epiphytes, (iii) Ulva is extremely developmentally plastic, which can shed light on the transition from simple to complex multicellularity and (iv) Ulva will provide additional information about the evolution of the green lineage.

Sponge cell reaggregation: Cellular structure and morphogenetic potencies of multicellular aggregates.

Science.gov (United States)

Lavrov, Andrey I; Kosevich, Igor A

2016-02-01

Sponges (phylum Porifera) are one of the most ancient extant multicellular animals and can provide valuable insights into origin and early evolution of Metazoa. High plasticity of cell differentiations and anatomical structure is characteristic feature of sponges. Present study deals with sponge cell reaggregation after dissociation as the most outstanding case of sponge plasticity. Dynamic of cell reaggregation and structure of multicellular aggregates of three demosponge species (Halichondria panicea (Pallas, 1766), Haliclona aquaeductus (Sсhmidt, 1862), and Halisarca dujardinii Johnston, 1842) were studied. Sponge tissue dissociation was performed mechanically. Resulting cell suspensions were cultured at 8-10°C for at least 5 days. Structure of multicellular aggregates was studied by light, transmission and scanning electron microscopy. Studied species share common stages of cell reaggregation-primary multicellular aggregates, early-stage primmorphs and primmorphs, but the rate of reaggregation varies considerably among species. Only cells of H. dujardinii are able to reconstruct functional and viable sponge after primmorphs formation. Sponge reconstruction in this species occurs due to active cell locomotion. Development of H. aquaeductus and H. panicea cells ceases at the stages of early primmorphs and primmorphs, respectively. Development of aggregates of these species is most likely arrested due to immobility of the majority of cells inside them. However, the inability of certain sponge species to reconstruct functional and viable individuals during cell reaggregation may be not a permanent species-specific characteristic, but depends on various factors, including the stage of the life cycle and experimental conditions. © 2016 Wiley Periodicals, Inc.

Genomic analysis of organismal complexity in the multicellular green alga Volvox carteri

Energy Technology Data Exchange (ETDEWEB)

Prochnik, Simon E.; Umen, James; Nedelcu, Aurora; Hallmann, Armin; Miller, Stephen M.; Nishii, Ichiro; Ferris, Patrick; Kuo, Alan; Mitros, Therese; Fritz-Laylin, Lillian K.; Hellsten, Uffe; Chapman, Jarrod; Simakov, Oleg; Rensing, Stefan A.; Terry, Astrid; Pangilinan, Jasmyn; Kapitonov, Vladimir; Jurka, Jerzy; Salamov, Asaf; Shapiro, Harris; Schmutz, Jeremy; Grimwood, Jane; Lindquist, Erika; Lucas, Susan; Grigoriev, Igor V.; Schmitt, Rudiger; Kirk, David; Rokhsar, Daniel S.

2010-07-01

Analysis of the Volvox carteri genome reveals that this green alga's increased organismal complexity and multicellularity are associated with modifications in protein families shared with its unicellular ancestor, and not with large-scale innovations in protein coding capacity. The multicellular green alga Volvox carteri and its morphologically diverse close relatives (the volvocine algae) are uniquely suited for investigating the evolution of multicellularity and development. We sequenced the 138 Mb genome of V. carteri and compared its {approx}14,500 predicted proteins to those of its unicellular relative, Chlamydomonas reinhardtii. Despite fundamental differences in organismal complexity and life history, the two species have similar protein-coding potentials, and few species-specific protein-coding gene predictions. Interestingly, volvocine algal-specific proteins are enriched in Volvox, including those associated with an expanded and highly compartmentalized extracellular matrix. Our analysis shows that increases in organismal complexity can be associated with modifications of lineage-specific proteins rather than large-scale invention of protein-coding capacity.

Cell motility dynamics: a novel segmentation algorithm to quantify multi-cellular bright field microscopy images.

Directory of Open Access Journals (Sweden)

Assaf Zaritsky

Full Text Available Confocal microscopy analysis of fluorescence and morphology is becoming the standard tool in cell biology and molecular imaging. Accurate quantification algorithms are required to enhance the understanding of different biological phenomena. We present a novel approach based on image-segmentation of multi-cellular regions in bright field images demonstrating enhanced quantitative analyses and better understanding of cell motility. We present MultiCellSeg, a segmentation algorithm to separate between multi-cellular and background regions for bright field images, which is based on classification of local patches within an image: a cascade of Support Vector Machines (SVMs is applied using basic image features. Post processing includes additional classification and graph-cut segmentation to reclassify erroneous regions and refine the segmentation. This approach leads to a parameter-free and robust algorithm. Comparison to an alternative algorithm on wound healing assay images demonstrates its superiority. The proposed approach was used to evaluate common cell migration models such as wound healing and scatter assay. It was applied to quantify the acceleration effect of Hepatocyte growth factor/scatter factor (HGF/SF on healing rate in a time lapse confocal microscopy wound healing assay and demonstrated that the healing rate is linear in both treated and untreated cells, and that HGF/SF accelerates the healing rate by approximately two-fold. A novel fully automated, accurate, zero-parameters method to classify and score scatter-assay images was developed and demonstrated that multi-cellular texture is an excellent descriptor to measure HGF/SF-induced cell scattering. We show that exploitation of textural information from differential interference contrast (DIC images on the multi-cellular level can prove beneficial for the analyses of wound healing and scatter assays. The proposed approach is generic and can be used alone or alongside traditional

Cell motility dynamics: a novel segmentation algorithm to quantify multi-cellular bright field microscopy images.

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Zaritsky, Assaf; Natan, Sari; Horev, Judith; Hecht, Inbal; Wolf, Lior; Ben-Jacob, Eshel; Tsarfaty, Ilan

2011-01-01

Confocal microscopy analysis of fluorescence and morphology is becoming the standard tool in cell biology and molecular imaging. Accurate quantification algorithms are required to enhance the understanding of different biological phenomena. We present a novel approach based on image-segmentation of multi-cellular regions in bright field images demonstrating enhanced quantitative analyses and better understanding of cell motility. We present MultiCellSeg, a segmentation algorithm to separate between multi-cellular and background regions for bright field images, which is based on classification of local patches within an image: a cascade of Support Vector Machines (SVMs) is applied using basic image features. Post processing includes additional classification and graph-cut segmentation to reclassify erroneous regions and refine the segmentation. This approach leads to a parameter-free and robust algorithm. Comparison to an alternative algorithm on wound healing assay images demonstrates its superiority. The proposed approach was used to evaluate common cell migration models such as wound healing and scatter assay. It was applied to quantify the acceleration effect of Hepatocyte growth factor/scatter factor (HGF/SF) on healing rate in a time lapse confocal microscopy wound healing assay and demonstrated that the healing rate is linear in both treated and untreated cells, and that HGF/SF accelerates the healing rate by approximately two-fold. A novel fully automated, accurate, zero-parameters method to classify and score scatter-assay images was developed and demonstrated that multi-cellular texture is an excellent descriptor to measure HGF/SF-induced cell scattering. We show that exploitation of textural information from differential interference contrast (DIC) images on the multi-cellular level can prove beneficial for the analyses of wound healing and scatter assays. The proposed approach is generic and can be used alone or alongside traditional fluorescence single

Processing and characterization of multi-cellular monolithic bioceramics for bone regenerative scaffolds

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Ari-Wahjoedi, Bambang; Ginta, Turnad Lenggo; Parman, Setyamartana; Abustaman, Mohd Zikri Ahmad

2014-10-01

Multicellular monolithic ceramic body is a ceramic material which has many gas or liquid passages partitioned by thin walls throughout the bulk material. There are many currently known advanced industrial applications of multicellular ceramics structures i.e. as supports for various catalysts, electrode support structure for solid oxide fuel cells, refractories, electric/electronic materials, aerospace vehicle re-entry heat shields and biomaterials for dental as well as orthopaedic implants by naming only a few. Multicellular ceramic bodies are usually made of ceramic phases such as mullite, cordierite, aluminum titanate or pure oxides such as silica, zirconia and alumina. What make alumina ceramics is excellent for the above functions are the intrinsic properties of alumina which are hard, wear resistant, excellent dielectric properties, resists strong acid and alkali attacks at elevated temperatures, good thermal conductivities, high strength and stiffness as well as biocompatible. In this work the processing technology leading to truly multicellular monolithic alumina ceramic bodies and their characterization are reported. Ceramic slip with 66 wt.% solid loading was found to be optimum as impregnant to the polyurethane foam template. Mullitic ceramic composite of alumina-sodium alumino disilicate-Leucite-like phases with bulk and true densities of 0.852 and 1.241 g cm-3 respectively, pore linear density of ±35 cm-1, linear and bulk volume shrinkages of 7-16% and 32 vol.% were obtained. The compressive strength and elastic modulus of the bioceramics are ≈0.5-1.0 and ≈20 MPa respectively.

Generation of multicellular tumor spheroids by the hanging-drop method.

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Timmins, Nicholas E; Nielsen, Lars K

2007-01-01

Owing to their in vivo-like characteristics, three-dimensional (3D) multicellular tumor spheroid (MCTS) cultures are gaining increasing popularity as an in vitro model of tumors. A straightforward and simple approach to the cultivation of these MCTS is the hanging-drop method. Cells are suspended in droplets of medium, where they develop into coherent 3D aggregates and are readily accessed for analysis. In addition to being simple, the method eliminates surface interactions with an underlying substratum (e.g., polystyrene plastic or agarose), requires only a low number of starting cells, and is highly reproducible. This method has also been applied to the co-cultivation of mixed cell populations, including the co-cultivation of endothelial cells and tumor cells as a model of early tumor angiogenesis.

Generation model of positional values as cell operation during the development of multicellular organisms.

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Ogawa, Ken-ichiro; Miyake, Yoshihiro

2011-03-01

Many conventional models have used the positional information hypothesis to explain each elementary process of morphogenesis during the development of multicellular organisms. Their models assume that the steady concentration patterns of morphogens formed in an extracellular environment have an important property of positional information, so-called "robustness". However, recent experiments reported that a steady morphogen pattern, the concentration gradient of the Bicoid protein, during early Drosophila embryonic development is not robust for embryo-to-embryo variability. These reports encourage a reconsideration of a long-standing problem in systematic cell differentiation: what is the entity of positional information for cells? And, what is the origin of the robust boundary of gene expression? To address these problems at a cellular level, in this article we pay attention to the re-generative phenomena that show another important property of positional information, "size invariance". In view of regenerative phenomena, we propose a new mathematical model to describe the generation mechanism of a spatial pattern of positional values. In this model, the positional values are defined as the values into which differentiable cells transform a spatial pattern providing positional information. The model is mathematically described as an associative algebra composed of various terms, each of which is the multiplication of some fundamental operators under the assumption that the operators are derived from the remarkable properties of cell differentiation on an amputation surface in regenerative phenomena. We apply this model to the concentration pattern of the Bicoid protein during the anterior-posterior axis formation in Drosophila, and consider the conditions needed to establish the robust boundary of the expression of the hunchback gene. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Targeting tumor multicellular aggregation through IGPR-1 inhibits colon cancer growth and improves chemotherapy.

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Woolf, N; Pearson, B E; Bondzie, P A; Meyer, R D; Lavaei, M; Belkina, A C; Chitalia, V; Rahimi, N

2017-09-18

Adhesion to extracellular matrix (ECM) is crucially important for survival of normal epithelial cells as detachment from ECM triggers specific apoptosis known as anoikis. As tumor cells lose the requirement for anchorage to ECM, they rely on cell-cell adhesion 'multicellular aggregation' for survival. Multicellular aggregation of tumor cells also significantly determines the sensitivity of tumor cells to the cytotoxic effects of chemotherapeutics. In this report, we demonstrate that expression of immunoglobulin containing and proline-rich receptor-1 (IGPR-1) is upregulated in human primary colon cancer. Our study demonstrates that IGPR-1 promotes tumor multicellular aggregation, and interfering with its adhesive function inhibits multicellular aggregation and, increases cell death. IGPR-1 supports colon carcinoma tumor xenograft growth in mouse, and inhibiting its activity by shRNA or blocking antibody inhibits tumor growth. More importantly, IGPR-1 regulates sensitivity of tumor cells to the chemotherapeutic agent, doxorubicin/adriamycin by a mechanism that involves doxorubicin-induced AKT activation and phosphorylation of IGPR-1 at Ser220. Our findings offer novel insight into IGPR-1's role in colorectal tumor growth, tumor chemosensitivity, and as a possible novel anti-cancer target.

Combined exposure of diesel exhaust particles and respirable Soufrière Hills volcanic ash causes a (pro-)inflammatory response in an in vitro multicellular epithelial tissue barrier model

Science.gov (United States)

Tomašek, Ines; Horwell, Claire J.; Damby, David; Barošová, Hana; Geers, Christoph; Petri-Fink, Alke; Rothen-Rutishauser, Barbara; Clift, Martin J. D.

2016-01-01

three cell types of the multicellular system was observed by SEM.ConclusionsCombined exposure of respirable Soufrière Hills VA with DEP causes a (pro-)inflammatory effect in an advanced in vitro multicellular model of the epithelial airway barrier. This finding suggests that the combined exposure to volcanic and urban particulate matter should be further investigated in order to deduce the potential human health hazard, especially how it may influence the respiratory function of susceptible individuals (i.e. with pre-existing lung diseases) in the population.

Structurally diverse natural products that cause potassium leakage trigger multicellularity in Bacillus subtilis.

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López, Daniel; Fischbach, Michael A; Chu, Frances; Losick, Richard; Kolter, Roberto

2009-01-06

We report a previously undescribed quorum-sensing mechanism for triggering multicellularity in Bacillus subtilis. B. subtilis forms communities of cells known as biofilms in response to an unknown signal. We discovered that biofilm formation is stimulated by a variety of small molecules produced by bacteria--including the B. subtilis nonribosomal peptide surfactin--that share the ability to induce potassium leakage. Natural products that do not cause potassium leakage failed to induce multicellularity. Small-molecule-induced multicellularity was prevented by the addition of potassium, but not sodium or lithium. Evidence is presented that potassium leakage stimulates the activity of a membrane protein kinase, KinC, which governs the expression of genes involved in biofilm formation. We propose that KinC responds to lowered intracellular potassium concentration and that this is a quorum-sensing mechanism that enables B. subtilis to respond to related and unrelated bacteria.

Radiosensitivity of different human tumor cells lines grown as multicellular spheroids determined from growth curves and survival data

International Nuclear Information System (INIS)

Schwachoefer, J.H.C.; Crooijmans, R.P.; van Gasteren, J.J.; Hoogenhout, J.; Jerusalem, C.R.; Kal, H.B.; Theeuwes, A.G.

1989-01-01

Five human tumor cell lines were grown as multicellular tumor spheroids (MTS) to determine whether multicellular tumor spheroids derived from different types of tumors would show tumor-type dependent differences in response to single-dose irradiation, and whether these differences paralleled clinical behavior. Multicellular tumor spheroids of two neuroblastoma, one lung adenocarcinoma, one melanoma, and a squamous cell carcinoma of the oral tongue, were studied in terms of growth delay, calculated cell survival, and spheroid control dose50 (SCD50). Growth delay and cell survival analysis for the tumor cell lines showed sensitivities that correlated well with clinical behavior of the tumor types of origin. Similar to other studies on melanoma multicellular tumor spheroids our spheroid control dose50 results for the melanoma cell line deviated from the general pattern of sensitivity. This might be due to the location of surviving cells, which prohibits proliferation of surviving cells and hence growth of melanoma multicellular tumor spheroids. This study demonstrates that radiosensitivity of human tumor cell lines can be evaluated in terms of growth delay, calculated cell survival, and spheroid control dose50 when grown as multicellular tumor spheroids. The sensitivity established from these evaluations parallels clinical behavior, thus offering a unique tool for the in vitro analysis of human tumor radiosensitivity

Mass Spectrometry Analyses of Multicellular Tumor Spheroids.

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Acland, Mitchell; Mittal, Parul; Lokman, Noor A; Klingler-Hoffmann, Manuela; Oehler, Martin K; Hoffmann, Peter

2018-05-01

Multicellular tumor spheroids (MCTS) are a powerful biological in vitro model, which closely mimics the 3D structure of primary avascularized tumors. Mass spectrometry (MS) has established itself as a powerful analytical tool, not only to better understand and describe the complex structure of MCTS, but also to monitor their response to cancer therapeutics. The first part of this review focuses on traditional mass spectrometry approaches with an emphasis on elucidating the molecular characteristics of these structures. Then the mass spectrometry imaging (MSI) approaches used to obtain spatially defined information from MCTS is described. Finally the analysis of primary spheroids, such as those present in ovarian cancer, and the great potential that mass spectrometry analysis of these structures has for improved understanding of cancer progression and for personalized in vitro therapeutic testing is discussed. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

RssAB signaling coordinates early development of surface multicellularity in Serratia marcescens.

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Yu-Huan Tsai

Full Text Available Bacteria can coordinate several multicellular behaviors in response to environmental changes. Among these, swarming and biofilm formation have attracted significant attention for their correlation with bacterial pathogenicity. However, little is known about when and where the signaling occurs to trigger either swarming or biofilm formation. We have previously identified an RssAB two-component system involved in the regulation of swarming motility and biofilm formation in Serratia marcescens. Here we monitored the RssAB signaling status within single cells by tracing the location of the translational fusion protein EGFP-RssB following development of swarming or biofilm formation. RssAB signaling is specifically activated before surface migration in swarming development and during the early stage of biofilm formation. The activation results in the release of RssB from its cognate inner membrane sensor kinase, RssA, to the cytoplasm where the downstream gene promoters are located. Such dynamic localization of RssB requires phosphorylation of this regulator. By revealing the temporal activation of RssAB signaling following development of surface multicellular behavior, our findings contribute to an improved understanding of how bacteria coordinate their lifestyle on a surface.

Processing and characterization of multi-cellular monolithic bioceramics for bone regenerative scaffolds

International Nuclear Information System (INIS)

Ari-Wahjoedi, Bambang; Ginta, Turnad Lenggo; Parman, Setyamartana; Abustaman, Mohd Zikri Ahmad

2014-01-01

Multicellular monolithic ceramic body is a ceramic material which has many gas or liquid passages partitioned by thin walls throughout the bulk material. There are many currently known advanced industrial applications of multicellular ceramics structures i.e. as supports for various catalysts, electrode support structure for solid oxide fuel cells, refractories, electric/electronic materials, aerospace vehicle re-entry heat shields and biomaterials for dental as well as orthopaedic implants by naming only a few. Multicellular ceramic bodies are usually made of ceramic phases such as mullite, cordierite, aluminum titanate or pure oxides such as silica, zirconia and alumina. What make alumina ceramics is excellent for the above functions are the intrinsic properties of alumina which are hard, wear resistant, excellent dielectric properties, resists strong acid and alkali attacks at elevated temperatures, good thermal conductivities, high strength and stiffness as well as biocompatible. In this work the processing technology leading to truly multicellular monolithic alumina ceramic bodies and their characterization are reported. Ceramic slip with 66 wt.% solid loading was found to be optimum as impregnant to the polyurethane foam template. Mullitic ceramic composite of alumina-sodium alumino disilicate-Leucite-like phases with bulk and true densities of 0.852 and 1.241 g cm −3 respectively, pore linear density of ±35 cm −1 , linear and bulk volume shrinkages of 7-16% and 32 vol.% were obtained. The compressive strength and elastic modulus of the bioceramics are ≈0.5-1.0 and ≈20 MPa respectively

Processing and characterization of multi-cellular monolithic bioceramics for bone regenerative scaffolds

Energy Technology Data Exchange (ETDEWEB)

Ari-Wahjoedi, Bambang, E-mail: bambang-ariwahjoedi@petronas.com.my [Department of Fundamental and Applied Sciences, Universiti Teknologi PETRONAS, Bandar Seri Iskandar, 31750 Tronoh, Perak Darul Ridzuan (Malaysia); Centre for Intelligent Signal and Imaging Research, Universiti Teknologi PETRONAS, Bandar Seri Iskandar (Malaysia); Ginta, Turnad Lenggo [Department of Mechanical Engineering, Universiti Teknologi PETRONAS, Bandar Seri Iskandar, 31750 Tronoh, Perak Darul Ridzuan (Malaysia); Centre for Intelligent Signal and Imaging Research, Universiti Teknologi PETRONAS, Bandar Seri Iskandar, 31750 Tro (Malaysia); Parman, Setyamartana [Department of Mechanical Engineering, Universiti Teknologi PETRONAS, Bandar Seri Iskandar, 31750 Tronoh, Perak Darul Ridzuan (Malaysia); Abustaman, Mohd Zikri Ahmad [Kebabangan Petroleum Operating Company Sdn Bhd, Lvl. 52, Tower 2, PETRONAS Twin Towers, KLCC, 50088 Kuala Lumpur (Malaysia)

2014-10-24

Multicellular monolithic ceramic body is a ceramic material which has many gas or liquid passages partitioned by thin walls throughout the bulk material. There are many currently known advanced industrial applications of multicellular ceramics structures i.e. as supports for various catalysts, electrode support structure for solid oxide fuel cells, refractories, electric/electronic materials, aerospace vehicle re-entry heat shields and biomaterials for dental as well as orthopaedic implants by naming only a few. Multicellular ceramic bodies are usually made of ceramic phases such as mullite, cordierite, aluminum titanate or pure oxides such as silica, zirconia and alumina. What make alumina ceramics is excellent for the above functions are the intrinsic properties of alumina which are hard, wear resistant, excellent dielectric properties, resists strong acid and alkali attacks at elevated temperatures, good thermal conductivities, high strength and stiffness as well as biocompatible. In this work the processing technology leading to truly multicellular monolithic alumina ceramic bodies and their characterization are reported. Ceramic slip with 66 wt.% solid loading was found to be optimum as impregnant to the polyurethane foam template. Mullitic ceramic composite of alumina-sodium alumino disilicate-Leucite-like phases with bulk and true densities of 0.852 and 1.241 g cm{sup −3} respectively, pore linear density of ±35 cm{sup −1}, linear and bulk volume shrinkages of 7-16% and 32 vol.% were obtained. The compressive strength and elastic modulus of the bioceramics are ≈0.5-1.0 and ≈20 MPa respectively.

Integrative multicellular biological modeling: a case study of 3D epidermal development using GPU algorithms

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Christley Scott

2010-08-01

Full Text Available Abstract Background Simulation of sophisticated biological models requires considerable computational power. These models typically integrate together numerous biological phenomena such as spatially-explicit heterogeneous cells, cell-cell interactions, cell-environment interactions and intracellular gene networks. The recent advent of programming for graphical processing units (GPU opens up the possibility of developing more integrative, detailed and predictive biological models while at the same time decreasing the computational cost to simulate those models. Results We construct a 3D model of epidermal development and provide a set of GPU algorithms that executes significantly faster than sequential central processing unit (CPU code. We provide a parallel implementation of the subcellular element method for individual cells residing in a lattice-free spatial environment. Each cell in our epidermal model includes an internal gene network, which integrates cellular interaction of Notch signaling together with environmental interaction of basement membrane adhesion, to specify cellular state and behaviors such as growth and division. We take a pedagogical approach to describing how modeling methods are efficiently implemented on the GPU including memory layout of data structures and functional decomposition. We discuss various programmatic issues and provide a set of design guidelines for GPU programming that are instructive to avoid common pitfalls as well as to extract performance from the GPU architecture. Conclusions We demonstrate that GPU algorithms represent a significant technological advance for the simulation of complex biological models. We further demonstrate with our epidermal model that the integration of multiple complex modeling methods for heterogeneous multicellular biological processes is both feasible and computationally tractable using this new technology. We hope that the provided algorithms and source code will be a

Directed self-assembly of large scaffold-free multi-cellular honeycomb structures

International Nuclear Information System (INIS)

Tejavibulya, Nalin; Youssef, Jacquelyn; Bao, Brian; Ferruccio, Toni-Marie; Morgan, Jeffrey R

2011-01-01

A significant challenge to the field of biofabrication is the rapid construction of large three-dimensional (3D) living tissues and organs. Multi-cellular spheroids have been used as building blocks. In this paper, we create large multi-cellular honeycomb building blocks using directed self-assembly, whereby cell-to-cell adhesion, in the context of the shape and obstacles of a micro-mold, drives the formation of a 3D structure. Computer-aided design, rapid prototyping and replica molding were used to fabricate honeycomb-shaped micro-molds. Nonadhesive hydrogels cast from these micro-molds were equilibrated in the cell culture medium and seeded with two types of mammalian cells. The cells settled into the honeycomb recess were unable to attach to the nonadhesive hydrogel and so cell-to-cell adhesion drove the self-assembly of a large multi-cellular honeycomb within 24 h. Distinct morphological changes occurred to the honeycomb and its cells indicating the presence of significant cell-mediated tension. Unlike the spheroid, whose size is constrained by a critical diffusion distance needed to maintain cell viability, the overall size of the honeycomb is not limited. The rapid production of the honeycomb building unit, with its multiple rings of high-density cells and open lumen spaces, offers interesting new possibilities for biofabrication strategies.

Hazard identification of exhausts from gasoline-ethanol fuel blends using a multi-cellular human lung model.

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Bisig, Christoph; Roth, Michèle; Müller, Loretta; Comte, Pierre; Heeb, Norbert; Mayer, Andreas; Czerwinski, Jan; Petri-Fink, Alke; Rothen-Rutishauser, Barbara

2016-11-01

Ethanol can be produced from biomass and as such is renewable, unlike petroleum-based fuel. Almost all gasoline cars can drive with fuel containing 10% ethanol (E10), flex-fuel cars can even use 85% ethanol (E85). Brazil and the USA already include 10-27% ethanol in their standard fuel by law. Most health effect studies on car emissions are however performed with diesel exhausts, and only few data exists for other fuels. In this work we investigated possible toxic effects of exhaust aerosols from ethanol-gasoline blends using a multi-cellular model of the human lung. A flex-fuel passenger car was driven on a chassis dynamometer and fueled with E10, E85, or pure gasoline (E0). Exhausts obtained from a steady state cycle were directly applied for 6h at a dilution of 1:10 onto a multi-cellular human lung model mimicking the bronchial compartment composed of human bronchial cells (16HBE14o-), supplemented with human monocyte-derived dendritic cells and monocyte-derived macrophages, cultured at the air-liquid interface. Biological endpoints were assessed after 6h post incubation and included cytotoxicity, pro-inflammation, oxidative stress, and DNA damage. Filtered air was applied to control cells in parallel to the different exhausts; for comparison an exposure to diesel exhaust was also included in the study. No differences were measured for the volatile compounds, i.e. CO, NO x , and T.HC for the different ethanol supplemented exhausts. Average particle number were 6×10 2 #/cm 3 (E0), 1×10 5 #/cm 3 (E10), 3×10 3 #/cm 3 (E85), and 2.8×10 6 #/cm 3 (diesel). In ethanol-gasoline exposure conditions no cytotoxicity and no morphological changes were observed in the lung cell cultures, in addition no oxidative stress - as analyzed with the glutathione assay - was measured. Gene expression analysis also shows no induction in any of the tested genes, including mRNA levels of genes related to oxidative stress and pro-inflammation, as well as indoleamine 2,3-dioxygenase 1

Method for the determination of oxygen consumption rates and diffusion coefficients in multicellular spheroids

OpenAIRE

Mueller-Klieser, W.

1984-01-01

A method has been developed for the quantitative evaluation of oxygen tension (PO2) distributions in multicellular spheroids measured with O2-sensitive microelectrodes. The experimental data showed that multicellular tumor spheroids in stirred growth media were characterized by a diffusion-depleted zone surrounding the spheroids. This zone was elicited by an unstirred layer of medium next to the spheroid leading to a continuous decrease in the PO2 values from the bulk medium towards the spher...

Drug delivery to solid tumors: the predictive value of the multicellular tumor spheroid model for nanomedicine screening

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Millard M

2017-10-01

Full Text Available Marie Millard,1,2 Ilya Yakavets,1–3 Vladimir Zorin,3,4 Aigul Kulmukhamedova,1,2,5 Sophie Marchal,1,2 Lina Bezdetnaya1,2 1Centre de Recherche en Automatique de Nancy, Centre National de la Recherche Scientifique UMR 7039, Université de Lorraine, 2Research Department, Institut de Cancérologie de Lorraine, Vandœuvre-lès-Nancy, France; 3Laboratory of Biophysics and Biotechnology, 4International Sakharov Environmental Institute, Belarusian State University, Minsk, Belarus; 5Department of Radiology, Medical Company Sunkar, Almaty, Kazakhstan Abstract: The increasing number of publications on the subject shows that nanomedicine is an attractive field for investigations aiming to considerably improve anticancer chemotherapy. Based on selective tumor targeting while sparing healthy tissue, carrier-mediated drug delivery has been expected to provide significant benefits to patients. However, despite reduced systemic toxicity, most nanodrugs approved for clinical use have been less effective than previously anticipated. The gap between experimental results and clinical outcomes demonstrates the necessity to perform comprehensive drug screening by using powerful preclinical models. In this context, in vitro three-dimensional models can provide key information on drug behavior inside the tumor tissue. The multicellular tumor spheroid (MCTS model closely mimics a small avascular tumor with the presence of proliferative cells surrounding quiescent cells and a necrotic core. Oxygen, pH and nutrient gradients are similar to those of solid tumor. Furthermore, extracellular matrix (ECM components and stromal cells can be embedded in the most sophisticated spheroid design. All these elements together with the physicochemical properties of nanoparticles (NPs play a key role in drug transport, and therefore, the MCTS model is appropriate to assess the ability of NP to penetrate the tumor tissue. This review presents recent developments in MCTS models for a

Hypofractionated radiation induces a decrease in cell proliferation but no histological damage to organotypic multicellular spheroids of human glioblastomas

NARCIS (Netherlands)

Kaaijk, P.; Troost, D.; Sminia, P.; Hulshof, M. C.; van der Kracht, A. H.; Leenstra, S.; Bosch, D. A.

1997-01-01

The aim of this study was to examine the effect of radiation on glioblastoma, using an organotypic multicellular spheroid (OMS) model. Most glioblastoma cell lines are, in contrast to glioblastomas in vivo, relatively radiosensitive. This limits the value of using cell lines for studying the

Vorinostat eliminates multicellular resistance of mesothelioma 3D spheroids via restoration of Noxa expression.

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Dario Barbone

Full Text Available When grown in 3D cultures as spheroids, mesothelioma cells acquire a multicellular resistance to apoptosis that resembles that of solid tumors. We have previously found that resistance to the proteasome inhibitor bortezomib in 3D can be explained by a lack of upregulation of Noxa, the pro-apoptotic BH3 sensitizer that acts via displacement of the Bak/Bax-activator BH3-only protein, Bim. We hypothesized that the histone deacetylase inhibitor vorinostat might reverse this block to Noxa upregulation in 3D. Indeed, we found that vorinostat effectively restored upregulation of Noxa protein and message and abolished multicellular resistance to bortezomib in the 3D spheroids. The ability of vorinostat to reverse resistance was ablated by knockdown of Noxa or Bim, confirming the essential role of the Noxa/Bim axis in the response to vorinostat. Addition of vorinostat similarly increased the apoptotic response to bortezomib in another 3D model, the tumor fragment spheroid, which is grown from human mesothelioma ex vivo. In addition to its benefit when used with bortezomib, vorinostat also enhanced the response to cisplatin plus pemetrexed, as shown in both 3D models. Our results using clinically relevant 3D models show that the manipulation of the core apoptotic repertoire may improve the chemosensitivity of mesothelioma. Whereas neither vorinostat nor bortezomib alone has been clinically effective in mesothelioma, vorinostat may undermine chemoresistance to bortezomib and to other therapies thereby providing a rationale for combinatorial strategies.

Vorinostat Eliminates Multicellular Resistance of Mesothelioma 3D Spheroids via Restoration of Noxa Expression

Science.gov (United States)

Barbone, Dario; Cheung, Priscilla; Battula, Sailaja; Busacca, Sara; Gray, Steven G.; Longley, Daniel B.; Bueno, Raphael; Sugarbaker, David J.; Fennell, Dean A.; Broaddus, V. Courtney

2012-01-01

When grown in 3D cultures as spheroids, mesothelioma cells acquire a multicellular resistance to apoptosis that resembles that of solid tumors. We have previously found that resistance to the proteasome inhibitor bortezomib in 3D can be explained by a lack of upregulation of Noxa, the pro-apoptotic BH3 sensitizer that acts via displacement of the Bak/Bax-activator BH3-only protein, Bim. We hypothesized that the histone deacetylase inhibitor vorinostat might reverse this block to Noxa upregulation in 3D. Indeed, we found that vorinostat effectively restored upregulation of Noxa protein and message and abolished multicellular resistance to bortezomib in the 3D spheroids. The ability of vorinostat to reverse resistance was ablated by knockdown of Noxa or Bim, confirming the essential role of the Noxa/Bim axis in the response to vorinostat. Addition of vorinostat similarly increased the apoptotic response to bortezomib in another 3D model, the tumor fragment spheroid, which is grown from human mesothelioma ex vivo. In addition to its benefit when used with bortezomib, vorinostat also enhanced the response to cisplatin plus pemetrexed, as shown in both 3D models. Our results using clinically relevant 3D models show that the manipulation of the core apoptotic repertoire may improve the chemosensitivity of mesothelioma. Whereas neither vorinostat nor bortezomib alone has been clinically effective in mesothelioma, vorinostat may undermine chemoresistance to bortezomib and to other therapies thereby providing a rationale for combinatorial strategies. PMID:23300762

Rapid formation of size-controllable multicellular spheroids via 3D acoustic tweezers.

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Chen, Kejie; Wu, Mengxi; Guo, Feng; Li, Peng; Chan, Chung Yu; Mao, Zhangming; Li, Sixing; Ren, Liqiang; Zhang, Rui; Huang, Tony Jun

2016-07-05

The multicellular spheroid is an important 3D cell culture model for drug screening, tissue engineering, and fundamental biological research. Although several spheroid formation methods have been reported, the field still lacks high-throughput and simple fabrication methods to accelerate its adoption in drug development industry. Surface acoustic wave (SAW) based cell manipulation methods, which are known to be non-invasive, flexible, and high-throughput, have not been successfully developed for fabricating 3D cell assemblies or spheroids, due to the limited understanding on SAW-based vertical levitation. In this work, we demonstrated the capability of fabricating multicellular spheroids in the 3D acoustic tweezers platform. Our method used drag force from microstreaming to levitate cells in the vertical direction, and used radiation force from Gor'kov potential to aggregate cells in the horizontal plane. After optimizing the device geometry and input power, we demonstrated the rapid and high-throughput nature of our method by continuously fabricating more than 150 size-controllable spheroids and transferring them to Petri dishes every 30 minutes. The spheroids fabricated by our 3D acoustic tweezers can be cultured for a week with good cell viability. We further demonstrated that spheroids fabricated by this method could be used for drug testing. Unlike the 2D monolayer model, HepG2 spheroids fabricated by the 3D acoustic tweezers manifested distinct drug resistance, which matched existing reports. The 3D acoustic tweezers based method can serve as a novel bio-manufacturing tool to fabricate complex 3D cell assembles for biological research, tissue engineering, and drug development.

The development and structure of thick-walled, multicellular, aerial spores in Diheterospora chlamydosporia (=Verticillium chlamydosporium).

Science.gov (United States)

Cambell, W P; Griffiths, D A

1975-07-01

The aerial, thick-walled spores in Diheterospara chlamydosporia arose as terminal swellings on erect hyphae. Repeated septation of the continuously swelling spore resulted in a multicellular structure. Immediately after the onset of septation secondary wall material was laid down between the two-layered primary wall and the plasmalemma. The presence of secondary wall material indicates that the multicellular spore is a dictyochlamydospore and not an aleuriospore. The relationship between chlamydospores and aleuriospores in other fungi is discussed.

On the origin of biological construction, with a focus on multicellularity.

Science.gov (United States)

van Gestel, Jordi; Tarnita, Corina E

2017-10-17

Biology is marked by a hierarchical organization: all life consists of cells; in some cases, these cells assemble into groups, such as endosymbionts or multicellular organisms; in turn, multicellular organisms sometimes assemble into yet other groups, such as primate societies or ant colonies. The construction of new organizational layers results from hierarchical evolutionary transitions, in which biological units (e.g., cells) form groups that evolve into new units of biological organization (e.g., multicellular organisms). Despite considerable advances, there is no bottom-up, dynamical account of how, starting from the solitary ancestor, the first groups originate and subsequently evolve the organizing principles that qualify them as new units. Guided by six central questions, we propose an integrative bottom-up approach for studying the dynamics underlying hierarchical evolutionary transitions, which builds on and synthesizes existing knowledge. This approach highlights the crucial role of the ecology and development of the solitary ancestor in the emergence and subsequent evolution of groups, and it stresses the paramount importance of the life cycle: only by evaluating groups in the context of their life cycle can we unravel the evolutionary trajectory of hierarchical transitions. These insights also provide a starting point for understanding the types of subsequent organizational complexity. The central research questions outlined here naturally link existing research programs on biological construction (e.g., on cooperation, multilevel selection, self-organization, and development) and thereby help integrate knowledge stemming from diverse fields of biology.

Development of complex-shaped liver multicellular spheroids as a human-based model for nanoparticle toxicity assessment in vitro

Energy Technology Data Exchange (ETDEWEB)

Dubiak-Szepietowska, Monika, E-mail: Monika.Dubiak-Szepietowska@fh-jena.de [Department of Medical Engineering and Biotechnology, Ernst-Abbe-University of Applied Sciences Jena, Carl-Zeiss Promenade 2, 07745 Jena (Germany); Karczmarczyk, Aleksandra [Department of Medical Engineering and Biotechnology, Ernst-Abbe-University of Applied Sciences Jena, Carl-Zeiss Promenade 2, 07745 Jena (Germany); Jönsson-Niedziółka, Martin [Institute of Physical Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52, 01-224 Warszawa (Poland); Winckler, Thomas [Institute of Pharmacy, Friedrich Schiller University Jena, Semmelweissstraße 10, 07743 Jena (Germany); Feller, Karl-Heinz [Department of Medical Engineering and Biotechnology, Ernst-Abbe-University of Applied Sciences Jena, Carl-Zeiss Promenade 2, 07745 Jena (Germany)

2016-03-01

The emergence of human-based models is incontestably required for the study of complex physiological pathways and validation of reliable in vitro methods as alternative for in vivo studies in experimental animals for toxicity assessment. With this objective, we have developed and tested three dimensional environments for cells using different types of hydrogels including transglutaminase-cross-linked gelatin, collagen type I, and growth-factor depleted Matrigel. Cells grown in Matrigel exhibited the greatest cell proliferation and spheroid diameter. Moreover, analysis of urea and albumin biosynthesis revealed that the created system allowed the immortalized liver cell line HepG2 to re-establish normal hepatocyte-like properties which were not observed under the conditions of conventional cell cultures. This study presents a scalable technology for production of complex-shaped liver multicellular spheroids as a system which improves the predictive value of cell-based assays for safety and risk assessment. The time- and dose-dependent toxicity of nanoparticles demonstrates a higher cytotoxic effect when HepG2 cells grown as monolayer than embedded in hydrogels. The experimental setup provided evidence that the cell environment has significant influence on cell sensitivity and that liver spheroid is a useful and novel tool to examine nanoparticle dosing effect even at the level of in vitro studies. Therefore, this system can be applied to a wide variety of potentially hostile compounds in basic screening to provide initial warning of adverse effects and trigger subsequent analysis and remedial actions. - Highlights: • Comparison of HepG2 cells growth in Matrigel, Collagen I gel and gelatin gel. • Examination of nanoparticles (NP) dosing effect at the level of in vitro studies. • Influence of the cell culture media composition on the cytotoxic effect of NP.

Development of complex-shaped liver multicellular spheroids as a human-based model for nanoparticle toxicity assessment in vitro

International Nuclear Information System (INIS)

Dubiak-Szepietowska, Monika; Karczmarczyk, Aleksandra; Jönsson-Niedziółka, Martin; Winckler, Thomas; Feller, Karl-Heinz

2016-01-01

The emergence of human-based models is incontestably required for the study of complex physiological pathways and validation of reliable in vitro methods as alternative for in vivo studies in experimental animals for toxicity assessment. With this objective, we have developed and tested three dimensional environments for cells using different types of hydrogels including transglutaminase-cross-linked gelatin, collagen type I, and growth-factor depleted Matrigel. Cells grown in Matrigel exhibited the greatest cell proliferation and spheroid diameter. Moreover, analysis of urea and albumin biosynthesis revealed that the created system allowed the immortalized liver cell line HepG2 to re-establish normal hepatocyte-like properties which were not observed under the conditions of conventional cell cultures. This study presents a scalable technology for production of complex-shaped liver multicellular spheroids as a system which improves the predictive value of cell-based assays for safety and risk assessment. The time- and dose-dependent toxicity of nanoparticles demonstrates a higher cytotoxic effect when HepG2 cells grown as monolayer than embedded in hydrogels. The experimental setup provided evidence that the cell environment has significant influence on cell sensitivity and that liver spheroid is a useful and novel tool to examine nanoparticle dosing effect even at the level of in vitro studies. Therefore, this system can be applied to a wide variety of potentially hostile compounds in basic screening to provide initial warning of adverse effects and trigger subsequent analysis and remedial actions. - Highlights: • Comparison of HepG2 cells growth in Matrigel, Collagen I gel and gelatin gel. • Examination of nanoparticles (NP) dosing effect at the level of in vitro studies. • Influence of the cell culture media composition on the cytotoxic effect of NP.

Plug-and-Play Multicellular Circuits with Time-Dependent Dynamic Responses.

Science.gov (United States)

Urrios, Arturo; Gonzalez-Flo, Eva; Canadell, David; de Nadal, Eulàlia; Macia, Javier; Posas, Francesc

2018-04-20

Synthetic biology studies aim to develop cellular devices for biomedical applications. These devices, based on living instead of electronic or electromechanic technology, might provide alternative treatments for a wide range of diseases. However, the feasibility of these devices depends, in many cases, on complex genetic circuits that must fulfill physiological requirements. In this work, we explored the potential of multicellular architectures to act as an alternative to complex circuits for implementation of new devices. As a proof of concept, we developed specific circuits for insulin or glucagon production in response to different glucose levels. Here, we show that fundamental features, such as circuit's affinity or sensitivity, are dependent on the specific configuration of the multicellular consortia, providing a method for tuning these properties without genetic engineering. As an example, we have designed and built circuits with an incoherent feed-forward loop architecture (FFL) that can be easily adjusted to generate single pulse responses. Our results might serve as a blueprint for future development of cellular devices for glycemia regulation in diabetic patients.

Treatment Efficiency of Free and Nanoparticle-Loaded Mitoxantrone for Magnetic Drug Targeting in Multicellular Tumor Spheroids

Directory of Open Access Journals (Sweden)

Annkathrin Hornung

2015-09-01

Full Text Available Major problems of cancer treatment using systemic chemotherapy are severe side effects. Magnetic drug targeting (MDT employing superparamagnetic iron oxide nanoparticles (SPION loaded with chemotherapeutic agents may overcome this dilemma by increasing drug accumulation in the tumor and reducing toxic side effects in the healthy tissue. For translation of nanomedicine from bench to bedside, nanoparticle-mediated effects have to be studied carefully. In this study, we compare the effect of SPION, unloaded or loaded with the cytotoxic drug mitoxantrone (MTO with the effect of free MTO, on the viability and proliferation of HT-29 cells within three-dimensional multicellular tumor spheroids. Fluorescence microscopy and flow cytometry showed that both free MTO, as well as SPION-loaded MTO (SPIONMTO are able to penetrate into tumor spheroids and thereby kill tumor cells, whereas unloaded SPION did not affect cellular viability. Since SPIONMTO has herewith proven its effectivity also in complex multicellular tumor structures with its surrounding microenvironment, we conclude that it is a promising candidate for further use in magnetic drug targeting in vivo.

Radiobiological investigations of multicellular spheroids as an in vitro tumor model. 4

International Nuclear Information System (INIS)

Kopp, J.

1978-01-01

Multicellular spheroids of various size were irradiated with a single dose of X-rays or fast neutrons, incubated after irradiation in roller tubes for long time, and observed light-microscopically. The observed effects were found independent of the radiation used and dependent on dose (considering the RBE) and size of spheroids. After irradiation the spheroid surface showed a loosening phenomenon and the spheroid structure changed depending on dose in three various types. Up to the 10% survival fraction the spheroids recovered within some days to the structure of non-irradiated spheroids by the growth of the surviving cells. After higher doses single surviving cells inside the dead spheroid material seemed to migrate from the inner hypoxic into the rim zone. They can start proliferation many days after irradiation leading to repopulation of irradiated spheroids. The volume changes of irradiated spheroids were also dose-dependent, but the measurement of spheroid volume seems to be of limited value for predicting the effectiveness of irradiation because the spheroid volume of irradiated spheroids is not proportional to the number of cells per spheroid. (author)

On the surviving fraction in irradiated multicellular tumour spheroids: calculation of overall radiosensitivity parameters, influence of hypoxia and volume effects

International Nuclear Information System (INIS)

Horas, Jorge A; Olguin, Osvaldo R; Rizzotto, Marcos G

2005-01-01

We model the heterogeneous response to radiation of multicellular tumour spheroids assuming position- and volume-dependent radiosensitivity. We propose a method to calculate the overall radiosensitivity parameters to obtain the surviving fraction of tumours. A mathematical model of a spherical tumour with a hypoxic core and a viable rim which is a caricature of a real tumour is constructed. The model is embedded in a two-compartment linear-quadratic (LQ) model, assuming a mixed bivariated Gaussian distribution to attain the radiosensitivity parameters. Ergodicity, i.e., the equivalence between ensemble and volumetric averages is used to obtain the overall radiosensitivities for the two compartments. We obtain expressions for the overall radiosensitivity parameters resulting from the use of both a linear and a nonlinear dependence of the local radiosensitivity with position. The model's results are compared with experimental data of surviving fraction (SF) for multicellular spheroids of different sizes. We make one fit using only the smallest spheroid data and we are able to predict the SF for the larger spheroids. These predictions are acceptable particularly using bounded sensitivities. We conclude with the importance of taking into account the contribution of clonogenic hypoxic cells to radiosensitivity and with the convenience of using bounded local sensitivities to predict overall radiosensitivity parameters

Heavy-ion radiobiology of multicellular tumor spheroids

International Nuclear Information System (INIS)

Rodriguez, A.; Alpen, E.L.

1980-01-01

Experiments reported here were conducted with carbon ions, neon ions, and argon ions using rat brain gliosarcoma (9L) and Chinese hamster lung V79 cells grown as multicellular spheroids. Our studies were designed to evaluate high-LET radiation survival characteristics of cells grown in this relatively organized tissue-like environment. Our primary objectives were to determine the RBE values in plateau and spread Bragg peak regions of the carbon, neon, and argon beams, and evaluate with high and low LET radiation, the role of spheroid architecture in postirradiation survival of cells grown in this format

Characterizing emergent properties of immunological systems with multi-cellular rule-based computational modeling.

Science.gov (United States)

Chavali, Arvind K; Gianchandani, Erwin P; Tung, Kenneth S; Lawrence, Michael B; Peirce, Shayn M; Papin, Jason A

2008-12-01

The immune system is comprised of numerous components that interact with one another to give rise to phenotypic behaviors that are sometimes unexpected. Agent-based modeling (ABM) and cellular automata (CA) belong to a class of discrete mathematical approaches in which autonomous entities detect local information and act over time according to logical rules. The power of this approach lies in the emergence of behavior that arises from interactions between agents, which would otherwise be impossible to know a priori. Recent work exploring the immune system with ABM and CA has revealed novel insights into immunological processes. Here, we summarize these applications to immunology and, particularly, how ABM can help formulate hypotheses that might drive further experimental investigations of disease mechanisms.

Switching from a unicellular to multicellular organization in an Aspergillus niger hypha.

Science.gov (United States)

Bleichrodt, Robert-Jan; Hulsman, Marc; Wösten, Han A B; Reinders, Marcel J T

2015-03-03

Pores in fungal septa enable cytoplasmic streaming between hyphae and their compartments. Consequently, the mycelium can be considered unicellular. However, we show here that Woronin bodies close ~50% of the three most apical septa of growing hyphae of Aspergillus niger. The incidence of closure of the 9th and 10th septa was even ≥94%. Intercompartmental streaming of photoactivatable green fluorescent protein (PA-GFP) was not observed when the septa were closed, but open septa acted as a barrier, reducing the mobility rate of PA-GFP ~500 times. This mobility rate decreased with increasing septal age and under stress conditions, likely reflecting a regulatory mechanism affecting septal pore diameter. Modeling revealed that such regulation offers effective control of compound concentration between compartments. Modeling also showed that the incidence of septal closure in A. niger had an even stronger impact on cytoplasmic continuity. Cytoplasm of hyphal compartments was shown not to be in physical contact when separated by more than 4 septa. Together, data show that apical compartments of growing hyphae behave unicellularly, while older compartments have a multicellular organization. The hyphae of higher fungi are compartmentalized by porous septa that enable cytosolic streaming. Therefore, it is believed that the mycelium shares cytoplasm. However, it is shown here that the septa of Aspergillus niger are always closed in the oldest part of the hyphae, and therefore, these compartments are physically isolated from each other. In contrast, only part of the septa is closed in the youngest part of the hyphae. Still, compartments in this hyphal part are physically isolated when separated by more than 4 septa. Even open septa act as a barrier for cytoplasmic mixing. The mobility rate through such septa reduces with increasing septal age and under stress conditions. Modeling shows that the septal pore width is set such that its regulation offers maximal control of

Integrated biocircuits: engineering functional multicellular circuits and devices

Science.gov (United States)

Prox, Jordan; Smith, Tory; Holl, Chad; Chehade, Nick; Guo, Liang

2018-04-01

Objective. Implantable neurotechnologies have revolutionized neuromodulatory medicine for treating the dysfunction of diseased neural circuitry. However, challenges with biocompatibility and lack of full control over neural network communication and function limits the potential to create more stable and robust neuromodulation devices. Thus, we propose a platform technology of implantable and programmable cellular systems, namely Integrated Biocircuits, which use only cells as the functional components of the device. Approach. We envision the foundational principles for this concept begins with novel in vitro platforms used for the study and reconstruction of cellular circuitry. Additionally, recent advancements in organoid and 3D culture systems account for microenvironment factors of cytoarchitecture to construct multicellular circuits as they are normally formed in the brain. We explore the current state of the art of these platforms to provide knowledge of their advancements in circuit fabrication and identify the current biological principles that could be applied in designing integrated biocircuit devices. Main results. We have highlighted the exemplary methodologies and techniques of in vitro circuit fabrication and propose the integration of selected controllable parameters, which would be required in creating suitable biodevices. Significance. We provide our perspective and propose new insights into the future of neuromodulaion devices within the scope of living cellular systems that can be applied in designing more reliable and biocompatible stimulation-based neuroprosthetics.

Modelling and Simulating Complex Systems in Biology: introducing NetBioDyn : A Pedagogical and Intuitive Agent-Based Software

OpenAIRE

Ballet, Pascal; Rivière, Jérémy; Pothet, Alain; Théron, Michaël; Pichavant, Karine; Abautret, Frank; Fronville, Alexandra; Rodin, Vincent

2017-01-01

International audience; Modelling and teaching complex biological systems is a difficult process. Multi-Agent Based Simulations (MABS) have proved to be an appropriate approach both in research and education when dealing with such systems including emergent, self-organizing phenomena. This chapter presents NetBioDyn, an original software aimed at biologists (students, teachers, researchers) to easily build and simulate complex biological mechanisms observed in multicellular and molecular syst...

Molecular and functional assessment of multicellular cancer spheroids produced in double emulsions enabled by efficient airway resistance based selective surface treatment

Science.gov (United States)

Ma, Xiao; Leth Jepsen, Morten; Ivarsen, Anne Kathrine R.; Knudsen, Birgitta R.; Ho, Yi-Ping

2017-09-01

Multicellular spheroids have garnered significant attention as an in vitro three-dimensional cancer model which can mimick the in vivo microenvironmental features. While microfluidics generated double emulsions have become a potential method to generate spheroids, challenges remain on the tedious procedures. Enabled by a novel ‘airway resistance’ based selective surface treatment, this study presents an easy and facile generation of double emulsions for the initiation and cultivation of multicellular spheroids in a scaffold-free format. Combining with our previously developed DNA nanosensors, intestinal spheroids produced in the double emulsions have shown an elevated activities of an essential DNA modifying enzyme, the topoisomerase I. The observed molecular and functional characteristics of spheroids produced in double emulsions are similar to the counterparts produced by the commercially available ultra-low attachment plates. However, the double emulsions excel for their improved uniformity, and the consistency of the results obtained by subsequent analysis of the spheroids. The presented technique is expected to ease the burden of producing spheroids and to promote the spheroids model for cancer or stem cell study.

The Role of Functional Amyloids in Multicellular Growth and Development of Gram-Positive Bacteria

DEFF Research Database (Denmark)

Dragoš, Anna; Kovács, Ákos T.; Claessen, Dennis

2017-01-01

Amyloid fibrils play pivotal roles in all domains of life. In bacteria, these fibrillar structures are often part of an extracellular matrix that surrounds the producing organism and thereby provides protection to harsh environmental conditions. Here, we discuss the role of amyloid fibrils...... in the two distant Gram-positive bacteria, Streptomyces coelicolor and Bacillus subtilis. We describe how amyloid fibrils contribute to a multitude of developmental processes in each of these systems, including multicellular growth and community development. Despite this variety of tasks, we know...... surprisingly little about how their assembly is organized to fulfill all these roles....

A Novel Multiparametric Drug-Scoring Method for High-Throughput Screening of 3D Multicellular Tumor Spheroids Using the Celigo Image Cytometer.

Science.gov (United States)

Cribbes, Scott; Kessel, Sarah; McMenemy, Scott; Qiu, Jean; Chan, Leo Li-Ying

2017-06-01

Three-dimensional (3D) tumor models have been increasingly used to investigate and characterize cancer drug compounds. The ability to perform high-throughput screening of 3D multicellular tumor spheroids (MCTS) can highly improve the efficiency and cost-effectiveness of discovering potential cancer drug candidates. Previously, the Celigo Image Cytometer has demonstrated a novel method for high-throughput screening of 3D multicellular tumor spheroids. In this work, we employed the Celigo Image Cytometer to examine the effects of 14 cancer drug compounds on 3D MCTS of the glioblastoma cell line U87MG in 384-well plates. Using parameters such as MCTS diameter and invasion area, growth and invasion were monitored for 9 and 3 d, respectively. Furthermore, fluorescent staining with calcein AM, propidium iodide, Hoechst 33342, and caspase 3/7 was performed at day 9 posttreatment to measure viability and apoptosis. Using the kinetic and endpoint data generated, we created a novel multiparametric drug-scoring system for 3D MCTS that can be used to identify and classify potential drug candidates earlier in the drug discovery process. Furthermore, the combination of quantitative and qualitative image data can be used to delineate differences between drugs that induce cytotoxic and cytostatic effects. The 3D MCTS-based multiparametric scoring method described here can provide an alternative screening method to better qualify tested drug compounds.

Drosophila melanogaster--the model organism of choice for the complex biology of multi-cellular organisms

Science.gov (United States)

Beckingham, Kathleen M.; Armstrong, J. Douglas; Texada, Michael J.; Munjaal, Ravi; Baker, Dean A.

2005-01-01

Drosophila melanogaster has been intensely studied for almost 100 years. The sophisticated array of genetic and molecular tools that have evolved for analysis of gene function in this organism are unique. Further, Drosophila is a complex multi-cellular organism in which many aspects of development and behavior parallel those in human beings. These combined advantages have permitted research in Drosophila to make seminal contributions to the understanding of fundamental biological processes and ensure that Drosophila will continue to provide unique insights in the genomic era. An overview of the genetic methodologies available in Drosophila is given here, together with examples of outstanding recent contributions of Drosophila to our understanding of cell and organismal biology. The growing contribution of Drosophila to our knowledge of gravity-related responses is addressed.

Noise-induced effects on multicellular biopacemaker spontaneous activity: Differences between weak and strong pacemaker cells

Science.gov (United States)

Aghighi, Alireza; Comtois, Philippe

2017-09-01

Self-organization of spontaneous activity of a network of active elements is important to the general theory of reaction-diffusion systems as well as for pacemaking activity to initiate beating of the heart. Monolayer cultures of neonatal rat ventricular myocytes, consisting of resting and pacemaker cells, exhibit spontaneous activation of their electrical activity. Similarly, one proposed approach to the development of biopacemakers as an alternative to electronic pacemakers for cardiac therapy is based on heterogeneous cardiac cells with resting and spontaneously beating phenotypes. However, the combined effect of pacemaker characteristics, density, and spatial distribution of the pacemaker cells on spontaneous activity is unknown. Using a simple stochastic pattern formation algorithm, we previously showed a clear nonlinear dependency of spontaneous activity (occurrence and amplitude of spontaneous period) on the spatial patterns of pacemaker cells. In this study, we show that this behavior is dependent on the pacemaker cell characteristics, with weaker pacemaker cells requiring higher density and larger clusters to sustain multicellular activity. These multicellular structures also demonstrated an increased sensitivity to voltage noise that favored spontaneous activity at lower density while increasing temporal variation in the period of activity. This information will help researchers overcome the current limitations of biopacemakers.

Integrated light-sheet imaging and flow-based enquiry (iLIFE) system for 3D in-vivo imaging of multicellular organism

Science.gov (United States)

Rasmi, Chelur K.; Padmanabhan, Sreedevi; Shirlekar, Kalyanee; Rajan, Kanhirodan; Manjithaya, Ravi; Singh, Varsha; Mondal, Partha Pratim

2017-12-01

We propose and demonstrate a light-sheet-based 3D interrogation system on a microfluidic platform for screening biological specimens during flow. To achieve this, a diffraction-limited light-sheet (with a large field-of-view) is employed to optically section the specimens flowing through the microfluidic channel. This necessitates optimization of the parameters for the illumination sub-system (illumination intensity, light-sheet width, and thickness), microfluidic specimen platform (channel-width and flow-rate), and detection sub-system (camera exposure time and frame rate). Once optimized, these parameters facilitate cross-sectional imaging and 3D reconstruction of biological specimens. The proposed integrated light-sheet imaging and flow-based enquiry (iLIFE) imaging technique enables single-shot sectional imaging of a range of specimens of varying dimensions, ranging from a single cell (HeLa cell) to a multicellular organism (C. elegans). 3D reconstruction of the entire C. elegans is achieved in real-time and with an exposure time of few hundred micro-seconds. A maximum likelihood technique is developed and optimized for the iLIFE imaging system. We observed an intracellular resolution for mitochondria-labeled HeLa cells, which demonstrates the dynamic resolution of the iLIFE system. The proposed technique is a step towards achieving flow-based 3D imaging. We expect potential applications in diverse fields such as structural biology and biophysics.

A BABCOCK–LEIGHTON SOLAR DYNAMO MODEL WITH MULTI-CELLULAR MERIDIONAL CIRCULATION IN ADVECTION- AND DIFFUSION-DOMINATED REGIMES

Energy Technology Data Exchange (ETDEWEB)

Belucz, Bernadett; Forgács-Dajka, Emese [Eötvös University, Department of Astronomy, 1518 Budapest, Pf. 32 (Hungary); Dikpati, Mausumi, E-mail: bbelucz@astro.elte.hu, E-mail: dikpati@ucar.edu [High Altitude Observatory, National Center for Atmospheric Research, 3080 Center Green, Boulder, CO 80307-3000 (United States)

2015-06-20

Babcock–Leighton type-solar dynamo models with single-celled meridional circulation are successful in reproducing many solar cycle features. Recent observations and theoretical models of meridional circulation do not indicate a single-celled flow pattern. We examine the role of complex multi-cellular circulation patterns in a Babcock–Leighton solar dynamo in advection- and diffusion-dominated regimes. We show from simulations that the presence of a weak, second, high-latitude reverse cell speeds up the cycle and slightly enhances the poleward branch in the butterfly diagram, whereas the presence of a second cell in depth reverses the tilt of the butterfly wing to an antisolar type. A butterfly diagram constructed from the middle of convection zone yields a solar-like pattern, but this may be difficult to realize in the Sun because of magnetic buoyancy effects. Each of the above cases behaves similarly in higher and lower magnetic diffusivity regimes. However, our dynamo with a meridional circulation containing four cells in latitude behaves distinctly differently in the two regimes, producing solar-like butterfly diagrams with fast cycles in the higher diffusivity regime, and complex branches in butterfly diagrams in the lower diffusivity regime. We also find that dynamo solutions for a four-celled pattern, two in radius and two in latitude, prefer to quickly relax to quadrupolar parity if the bottom flow speed is strong enough, of similar order of magnitude as the surface flow speed.

A BABCOCK–LEIGHTON SOLAR DYNAMO MODEL WITH MULTI-CELLULAR MERIDIONAL CIRCULATION IN ADVECTION- AND DIFFUSION-DOMINATED REGIMES

International Nuclear Information System (INIS)

Belucz, Bernadett; Forgács-Dajka, Emese; Dikpati, Mausumi

2015-01-01

Babcock–Leighton type-solar dynamo models with single-celled meridional circulation are successful in reproducing many solar cycle features. Recent observations and theoretical models of meridional circulation do not indicate a single-celled flow pattern. We examine the role of complex multi-cellular circulation patterns in a Babcock–Leighton solar dynamo in advection- and diffusion-dominated regimes. We show from simulations that the presence of a weak, second, high-latitude reverse cell speeds up the cycle and slightly enhances the poleward branch in the butterfly diagram, whereas the presence of a second cell in depth reverses the tilt of the butterfly wing to an antisolar type. A butterfly diagram constructed from the middle of convection zone yields a solar-like pattern, but this may be difficult to realize in the Sun because of magnetic buoyancy effects. Each of the above cases behaves similarly in higher and lower magnetic diffusivity regimes. However, our dynamo with a meridional circulation containing four cells in latitude behaves distinctly differently in the two regimes, producing solar-like butterfly diagrams with fast cycles in the higher diffusivity regime, and complex branches in butterfly diagrams in the lower diffusivity regime. We also find that dynamo solutions for a four-celled pattern, two in radius and two in latitude, prefer to quickly relax to quadrupolar parity if the bottom flow speed is strong enough, of similar order of magnitude as the surface flow speed

Theoretical analysis of the spatio-temporal structure of bone multicellular units

International Nuclear Information System (INIS)

Buenzli, P R; Pivonka, P; Gardiner, B S; Smith, D W; Dunstan, C R; Mundy, G R

2010-01-01

Bone multicellular units (BMUs) maintain the viability of the skeletal tissue by coordinating locally the sequence of bone resorption and bone formation performed by cells of the osteoclastic and osteoblastic lineage. Understanding the emergence and the net bone balance of such structured microsystems out of the complex network of biochemical interactions between bone cells is fundamental for many bone-related diseases and the evaluation of fracture risk. Based on current experimental knowledge, we propose a spatio-temporal continuum model describing the interactions of osteoblastic and osteoclastic cells. We show that this model admits travelling-wave-like solutions with well-confined cell profiles upon specifying external conditions mimicking the environment encountered in cortical bone remodelling. The shapes of the various cell concentration profiles within this travelling structure are intrinsically linked to the parameters of the model such as differentiation, proliferation, and apoptosis rates of bone cells. The internal structure of BMUs is reproduced, allowing for experimental calibration. The spatial distribution of the key regulatory factors can also be exhibited, which in diseased states could give hints as to the biochemical agent most accountable for the disorder.

Modeling mechanical inhomogeneities in small populations of proliferating monolayers and spheroids.

Science.gov (United States)

Lejeune, Emma; Linder, Christian

2018-06-01

Understanding the mechanical behavior of multicellular monolayers and spheroids is fundamental to tissue culture, organism development, and the early stages of tumor growth. Proliferating cells in monolayers and spheroids experience mechanical forces as they grow and divide and local inhomogeneities in the mechanical microenvironment can cause individual cells within the multicellular system to grow and divide at different rates. This differential growth, combined with cell division and reorganization, leads to residual stress. Multiple different modeling approaches have been taken to understand and predict the residual stresses that arise in growing multicellular systems, particularly tumor spheroids. Here, we show that by using a mechanically robust agent-based model constructed with the peridynamic framework, we gain a better understanding of residual stresses in multicellular systems as they grow from a single cell. In particular, we focus on small populations of cells (1-100 s) where population behavior is highly stochastic and prior investigation has been limited. We compare the average strain energy density of cells in monolayers and spheroids using different growth and division rules and find that, on average, cells in spheroids have a higher strain energy density than cells in monolayers. We also find that cells in the interior of a growing spheroid are, on average, in compression. Finally, we demonstrate the importance of accounting for stochastic fluctuations in the mechanical environment, particularly when the cellular response to mechanical cues is nonlinear. The results presented here serve as a starting point for both further investigation with agent-based models, and for the incorporation of major findings from agent-based models into continuum scale models when explicit representation of individual cells is not computationally feasible.

The S(c)ensory Immune System Theory.

Science.gov (United States)

Veiga-Fernandes, Henrique; Freitas, António A

2017-10-01

Viewpoints on the immune system have evolved across different paradigms, including the clonal selection theory, the idiotypic network, and the danger and tolerance models. Herein, we propose that in multicellular organisms, where panoplies of cells from different germ layers interact and immune cells are constantly generated, the behavior of the immune system is defined by the rules governing cell survival, systems physiology and organismic homeostasis. Initially, these rules were imprinted at the single cell-protist level, but supervened modifications in the transition to multicellular organisms. This context determined the emergence of the 'sensory immune system', which operates in a s(c)ensor mode to ensure systems physiology, organismic homeostasis, and perpetuation of its replicating molecules. Copyright © 2017 Elsevier Ltd. All rights reserved.

Altered interactions between unicellular and multicellular genes drive hallmarks of transformation in a diverse range of solid tumors.

Science.gov (United States)

Trigos, Anna S; Pearson, Richard B; Papenfuss, Anthony T; Goode, David L

2017-06-13

Tumors of distinct tissues of origin and genetic makeup display common hallmark cellular phenotypes, including sustained proliferation, suppression of cell death, and altered metabolism. These phenotypic commonalities have been proposed to stem from disruption of conserved regulatory mechanisms evolved during the transition to multicellularity to control fundamental cellular processes such as growth and replication. Dating the evolutionary emergence of human genes through phylostratigraphy uncovered close association between gene age and expression level in RNA sequencing data from The Cancer Genome Atlas for seven solid cancers. Genes conserved with unicellular organisms were strongly up-regulated, whereas genes of metazoan origin were primarily inactivated. These patterns were most consistent for processes known to be important in cancer, implicating both selection and active regulation during malignant transformation. The coordinated expression of strongly interacting multicellularity and unicellularity processes was lost in tumors. This separation of unicellular and multicellular functions appeared to be mediated by 12 highly connected genes, marking them as important general drivers of tumorigenesis. Our findings suggest common principles closely tied to the evolutionary history of genes underlie convergent changes at the cellular process level across a range of solid cancers. We propose altered activity of genes at the interfaces between multicellular and unicellular regions of human gene regulatory networks activate primitive transcriptional programs, driving common hallmark features of cancer. Manipulation of cross-talk between biological processes of different evolutionary origins may thus present powerful and broadly applicable treatment strategies for cancer.

The Emergence of Multi-Cellular Robot Organisms through On-line On-board Evolution

NARCIS (Netherlands)

Weel, B.P.M.; Haasdijk, E.W.; Eiben, A.E.

2012-01-01

We investigate whether a swarm of robots can evolve controllers that cause aggregation into 'multi-cellular' robot organisms without a specific reward to do so. To this end, we create a world where aggregated robots receive more energy than individual ones and enable robots to evolve their

Ability of multicellular salt glands in Tamarix species to secrete Na+ and K+ selectively.

Science.gov (United States)

Ma, Haiyan; Tian, Changyan; Feng, Gu; Yuan, Junfeng

2011-03-01

The present study aimed to determine the mechanism of cation-selective secretion by multicellular salt glands. Using a hydroponic culture system, the secretion and accumulation of Na(+) and K(+) in Tamarix ramosissima and T. laxa under different salt stresses (NaCl, KCl and NaCl+KCl) were studied. Additionally, the effects of salt gland inhibitors (orthovanadate, Ba(2+), ouabain, tetraethylammonium (TEA) and verapamil) on Na(+) and K(+) secretion and accumulation were examined. Treatment with NaCl (at 0-200 mmol L(-1) levels) significantly increased Na(+) secretion, whereas KCl treatment (at 0-200 mmol L(-1) levels) significantly increased K(+) secretion. The ratio of secretion to accumulation of Na(+) was higher than that of K(+). The changes in Na(+) and K(+) secretion differed after adding different ions into the single-salt solutions. Addition of NaCl to the KCl solution (at 100 mmol L(-1) level, respectively) led to a significant decrease in K(+) secretion rate, whereas addition of KCl to the NaCl solution (at 100 mmol L(-1) level, respectively) had little impact on the Na(+) secretion rate. These results indicated that Na+ secretion in Tamarix was highly selective. In addition, Na(+) secretion was significantly inhibited by orthovanadate, ouabain, TEA and verapamil, and K(+) secretion was significantly inhibited by ouabain, TEA and verapamil. The different impacts of orthovanadate on Na(+) and K(+) secretion might be the primary cause for the different Na(+) and K(+) secretion abilities of multicellular salt glands in Tamarix.

Development of Three-Dimensional Multicellular Tissue-Like Constructs for Mutational Analysis Using Macroporous Microcarriers

Science.gov (United States)

Jordan, Jacqueline A.; Fraga, Denise N.; Gonda, Steve R.

2002-01-01

A three-dimensional (3-D), tissue-like model was developed for the genotoxic assessment of space environment. In previous experiments, we found that culturing mammalian cells in a NASA-designed bioreactor, using Cytodex-3 beads as a scaffold, generated 3-D multicellular spheroids. In an effort to generate scaffold-free spheroids, we developed a new 3-D tissue-like model by coculturing fibroblast and epithelial cell in a NASA bioreactor using macroporous Cultispher-S(TradeMark) microcarriers. Big Blue(Registered Trademark) Rat 2(Lambda) fibroblasts, genetically engineered to contain multiple copies (>60 copies/cell) of the Lac I target gene, were cocultured with radio-sensitive human epithelial cells, H184F5. Over an 8-day period, samples were periodically examined by microscopy and histology to confirm cell attachment, growth, and viability. Immunohistochemistry and western analysis were used to evaluate the expression of specific cytoskeletal and adhesion proteins. Key cell culture parameters (glucose, pH, and lactate concentrations) were monitored daily. Controls were two-dimensional mono layers of fibroblast or epithelial cells cultured in T-flasks. Analysis of 3-D spheroids from the bioreactor suggests fibroblast cells attached to and completely covered the bead surface and inner channels by day 3 in the bioreactor. Treatment of the 3-day spheroids with dispase II dissolved the Cultisphers(TradeMark) and produced multicellular, bead-less constructs. Immunohistochemistry confirmed the presence of vi.mentin, cytokeratin and E-cadherin in treated spheroids. Examination of the dispase II treated spheroids with transmission electron microscopy (TEM) also showed the presence of desmosomes. These results suggest that the controlled enzymatic degradation of an artificial matrix in the low shear environment of the NASA-designed bioreactor can produce 3-D tissue-like spheroids. 2

Differential thermo-resistance of multicellular tumor spheroids

International Nuclear Information System (INIS)

Khoei, S.; Goliaei, B.; Neshasteh-Rize, A.

2004-01-01

Many cell lines, when cultured under proper conditions, can form three dimensional structures called multicellular spheroids. These spheroids resemble in vivo tumor models in several aspects. Therefore, studying growth characteristics and behavior of spheroids is beneficial in understanding the behavior of tumors under various experimental conditions. In this work, we have studied the growth properties, along with the thermal characteristics of spheroids of Du 145 human prostate carcinoma cell lines and compared the results to monolayer cultures of these cells. For this purpose, The Du 145 cells were cultured either as monolayer or spheroids. At various times after initiation of cultures, the growth properties of spheroids as a function of seeding cell number was determined. To evaluate the thermal characteristics of spheroids, they were heated at various stages of growth at 43 d ig c for various periods. The thermal response was judged by the survival fraction of colony forming cells in spheroids or monolayer culture following heat treatment. The results showed spheroids were more resistant to heat than monolayer cultures at all stages of development. However, the extent of this thermal resistant was dependent on the age, and consequently, the size of the spheroid. The result suggests that the differential thermal resistance of the spheroid cultures develop gradually during the growth of spheroid cultures of Du 145 cell line

Synergistic interaction between cisplatin and gemcitabine in neuroblastoma cell lines and multicellular tumor spheroids

NARCIS (Netherlands)

Besançon, Odette G.; Tytgat, Godelieve A. M.; Meinsma, Rutger; Leen, René; Hoebink, Jerry; Kalayda, Ganna V.; Jaehde, Ulrich; Caron, Huib N.; van Kuilenburg, André B. P.

2012-01-01

The efficacy and mechanism of action of cisplatin and gemcitabine were investigated in a panel of neuroblastoma cell lines and multicellular tumor spheroids. In neuroblastoma spheroids, the combination of cisplatin and gemcitabine induced a complete cytostasis at clinical relevant concentrations. A

A Duo of Potassium-Responsive Histidine Kinases Govern the Multicellular Destiny of Bacillus subtilis

NARCIS (Netherlands)

Grau, Roberto R; de Oña, Paula; Kunert, Maritta; Leñini, Cecilia; Gallegos-Monterrosa, Ramses; Mhatre, Eisha; Vileta, Darío; Donato, Verónica; Hölscher, Theresa; Boland, Wilhelm; Kuipers, Oscar P; Kovács, Ákos T

2015-01-01

Multicellular biofilm formation and surface motility are bacterial behaviors considered mutually exclusive. However, the basic decision to move over or stay attached to a surface is poorly understood. Here, we discover that in Bacillus subtilis, the key root biofilm-controlling transcription factor

Multicellular tumor spheroid interactions with bone cells and bone

International Nuclear Information System (INIS)

Wezeman, F.H.; Guzzino, K.M.; Waxler, B.

1985-01-01

In vitro coculture techniques were used to study HSDM1C1 murine fibrosarcoma multicellular tumor spheroid (HSDM1C1-MTS) interactions with mouse calvarial bone cells having osteoblastic characteristics and mouse bone explants. HSDM1C1-MTS attached to confluent bone cell monolayers and their attachment rate was quantified. HSDM1C1-MTS interaction with bone cells was further demonstrated by the release of 3 H-deoxyuridine from prelabeled bone cells during coculture with multicellular tumor spheroids. HSDM1C1-MTS-induced cytotoxicity was mimicked by the addition of 10(-5) M prostaglandin E2 (PGE2) to 3 H-deoxyuridine-labeled bone cells. The effects of low (10(-9) M) and high (10(-5) M) concentrations of PGE2 on bone cell proliferation were also studied. Higher concentrations of PGE2 inhibited bone cell proliferation. HSDM1C1-MTS resorbed living explants in the presence of indomethacin, suggesting that other tumor cell products may also participate in bone resorption. HSDM1C1-MTS caused direct bone resorption as measured by the significantly elevated release of 45 Ca from prelabeled, devitalized calvaria. However, the growth of a confluent bone cell layer on devitalized, 45 Ca-prelabeled calvaria resulted in a significant reduction in the amount of 45 Ca released subsequent to the seeding of HSDM1C1-MTS onto the explants. Bone cells at the bone surface may act as a barrier against invasion and tumor cell-mediated bone resorption. Violation of this cellular barrier is achieved, in part, by tumor cell products

Differential superiority of heavy charged-particle irradiation to x-rays: Studies on biological effectivenes and side effect mechanisms in multicellular tumor and normal tissue models

Directory of Open Access Journals (Sweden)

Stefan eWalenta

2016-02-01

Full Text Available This review is focused on the radiobiology of carbon ions compared to x-rays using multicellular models of tumors and normal mucosa. The first part summarizes basic radiobiological effects, as observed in cancer cells. The second, more clinically oriented part of the review deals with radiation-induced cell migration and mucositis.Multicellular spheroids (MCS from V79 hamster cells were irradiated with x-rays or carbon ions under ambient or restricted oxygen supply conditions. Oxygen enhancement ratios (OER were 2.9, 2.8, and 1.4 for irradiation with photons, 12C+6 in the plateau region, and 12C+6 in the Bragg peak, respectively. A relative biological effectiveness (RBE of 4.3 and 2.1 for ambient pO2 and hypoxia was obtained, respectively. The high effectiveness of carbon ions was reflected by an enhanced accumulation of cells in G2/M, and a dose-dependent massive induction of apoptosis. Clinically relevant doses (3 Gy of x-rays induced an increase in migratory activity of U87 but not of LN229 or HCT116 tumor cells. Such an increase in cell motility following irradiation in situ could be the source of recurrence. In contrast, carbon ion treatment was associated with a dose-dependent decrease in migration with all cell lines and under all conditions investigated. The radiation-induced loss of cell motility was correlated, in most cases, with corresponding changes in 1 integrin expression. Unlike with particles, the photon-induced increase in cell migration was paralleled by an elevated phosphorylation status of the epidermal growth factor receptor (EGFR and AKT-ERK1/2 pathway. Comparing the gene toxicity of x-rays with that of particles using the gamma-H2AX technique in organotypic cultures of the oral mucosa, the superior effectiveness of heavy ions was confirmed by a two-fold higher number of foci per nucleus. Pro-inflammatory signs, however, were similar for both treatment modalities, e. g., the activation of NFkappaB, and the release of IL

Time-lapse 3-D measurements of a glucose biosensor in multicellular spheroids by light sheet fluorescence microscopy in commercial 96-well plates.

Science.gov (United States)

Maioli, Vincent; Chennell, George; Sparks, Hugh; Lana, Tobia; Kumar, Sunil; Carling, David; Sardini, Alessandro; Dunsby, Chris

2016-11-25

Light sheet fluorescence microscopy has previously been demonstrated on a commercially available inverted fluorescence microscope frame using the method of oblique plane microscopy (OPM). In this paper, OPM is adapted to allow time-lapse 3-D imaging of 3-D biological cultures in commercially available glass-bottomed 96-well plates using a stage-scanning OPM approach (ssOPM). Time-lapse 3-D imaging of multicellular spheroids expressing a glucose Förster resonance energy transfer (FRET) biosensor is demonstrated in 16 fields of view with image acquisition at 10 minute intervals. As a proof-of-principle, the ssOPM system is also used to acquire a dose response curve with the concentration of glucose in the culture medium being varied across 42 wells of a 96-well plate with the whole acquisition taking 9 min. The 3-D image data enable the FRET ratio to be measured as a function of distance from the surface of the spheroid. Overall, the results demonstrate the capability of the OPM system to measure spatio-temporal changes in FRET ratio in 3-D in multicellular spheroids over time in a multi-well plate format.

Multiscale Systems Modeling of Male Reproductive Tract ...

Science.gov (United States)

The reproductive tract is a complex, integrated organ system with diverse embryology and unique sensitivity to prenatal environmental exposures that disrupt morphoregulatory processes and endocrine signaling. U.S. EPA’s in vitro high-throughput screening (HTS) database (ToxCastDB) was used to profile the bioactivity of 54 chemicals with male developmental consequences across ~800 molecular and cellular features [Leung et al., accepted manuscript]. The in vitro bioactivity on molecular targets could be condensed into 156 gene annotations in a bipartite network. These results highlighted the role of estrogen and androgen signaling pathways in male reproductive tract development, and importantly, broadened the list of molecular targets to include GPCRs, cytochrome-P450s, vascular remodeling proteins, and retinoic acid signaling. A multicellular agent-based model was used to simulate the complex interactions between morphoregulatory, endocrine, and environmental influences during genital tubercle (GT) development. Spatially dynamic signals (e.g., SHH, FGF10, and androgen) were implemented in the model to address differential adhesion, cell motility, proliferation, and apoptosis. Urethral tube closure was an emergent feature of the model that was linked to gender-specific rates of ventral mesenchymal proliferation and urethral plate endodermal apoptosis, both under control of androgen signaling [Leung et al., manuscript in preparation]. A systemic parameter sweep w

Symbiotic Cell Differentiation and Cooperative Growth in Multicellular Aggregates.

Directory of Open Access Journals (Sweden)

Jumpei F Yamagishi

2016-10-01

Full Text Available As cells grow and divide under a given environment, they become crowded and resources are limited, as seen in bacterial biofilms and multicellular aggregates. These cells often show strong interactions through exchanging chemicals, as evident in quorum sensing, to achieve mutualism and division of labor. Here, to achieve stable division of labor, three characteristics are required. First, isogenous cells differentiate into several types. Second, this aggregate of distinct cell types shows better growth than that of isolated cells without interaction and differentiation, by achieving division of labor. Third, this cell aggregate is robust with respect to the number distribution of differentiated cell types. Indeed, theoretical studies have thus far considered how such cooperation is achieved when the ability of cell differentiation is presumed. Here, we address how cells acquire the ability of cell differentiation and division of labor simultaneously, which is also connected with the robustness of a cell society. For this purpose, we developed a dynamical-systems model of cells consisting of chemical components with intracellular catalytic reaction dynamics. The reactions convert external nutrients into internal components for cellular growth, and the divided cells interact through chemical diffusion. We found that cells sharing an identical catalytic network spontaneously differentiate via induction from cell-cell interactions, and then achieve division of labor, enabling a higher growth rate than that in the unicellular case. This symbiotic differentiation emerged for a class of reaction networks under the condition of nutrient limitation and strong cell-cell interactions. Then, robustness in the cell type distribution was achieved, while instability of collective growth could emerge even among the cooperative cells when the internal reserves of products were dominant. The present mechanism is simple and general as a natural consequence of

A mechanistic model for the evolution of multicellularity

Science.gov (United States)

Amado, André; Batista, Carlos; Campos, Paulo R. A.

2018-02-01

Through a mechanistic approach we investigate the formation of aggregates of variable sizes, accounting mechanisms of aggregation, dissociation, death and reproduction. In our model, cells can produce two metabolites, but the simultaneous production of both metabolites is costly in terms of fitness. Thus, the formation of larger groups can favor the aggregates to evolve to a configuration where division of labor arises. It is assumed that the states of the cells in a group are those that maximize organismal fitness. In the model it is considered that the groups can grow linearly, forming a chain, or compactly keeping a roughly spherical shape. Starting from a population consisting of single-celled organisms, we observe the formation of groups with variable sizes and usually much larger than two-cell aggregates. Natural selection can favor the formation of large groups, which allows the system to achieve new and larger fitness maxima.

The Paramyxea Levine 1979: An original example of evolution towards multicellularity

Science.gov (United States)

Desportes, Isabelle

1984-03-01

The Paramyxea are parasitic in marine invertebrates. Their development is a sporulation involving the differentiation within a stem cell of several sporonts which produce spores made of cells enclosed inside each other. Three genera are recognized according to the number of spores and sporal cells, and the taxonomic position of the host (Polychaeta, Mollusca, Crustacea). The Paramyxea exhibit both protistan and metazoan characters. Their nine singlets centrioles are observed in different Protoctists whereas the fact that their sporal cells acquire distinctive cytological features may be interpreted as an evolution towards multicellularity.

Optimization of the formation of embedded multicellular spheroids of MCF-7 cells: How to reliably produce a biomimetic 3D model.

Science.gov (United States)

Zhang, Wenli; Li, Caibin; Baguley, Bruce C; Zhou, Fang; Zhou, Weisai; Shaw, John P; Wang, Zhen; Wu, Zimei; Liu, Jianping

2016-12-15

To obtain a multicellular MCF-7 spheroid model to mimic the three-dimensional (3D) of tumors, the microwell liquid overlay (A) and hanging-drop/agar (B) methods were first compared for their technical parameters. Then a method for embedding spheroids within collagen was optimized. For method A, centrifugation assisted cells form irregular aggregates but not spheroids. For method B, an extended sedimentation period of over 24 h for cell suspensions and increased viscosity of the culture medium using methylcellulose were necessary to harvest a dense and regular cell spheroid. When the number was less than 5000 cells/drop, embedded spheroids showed no tight cores and higher viability than the unembedded. However, above 5000 cells/drop, cellular viability of embedded spheroids was not significantly different from unembedded spheroids and cells invading through the collagen were in a sun-burst pattern with tight cores. Propidium Iodide staining indicated that spheroids had necrotic cores. The doxorubicin cytotoxicity demonstrated that spheroids were less susceptible to DOX than their monolayer cells. A reliable and reproducible method for embedding spheroids using the hanging-drop/agarose method within collagen is described herein. The cell culture model can be used to guide experimental manipulation of 3D cell cultures and to evaluate anticancer drug efficacy. Copyright © 2016 Elsevier Inc. All rights reserved.

A Novel Method to Verify Multilevel Computational Models of Biological Systems Using Multiscale Spatio-Temporal Meta Model Checking.

Science.gov (United States)

Pârvu, Ovidiu; Gilbert, David

2016-01-01

Insights gained from multilevel computational models of biological systems can be translated into real-life applications only if the model correctness has been verified first. One of the most frequently employed in silico techniques for computational model verification is model checking. Traditional model checking approaches only consider the evolution of numeric values, such as concentrations, over time and are appropriate for computational models of small scale systems (e.g. intracellular networks). However for gaining a systems level understanding of how biological organisms function it is essential to consider more complex large scale biological systems (e.g. organs). Verifying computational models of such systems requires capturing both how numeric values and properties of (emergent) spatial structures (e.g. area of multicellular population) change over time and across multiple levels of organization, which are not considered by existing model checking approaches. To address this limitation we have developed a novel approximate probabilistic multiscale spatio-temporal meta model checking methodology for verifying multilevel computational models relative to specifications describing the desired/expected system behaviour. The methodology is generic and supports computational models encoded using various high-level modelling formalisms because it is defined relative to time series data and not the models used to generate it. In addition, the methodology can be automatically adapted to case study specific types of spatial structures and properties using the spatio-temporal meta model checking concept. To automate the computational model verification process we have implemented the model checking approach in the software tool Mule (http://mule.modelchecking.org). Its applicability is illustrated against four systems biology computational models previously published in the literature encoding the rat cardiovascular system dynamics, the uterine contractions of labour

Tissues development in stems of Aristolochia clematitis L. in the point of view of multicellular complexes formation

Directory of Open Access Journals (Sweden)

Zofia Puławska

2014-01-01

Full Text Available After cytokinesis the cells do not separate but remain within the wall of the mother cell. After a series of divisions a multicellular complex arises. In the stems of Aristolochia clematitis procambium is closer related to protoxylem than to protophloem, and metaphloem is closer related to metaxylem than to protophloem. Since protophloem has a closer common origin with fibre primordia than with the remaining tissues, it cannot be decided unequivocally what is the origin of the fibres or when procambium differentiates. The common origin of the primary vascular tissues is visible in the pattern of the multicellular complexes, whereas the common origin of the secondary vascular tissue developing in the underground several-year-old parts of the stem can be traced in the arrangement of the single radial tiers. Some characteristics of symplastic growth are discussed.

Multi-cellular natural killer (NK) cell clusters enhance NK cell activation through localizing IL-2 within the cluster

Science.gov (United States)

Kim, Miju; Kim, Tae-Jin; Kim, Hye Mi; Doh, Junsang; Lee, Kyung-Mi

2017-01-01

Multi-cellular cluster formation of natural killer (NK) cells occurs during in vivo priming and potentiates their activation to IL-2. However, the precise mechanism underlying this synergy within NK cell clusters remains unclear. We employed lymphocyte-laden microwell technologies to modulate contact-mediated multi-cellular interactions among activating NK cells and to quantitatively assess the molecular events occurring in multi-cellular clusters of NK cells. NK cells in social microwells, which allow cell-to-cell contact, exhibited significantly higher levels of IL-2 receptor (IL-2R) signaling compared with those in lonesome microwells, which prevent intercellular contact. Further, CD25, an IL-2R α chain, and lytic granules of NK cells in social microwells were polarized toward MTOC. Live cell imaging of lytic granules revealed their dynamic and prolonged polarization toward neighboring NK cells without degranulation. These results suggest that IL-2 bound on CD25 of one NK cells triggered IL-2 signaling of neighboring NK cells. These results were further corroborated by findings that CD25-KO NK cells exhibited lower proliferation than WT NK cells, and when mixed with WT NK cells, underwent significantly higher level of proliferation. These data highlights the existence of IL-2 trans-presentation between NK cells in the local microenvironment where the availability of IL-2 is limited.

Minimal resin embedding of multicellular specimens for targeted FIB-SEM imaging.

Science.gov (United States)

Schieber, Nicole L; Machado, Pedro; Markert, Sebastian M; Stigloher, Christian; Schwab, Yannick; Steyer, Anna M

2017-01-01

Correlative light and electron microscopy (CLEM) is a powerful tool to perform ultrastructural analysis of targeted tissues or cells. The large field of view of the light microscope (LM) enables quick and efficient surveys of the whole specimen. It is also compatible with live imaging, giving access to functional assays. CLEM protocols take advantage of the features to efficiently retrace the position of targeted sites when switching from one modality to the other. They more often rely on anatomical cues that are visible both by light and electron microscopy. We present here a simple workflow where multicellular specimens are embedded in minimal amounts of resin, exposing their surface topology that can be imaged by scanning electron microscopy (SEM). LM and SEM both benefit from a large field of view that can cover whole model organisms. As a result, targeting specific anatomic locations by focused ion beam-SEM (FIB-SEM) tomography becomes straightforward. We illustrate this application on three different model organisms, used in our laboratory: the zebrafish embryo Danio rerio, the marine worm Platynereis dumerilii, and the dauer larva of the nematode Caenorhabditis elegans. Here we focus on the experimental steps to reduce the amount of resin covering the samples and to image the specimens inside an FIB-SEM. We expect this approach to have widespread applications for volume electron microscopy on multiple model organisms. Copyright © 2017 Elsevier Inc. All rights reserved.

The green seaweed Ulva: A model system to study morphogenesis

OpenAIRE

Thomas eWichard; Benedicte eCharrier; Benedicte eCharrier; Frédéric eMineur; John Henry Bothwell; Olivier eDe Clerck; Juliet C. Coates

2015-01-01

Green macroalgae, mostly represented by the Ulvophyceae, the main multicellular branch of the Chlorophyceae, constitute important primary producers of marine and brackish coastal ecosystems. Ulva or sea lettuce species are some of the most abundant representatives, being ubiquitous in coastal benthic communities around the world. Nonetheless the genus also remains largely understudied. This review highlights Ulva as an exciting novel model organism for studies of algal growth, development and...

The green seaweed Ulva: a model system to study morphogenesis

OpenAIRE

Wichard, Thomas; Charrier, Bénédicte; Mineur, Frédéric; Bothwell, John H; De Clerck, Olivier; Coates, Juliet C

2015-01-01

International audience; Green macroalgae, mostly represented by the Ulvophyceae, the main multicellular branch of the Chlorophyceae, constitute important primary producers of marine and brackish coastal ecosystems. Ulva or sea lettuce species are some of the most abundant representatives, being ubiquitous in coastal benthic communities around the world. Nonetheless the genus also remains largely understudied. This review highlights Ulva as an exciting novel model organism for studies of algal...

Low-temperature plasma-induced antiproliferative effects on multi-cellular tumor spheroids

International Nuclear Information System (INIS)

Plewa, Joseph-Marie; Yousfi, Mohammed; Eichwald, Olivier; Merbahi, Nofel; Frongia, Céline; Ducommun, Bernard; Lobjois, Valérie

2014-01-01

Biomedical applications of low-temperature plasmas are of growing interest, especially in the field of plasma-induced anti-tumor effects. The present work is aimed at investigating the regionalized antiproliferative effects of low-temperature plasmas on a multicellular tumor spheroid (MCTS), a model that mimics the 3D organization and regionalization of a microtumor region. We report that a low-temperature plasma jet, using helium flow in open air, inhibits HCT116 colon carcinoma MCTS growth in a dose-dependent manner. This growth inhibition is associated with the loss of Ki67, and the regionalized accumulation of DNA damage detected by histone H2AX phosphorylation. This regionalized genotoxic effect leads to massive cell death and loss of the MCTS proliferative region. The use of reactive oxygen species (ROS), scavenger N-acetyl cysteine (NAC) and plasma-conditioned media demonstrate that the ROS generated in the media after exposure to low-temperature plasma play a major role in these observed effects. These findings strengthen the interest in the use of MCTS for the evaluation of antiproliferative strategies, and open new perspectives for studies dedicated to demonstrate the potential of low-temperature plasma in cancer therapy

Low-temperature plasma-induced antiproliferative effects on multi-cellular tumor spheroids

Science.gov (United States)

Plewa, Joseph-Marie; Yousfi, Mohammed; Frongia, Céline; Eichwald, Olivier; Ducommun, Bernard; Merbahi, Nofel; Lobjois, Valérie

2014-04-01

Biomedical applications of low-temperature plasmas are of growing interest, especially in the field of plasma-induced anti-tumor effects. The present work is aimed at investigating the regionalized antiproliferative effects of low-temperature plasmas on a multicellular tumor spheroid (MCTS), a model that mimics the 3D organization and regionalization of a microtumor region. We report that a low-temperature plasma jet, using helium flow in open air, inhibits HCT116 colon carcinoma MCTS growth in a dose-dependent manner. This growth inhibition is associated with the loss of Ki67, and the regionalized accumulation of DNA damage detected by histone H2AX phosphorylation. This regionalized genotoxic effect leads to massive cell death and loss of the MCTS proliferative region. The use of reactive oxygen species (ROS), scavenger N-acetyl cysteine (NAC) and plasma-conditioned media demonstrate that the ROS generated in the media after exposure to low-temperature plasma play a major role in these observed effects. These findings strengthen the interest in the use of MCTS for the evaluation of antiproliferative strategies, and open new perspectives for studies dedicated to demonstrate the potential of low-temperature plasma in cancer therapy.

A Duo of Potassium-Responsive Histidine Kinases Govern the Multicellular Destiny of Bacillus subtilis.

Science.gov (United States)

Grau, Roberto R; de Oña, Paula; Kunert, Maritta; Leñini, Cecilia; Gallegos-Monterrosa, Ramses; Mhatre, Eisha; Vileta, Darío; Donato, Verónica; Hölscher, Theresa; Boland, Wilhelm; Kuipers, Oscar P; Kovács, Ákos T

2015-07-07

decision to move over or stay attached to a surface controlled? Here, we use the model plant-beneficial bacterium Bacillus subtilis to answer this question. Remarkably, we discover that sessile biofilm formation and social sliding motility share the same structural components and the Spo0A regulatory network via sensor kinases, KinB and KinC. Potassium, an inhibitor of KinC-dependent biofilm formation, triggers sliding via a potassium-perceiving cytosolic domain of KinB that resembles the selectivity filter of potassium channels. The spatiotemporal response of these kinases to variable potassium levels and the gradual increase in Spo0A~Pi levels that orchestrates the activation of sliding before biofilm formation shed light on how multicellular behaviors formerly believed to be antagonistic work together to benefit the population fitness. Copyright © 2015 Grau et al.

In vitro extracellular matrix model to evaluate stroma cell response to transvaginal mesh.

Science.gov (United States)

Wu, Ming-Ping; Huang, Kuan-Hui; Long, Cheng-Yu; Yang, Chau-Chen; Tong, Yat-Ching

2014-04-01

The use of surgical mesh for female pelvic floor reconstruction has increased in recent years. However, there is paucity of information about the biological responses of host stroma cells to different meshes. This study was aimed to establish an in vitro experimental model to study the micro-environment of extracellular matrix (ECM) with embedded mesh and the stroma cell behaviors to different synthetic meshes. Matrigel multi-cellular co-culture system with embedded mesh was used to evaluate the interaction of stroma cells and synthetic mesh in a simulated ECM environment. Human umbilical vein endothelial cells (HUVEC) and NIH3T3 fibroblasts were inoculated in the system. The established multi-cellular Matrigel co-culture system was used to detect stroma cell recruitment and tube formation ability for different synthetic meshes. HUVEC and NIH3T3 cells were recruited into the mesh interstices and organized into tube-like structures in type I mesh material from Perigee, Marlex and Prolift 24 hr after cell inoculation. On the contrary, there was little recruitment of HUVEC and NIH3T3 cells into the type III mesh of intra-vaginal sling (IVS). The Matrigel multi-cellular co-culture system with embedded mesh offers a useful in vitro model to study the biological behaviors of stroma cells in response to different types of synthetic meshes. The system can help to select ideal mesh candidates before actual implantation into the human body. © 2013 Wiley Periodicals, Inc.

The sensitivity of Turing self-organization to biological feedback delays: 2D models of fish pigmentation

KAUST Repository

Gaffney, E. A.; Lee, S. S.

2013-01-01

© The authors 2013. Turing morphogen models have been extensively explored in the context of large-scale self-organization in multicellular biological systems. However, reconciling the detailed biology of morphogen dynamics, while accounting

Response of the MG-63 human osteosarcoma cell line grown as multicellular spheroids to neutron irradiation

International Nuclear Information System (INIS)

Kubota, Nobuo; Kakehi, Masae; Matsubara, Shou; Koike, Sachiko; Ando, Koichi.

1993-01-01

Multicellular tumor spheroids are composed of the mixed populations of cells with regard to cell proliferation, nutrition, oxygenation and radiosensitivity. Human osteogenic sarcoma is generally considered clinically radioresistant. However, the in vitro cell survival curves for human osteogenic sarcoma cell lines do not differ from those of other tumor cell lines. In this study, the responses of human osteogenic sarcoma cell line to gamma ray and neutrons were investigated by using spheroid system. The spheroids of the osteogenic sarcoma cell line are considered to be a good in vitro model of radioresistant tumors. The purpose of this study is to measure the response of the spheroids to fast neutron irradiation. MG-63 human osteogenic sarcoma cell line was used for this study. The cell line was cultured in alpha-MEM with supplement. Cell survival was estimated after the trypsinization of spheroids 24 hours after irradiation. The method of measuring spheroid cure is explained. The mean number of surviving cells per spheroid can be obtained from the mean clonogenic number and cell survival curve. The cell survival of MG-63 spheroids exposed to gamma ray and neutrons and the dose effect curves for spheroid cure after irradiation are shown. (K.I.)

Realisation and qualification of a tissue equivalent proportional counter with a multi-cellular geometry for the individual neutron dosimetry

International Nuclear Information System (INIS)

Hoflack, Ch.

1999-01-01

The present day dosimetry means for radiations with a strong ionization density cannot fulfill the future radioprotection regulations which will require an individual dosimetry with active dosemeters. The aim of this work is the study and development of an individual dosemeter based on a tissue equivalent proportional counter and with a multi-cellular geometry allowing to reach a sensibility equivalent to environmental dosemeters. A pressure regulation bench has been added to the detector in order to reduce the degassing of the detector parts and to reach a sufficient service life for the implementation of the characterization tests. The hole counter system has been adopted for the first prototypes in order to reduce the sensibility of the wires multiplication system with respect to mechanical vibrations. Tests performed with an internal alpha source have shown that a better electrical efficiency can be reached when more severe mechanical limits are adopted during the construction. The dose equivalent response of the prototype for mono-energy neutrons of 144 keV to 2.5 MeV is analyzed experimentally and by simulation. During experiments with normal incidence neutrons, the prototype fulfills the requirements of the CEI N O 1323 standard for energies comprised between 400 keV and 2.5 MeV, while the simulation indicates a satisfactory response up to 200 keV. A preliminary study of the behaviour of the detector with respect to the neutrons incidence indicates that the multi-cellular geometry is efficient for large angles (the sensibility of the prototype is increased by a factor 3). Finally, simulation studies have to be made to optimize the electrical operation and the geometry of the next prototype. (J.S.)

The triple helix of collagens - an ancient protein structure that enabled animal multicellularity and tissue evolution.

Science.gov (United States)

Fidler, Aaron L; Boudko, Sergei P; Rokas, Antonis; Hudson, Billy G

2018-04-09

The cellular microenvironment, characterized by an extracellular matrix (ECM), played an essential role in the transition from unicellularity to multicellularity in animals (metazoans), and in the subsequent evolution of diverse animal tissues and organs. A major ECM component are members of the collagen superfamily -comprising 28 types in vertebrates - that exist in diverse supramolecular assemblies ranging from networks to fibrils. Each assembly is characterized by a hallmark feature, a protein structure called a triple helix. A current gap in knowledge is understanding the mechanisms of how the triple helix encodes and utilizes information in building scaffolds on the outside of cells. Type IV collagen, recently revealed as the evolutionarily most ancient member of the collagen superfamily, serves as an archetype for a fresh view of fundamental structural features of a triple helix that underlie the diversity of biological activities of collagens. In this Opinion, we argue that the triple helix is a protein structure of fundamental importance in building the extracellular matrix, which enabled animal multicellularity and tissue evolution. © 2018. Published by The Company of Biologists Ltd.

Differential Superiority of Heavy Charged-Particle Irradiation to X-Rays: Studies on Biological Effectiveness and Side Effect Mechanisms in Multicellular Tumor and Normal Tissue Models.

Science.gov (United States)

Walenta, Stefan; Mueller-Klieser, Wolfgang

2016-01-01

This review is focused on the radiobiology of carbon ions compared to X-rays using multicellular models of tumors and normal mucosa. The first part summarizes basic radiobiological effects, as observed in cancer cells. The second, more clinically oriented part of the review, deals with radiation-induced cell migration and mucositis. Multicellular spheroids from V79 hamster cells were irradiated with X-rays or carbon ions under ambient or restricted oxygen supply conditions. Reliable oxygen enhancement ratios could be derived to be 2.9, 2.8, and 1.4 for irradiation with photons, (12)C(+6) in the plateau region, and (12)C(+6) in the Bragg peak, respectively. Similarly, a relative biological effectiveness of 4.3 and 2.1 for ambient pO2 and hypoxia was obtained, respectively. The high effectiveness of carbon ions was reflected by an enhanced accumulation of cells in G2/M and a dose-dependent massive induction of apoptosis. These data clearly show that heavy charged particles are more efficient in sterilizing tumor cells than conventional irradiation even under hypoxic conditions. Clinically relevant doses (3 Gy) of X-rays induced an increase in migratory activity of U87 but not of LN229 or HCT116 tumor cells. Such an increase in cell motility following irradiation in situ could be the source of recurrence. In contrast, carbon ion treatment was associated with a dose-dependent decrease in migration with all cell lines and under all conditions investigated. The radiation-induced loss of cell motility was correlated, in most cases, with corresponding changes in β1 integrin expression. The photon-induced increase in cell migration was paralleled by an elevated phosphorylation status of the epidermal growth factor receptor and AKT-ERK1/2 pathway. Such a hyperphosphorylation did not occur during (12)C(+6) irradiation under all conditions registered. Comparing the gene toxicity of X-rays with that of particles using the γH2AX technique in organotypic cultures of the oral

Differential Superiority of Heavy Charged-Particle Irradiation to X-Rays: Studies on Biological Effectiveness and Side Effect Mechanisms in Multicellular Tumor and Normal Tissue Models

Science.gov (United States)

Walenta, Stefan; Mueller-Klieser, Wolfgang

2016-01-01

This review is focused on the radiobiology of carbon ions compared to X-rays using multicellular models of tumors and normal mucosa. The first part summarizes basic radiobiological effects, as observed in cancer cells. The second, more clinically oriented part of the review, deals with radiation-induced cell migration and mucositis. Multicellular spheroids from V79 hamster cells were irradiated with X-rays or carbon ions under ambient or restricted oxygen supply conditions. Reliable oxygen enhancement ratios could be derived to be 2.9, 2.8, and 1.4 for irradiation with photons, 12C+6 in the plateau region, and 12C+6 in the Bragg peak, respectively. Similarly, a relative biological effectiveness of 4.3 and 2.1 for ambient pO2 and hypoxia was obtained, respectively. The high effectiveness of carbon ions was reflected by an enhanced accumulation of cells in G2/M and a dose-dependent massive induction of apoptosis. These data clearly show that heavy charged particles are more efficient in sterilizing tumor cells than conventional irradiation even under hypoxic conditions. Clinically relevant doses (3 Gy) of X-rays induced an increase in migratory activity of U87 but not of LN229 or HCT116 tumor cells. Such an increase in cell motility following irradiation in situ could be the source of recurrence. In contrast, carbon ion treatment was associated with a dose-dependent decrease in migration with all cell lines and under all conditions investigated. The radiation-induced loss of cell motility was correlated, in most cases, with corresponding changes in β1 integrin expression. The photon-induced increase in cell migration was paralleled by an elevated phosphorylation status of the epidermal growth factor receptor and AKT-ERK1/2 pathway. Such a hyperphosphorylation did not occur during 12C+6 irradiation under all conditions registered. Comparing the gene toxicity of X-rays with that of particles using the γH2AX technique in organotypic cultures of the oral mucosa, the

Cyclooxygenase-2 inhibitor is a robust enhancer of anticancer agents against hepatocellular carcinoma multicellular spheroids

Directory of Open Access Journals (Sweden)

Cui J

2014-02-01

Full Text Available Jie Cui,1,2 Ya-Huan Guo,3 Hong-Yi Zhang,4 Li-Li Jiang,1 Jie-Qun Ma,1 Wen-Juan Wang,1 Min-Cong Wang,1 Cheng-Cheng Yang,1 Ke-Jun Nan,1 Li-Ping Song5 1Department of Oncology, First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, 2Department of Oncology, Yan'an University Affiliated Hospital, Yan'an, 3Department of Oncology, Shaanxi Province Cancer Hospital, Xi'an, 4Department of Urology, Yan'an University Affiliated Hospital, Yan'an, 5Department of Radiotherapy, First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, People's Republic of China Purpose: Celecoxib, an inhibitor of cyclooxygenase-2 (COX2, was investigated for enhancement of chemotherapeutic efficacy in cancer clinical trials. This study aimed to determine whether celecoxib combined with 5-fluorouracil or sorafenib or gefitinib is beneficial in HepG2 multicellular spheroids (MCSs, as well as elucidate the underlying mechanisms. Methods: The human hepatocellular carcinoma cell line HepG2 MCSs were used as in vitro models to investigate the effects of celecoxib combined with 5-fluorouracil or sorafenib or gefitinib treatment on cell growth, apoptosis, and signaling pathway. Results: MCSs showed resistance to drugs compared with monolayer cells. Celecoxib combined with 5-fluorouracil or sorafenib exhibited a synergistic action. Exposure to celecoxib (21.8 µmol/L plus 5-fluorouracil (8.1 × 10-3 g/L or sorafenib (4.4 µmol/L increased apoptosis but exerted no effect on COX2, phosphorylated epidermal growth-factor receptor (p-EGFR and phosphorylated (p-AKT expression. Gefitinib (5 µmol/L, which exhibits no growth-inhibition activity as a single agent, increased the inhibitory effect of celecoxib. Gefitinib (5 µmol/L plus celecoxib (21.8 µmol/L increased apoptosis. COX2, p-EGFR, and p-AKT were inhibited. Conclusion: Celecoxib combined with 5-fluorouracil or sorafenib or gefitinib may be superior to single-agent therapy in HepG2

Study of the tensile properties of individual multicellular fibres generated by Bacillus subtilis

Science.gov (United States)

Ye, Xuan; Zhao, Liang; Liang, Jiecun; Li, Xide; Chen, Guo-Qiang

2017-04-01

Multicellular fibres formed by Bacillus subtilis (B. subtilis) are attracting interest because of their potential application as degradable biomaterials. However, mechanical properties of individual fibres remain unknown because of their small dimensions. Herein, a new approach is developed to investigate the tensile properties of individual fibres with an average diameter of 0.7 μm and a length range of 25.7-254.3 μm. Variations in the tensile strengths of fibres are found to be the result of variable interactions among pairs of microbial cells known as septa. Using Weibull weakest-link model to study this mechanical variability, we predict the length effect of the sample. Moreover, the mechanical properties of fibres are found to depend highly on relative humidity (RH), with a brittle-ductile transition occurring around RH = 45%. The elastic modulus is 5.8 GPa in the brittle state, while decreases to 62.2 MPa in the ductile state. The properties of fibres are investigated by using a spring model (RH  45%) for the time-dependent response. Loading-unloading experiments and numerical calculations demonstrate that necking instability comes from structural changes (septa) and viscoelasticity dominates the deformation of fibres at high RH.

The diversification of the LIM superclass at the base of the metazoa increased subcellular complexity and promoted multicellular specialization.

Directory of Open Access Journals (Sweden)

Bernard J Koch

Full Text Available Throughout evolution, the LIM domain has been deployed in many different domain configurations, which has led to the formation of a large and distinct group of proteins. LIM proteins are involved in relaying stimuli received at the cell surface to the nucleus in order to regulate cell structure, motility, and division. Despite their fundamental roles in cellular processes and human disease, little is known about the evolution of the LIM superclass.We have identified and characterized all known LIM domain-containing proteins in six metazoans and three non-metazoans. In addition, we performed a phylogenetic analysis on all LIM domains and, in the process, have identified a number of novel non-LIM domains and motifs in each of these proteins. Based on these results, we have formalized a classification system for LIM proteins, provided reasonable timing for class and family origin events; and identified lineage-specific loss events. Our analysis is the first detailed description of the full set of LIM proteins from the non-bilaterian species examined in this study.Six of the 14 LIM classes originated in the stem lineage of the Metazoa. The expansion of the LIM superclass at the base of the Metazoa undoubtedly contributed to the increase in subcellular complexity required for the transition from a unicellular to multicellular lifestyle and, as such, was a critically important event in the history of animal multicellularity.

Coupling gene expression and multicellular morphogenesis during fruiting body formation in Myxococcus xanthus

DEFF Research Database (Denmark)

Søgaard-Andersen, L.; Overgaard, M.; Lobedanz, S.

2003-01-01

xanthus illustrates this coupling in the construction of a multicellular structure. Fruiting body formation involves two stages: aggregation of cells into mounds and the position-specific sporulation of cells that have accumulated inside mounds. Developmental gene expression propels these two processes...... morphogenesis. Accumulation of the C-signal is tightly regulated and involves transcriptional activation of the csgA gene and proteolysis of the full-length CsgA protein to produce the shorter cell surface-associated 17 kDa C-signal protein. The C-signal induces aggregation, sporulation and developmental gene...

Generation of Multicellular Tumor Spheroids with Microwell-Based Agarose Scaffolds for Drug Testing.

Directory of Open Access Journals (Sweden)

Xue Gong

Full Text Available Three dimensional multicellular aggregate, also referred to as cell spheroid or microtissue, is an indispensable tool for in vitro evaluating antitumor activity and drug efficacy. Compared with classical cellular monolayer, multicellular tumor spheroid (MCTS offers a more rational platform to predict in vivo drug efficacy and toxicity. Nevertheless, traditional processing methods such as plastic dish culture with nonadhesive surfaces are regularly time-consuming, laborious and difficult to provide uniform-sized spheroids, thus causing poor reproducibility of experimental data and impeding high-throughput drug screening. In order to provide a robust and effective platform for in vitro drug evaluation, we present an agarose scaffold prepared with the template containing uniform-sized micro-wells in commercially available cell culture plates. The agarose scaffold allows for good adjustment of MCTS size and large-scale production of MCTS. Transparent agarose scaffold also allows for monitoring of spheroid formation under an optical microscopy. The formation of MCTS from MCF-7 cells was prepared using different-size-well templates and systematically investigated in terms of spheroid growth curve, circularity, and cell viability. The doxorubicin cytotoxicity against MCF-7 spheroid and MCF-7 monolayer cells was compared. The drug penetration behavior, cell cycle distribution, cell apoptosis, and gene expression were also evaluated in MCF-7 spheroid. The findings of this study indicate that, compared with cellular monolayer, MCTS provides a valuable platform for the assessment of therapeutic candidates in an in vivo-mimic microenvironment, and thus has great potential for use in drug discovery and tumor biology research.

Down-regulation of DNA mismatch repair enhances initiation and growth of neuroblastoma and brain tumour multicellular spheroids.

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Samuel L Collins

Full Text Available Multicellular tumour spheroid (MCTS cultures are excellent model systems for simulating the development and microenvironmental conditions of in vivo tumour growth. Many documented cell lines can generate differentiated MCTS when cultured in suspension or in a non-adhesive environment. While physiological and biochemical properties of MCTS have been extensively characterized, insight into the events and conditions responsible for initiation of these structures is lacking. MCTS are formed by only a small subpopulation of cells during surface-associated growth but the processes responsible for this differentiation are poorly understood and have not been previously studied experimentally. Analysis of gene expression within spheroids has provided clues but to date it is not known if the observed differences are a cause or consequence of MCTS growth. One mechanism linked to tumourigenesis in a number of cancers is genetic instability arising from impaired DNA mismatch repair (MMR. This study aimed to determine the role of MMR in MCTS initiation and development. Using surface-associated N2a and CHLA-02-ATRT culture systems we have investigated the impact of impaired MMR on MCTS growth. Analysis of the DNA MMR genes MLH1 and PMS2 revealed both to be significantly down-regulated at the mRNA level compared with non-spheroid-forming cells. By using small interfering RNA (siRNA against these genes we show that silencing of MLH1 and PMS2 enhances both MCTS initiation and subsequent expansion. This effect was prolonged over several passages following siRNA transfection. Down-regulation of DNA MMR can contribute to tumour initiation and progression in N2a and CHLA-02-ATRT MCTS models. Studies of surface-associated MCTS differentiation may have broader applications in studying events in the initiation of cancer foci.

The phosphatomes of the multicellular myxobacteria Myxococcus xanthus and Sorangium cellulosum in comparison with other prokaryotic genomes.

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Anke Treuner-Lange

Full Text Available BACKGROUND: Analysis of the complete genomes from the multicellular myxobacteria Myxococcus xanthus and Sorangium cellulosum identified the highest number of eukaryotic-like protein kinases (ELKs compared to all other genomes analyzed. High numbers of protein phosphatases (PPs could therefore be anticipated, as reversible protein phosphorylation is a major regulation mechanism of fundamental biological processes. METHODOLOGY: Here we report an intensive analysis of the phosphatomes of M. xanthus and S. cellulosum in which we constructed phylogenetic trees to position these sequences relative to PPs from other prokaryotic organisms. PRINCIPAL FINDINGS: PREDOMINANT OBSERVATIONS WERE: (i M. xanthus and S. cellulosum possess predominantly Ser/Thr PPs; (ii S. cellulosum encodes the highest number of PP2c-type phosphatases so far reported for a prokaryotic organism; (iii in contrast to M. xanthus only S. cellulosum encodes high numbers of SpoIIE-like PPs; (iv there is a significant lack of synteny among M. xanthus and S. cellulosum, and (v the degree of co-organization between kinase and phosphatase genes is extremely low in these myxobacterial genomes. CONCLUSIONS: We conclude that there has been a greater expansion of ELKs than PPs in multicellular myxobacteria.

Small regulatory RNAs control the multi-cellular adhesive lifestyle of Escherichia coli

DEFF Research Database (Denmark)

Jørgensen, Mikkel Girke; Nielsen, Jesper Sejrup; Boysen, Anders

2012-01-01

Small regulatory RNA molecules have recently been recognized as important regulatory elements of developmental processes in both eukaryotes and bacteria. We here describe a striking example in Escherichia coli that can switch between a single-cell motile lifestyle and a multi-cellular, sessile....... Our demonstration that basal expression of each of the three RNA species is sufficient to downregulate CsgD synthesis and prevent curli formation indicates that all play a prominent role in the curli regulatory network. Our findings provide the first clue as to how the Rcs signalling pathway...... negatively regulates curli synthesis and increase the number of small regulatory RNAs that act directly on the csgD mRNA to five....

Apoptosis, energy metabolism, and fraction of radiobiologically hypoxic cells: a study of human melanoma multicellular spheroids.

Science.gov (United States)

Rofstad, E K; Eide, K; Skøyum, R; Hystad, M E; Lyng, H

1996-09-01

The magnitude of the fraction of radiobiologically hypoxic cells in tumours is generally believed to reflect the efficiency of the vascular network. Theoretical studies have suggested that the hypoxic fraction might also be influenced by biological properties of the tumour cells. Quantitative experimental results of cell energy metabolism, hypoxia- induced apoptosis, and radiobiological hypoxia are reported here. Human melanoma multicellular spheroids (BEX-c and WIX-c) were used as tumour models to avoid confounding effects of the vascular network. Radiobiological studies showed that the fractions of hypoxic cells in 1000-microM spheroids were 32 +/- 12% (BEX-c) and 2.5 +/- 1.1% (WIX-c). The spheroid hypoxic volume fractions (28 +/- 6% (BEX-c) and 1.4 +/- 7% (WIX-c)), calculated from the rate of oxygen consumption per cell, the cell packing density, and the thickness of the viable rim, were similar to the fractions of radiobiologically hypoxic cells. Large differences between tumours in fraction of hypoxic cells are therefore not necessarily a result of differences in the efficiency of the vascular network. Studies of monolayer cell cultures, performed to identify the biological properties of the BEX-c and WIX-c cells leading to this large difference in fraction of hypoxic cells, gave the following results: (1) WIX-c showed lower cell surviving fractions after exposure to hypoxia than BEX-c, (2) WIX-c showed higher glucose uptake and lactate release rates than BEX-c both under aerobic and hypoxic conditions, and (3) hypoxia induced apoptosis in WIX-c but not in BEX-c. These observations suggested that the difference between BEX-c and WIX-c spheroids in fraction of hypoxic cells resulted partly from differences in cell energy metabolism and partly from a difference in capacity to retain viability under hypoxic stress. The induction of apoptosis by hypoxia was identified as a phenomenon which has an important influence on the magnitude of the fraction of

Inter-specific coral chimerism: Genetically distinct multicellular structures associated with tissue loss in Montipora capitata

Science.gov (United States)

Work, Thierry M.; Forsman, Zac H.; Szabo, Zoltan; Lewis, Teresa D.; Aeby, Greta S.; Toonen, Robert J.

2011-01-01

Montipora white syndrome (MWS) results in tissue-loss that is often lethal to Montipora capitata, a major reef building coral that is abundant and dominant in the Hawai'ian Archipelago. Within some MWS-affected colonies in Kane'ohe Bay, Oahu, Hawai'i, we saw unusual motile multicellular structures within gastrovascular canals (hereafter referred to as invasive gastrovascular multicellular structure-IGMS) that were associated with thinning and fragmentation of the basal body wall. IGMS were in significantly greater densities in coral fragments manifesting tissue-loss compared to paired normal fragments. Mesenterial filaments from these colonies yielded typical M. capitata mitochondrial haplotypes (CO1, CR), while IGMS from the same colony consistently yielded distinct haplotypes previously only found in a different Montipora species (Montipora flabellata). Protein profiles showed consistent differences between paired mesenterial filaments and IGMS from the same colonies as did seven microsatellite loci that also exhibited an excess of alleles per locus inconsistent with a single diploid organism. We hypothesize that IGMS are a parasitic cellular lineage resulting from the chimeric fusion between M. capitata and M. flabellata larvae followed by morphological reabsorption of M. flabellata and subsequent formation of cell-lineage parasites. We term this disease Montiporaiasis. Although intra-specific chimerism is common in colonial animals, this is the first suspected inter-specific example and the first associated with tissue loss.

Cell shedding from X-irradiated multicellular spheroids of human lung carcinomas

International Nuclear Information System (INIS)

Sakata, K.; Okada, S.; Suzuki, N.; Majima, H.

1991-01-01

We studied the effect of radiation on cell shedding from the surface of multicellular spheroids. Spheroids were produced from two human lung cell lines, one adenocarcinoma (LCT1) and the other small cell carcinoma (LCT2), by using a liquid overlay culture technique. The number of cells shed from both kinds of spheroids did not change significantly when they were irradiated. The number of clonogenic cells shed from both kinds of irradiated spheroids decreased sharply as the dose of irradiation increases. There were no significant differences in clonogenic cell shedding per spheroid between LCT1 and LCT2 spheroids. 400 μm spheroids were more radioresistant to inhibition of clonogenic cell shedding than 250 μm spheroids. Shed cells were more radiosensitive than speroid cells. In these experiments, we did not obtain any results indicating that radiation enchances metastasis. (orig.) [de

Involvement of bacterial migration in the development of complex multicellular structures in Pseudomonas aeruginosa biofilms

DEFF Research Database (Denmark)

Klausen, Mikkel; Aaes-Jorgensen, A.; Molin, Søren

2003-01-01

development, we have performed an investigation with time-lapse confocal laser scanning microscopy of biofilms formed by various combinations of colour-coded P. aeruginosa wild type and motility mutants. We show that mushroom-shaped multicellular structures in P. aeruginosa biofilms can form in a sequential...... process involving a non-motile bacterial subpopulation and a migrating bacterial subpopulation. The non-motile bacteria form the mushroom stalks by growth in certain foci of the biofilm. The migrating bacteria form the mushroom caps by climbing the stalks and aggregating on the tops in a process which...

Implementation of Complex Biological Logic Circuits Using Spatially Distributed Multicellular Consortia

Science.gov (United States)

Urrios, Arturo; de Nadal, Eulàlia; Solé, Ricard; Posas, Francesc

2016-01-01

Engineered synthetic biological devices have been designed to perform a variety of functions from sensing molecules and bioremediation to energy production and biomedicine. Notwithstanding, a major limitation of in vivo circuit implementation is the constraint associated to the use of standard methodologies for circuit design. Thus, future success of these devices depends on obtaining circuits with scalable complexity and reusable parts. Here we show how to build complex computational devices using multicellular consortia and space as key computational elements. This spatial modular design grants scalability since its general architecture is independent of the circuit’s complexity, minimizes wiring requirements and allows component reusability with minimal genetic engineering. The potential use of this approach is demonstrated by implementation of complex logical functions with up to six inputs, thus demonstrating the scalability and flexibility of this method. The potential implications of our results are outlined. PMID:26829588

Computational Genetic Regulatory Networks Evolvable, Self-organizing Systems

CERN Document Server

Knabe, Johannes F

2013-01-01

Genetic Regulatory Networks (GRNs) in biological organisms are primary engines for cells to enact their engagements with environments, via incessant, continually active coupling. In differentiated multicellular organisms, tremendous complexity has arisen in the course of evolution of life on earth. Engineering and science have so far achieved no working system that can compare with this complexity, depth and scope of organization. Abstracting the dynamics of genetic regulatory control to a computational framework in which artificial GRNs in artificial simulated cells differentiate while connected in a changing topology, it is possible to apply Darwinian evolution in silico to study the capacity of such developmental/differentiated GRNs to evolve. In this volume an evolutionary GRN paradigm is investigated for its evolvability and robustness in models of biological clocks, in simple differentiated multicellularity, and in evolving artificial developing 'organisms' which grow and express an ontogeny starting fr...

Superparamagnetic iron oxide nanoparticles exert different cytotoxic effects on cells grown in monolayer cell culture versus as multicellular spheroids

Energy Technology Data Exchange (ETDEWEB)

Theumer, Anja; Gräfe, Christine; Bähring, Franziska [Department of Hematology and Oncology, Jena University Hospital, Erlanger Allee 101, 07747 Jena (Germany); Bergemann, Christian [Chemicell GmbH, Eresburgstrasse 22–23, 12103 Berlin (Germany); Hochhaus, Andreas [Department of Hematology and Oncology, Jena University Hospital, Erlanger Allee 101, 07747 Jena (Germany); Clement, Joachim H., E-mail: joachim.clement@med.uni-jena.de [Department of Hematology and Oncology, Jena University Hospital, Erlanger Allee 101, 07747 Jena (Germany)

2015-04-15

The aim of this study was to investigate the interaction of superparamagnetic iron oxide nanoparticles (SPION) with human blood–brain barrier-forming endothelial cells (HBMEC) in two-dimensional cell monolayers as well as in three-dimensional multicellular spheroids. The precise nanoparticle localisation and the influence of the NP on the cellular viability and the intracellular Akt signalling were studied in detail. Long-term effects of different polymer-coated nanoparticles (neutral fluidMAG-D, anionic fluidMAG-CMX and cationic fluidMAG-PEI) and the corresponding free polymers on cellular viability of HBMEC were investigated by real time cell analysis studies. Nanoparticles exert distinct effects on HBMEC depending on the nanoparticles' surface charge and concentration, duration of incubation and cellular context. The most severe effects were caused by PEI-coated nanoparticles. Concentrations above 25 µg/ml led to increased amounts of dead cells in monolayer culture as well as in multicellular spheroids. On the level of intracellular signalling, context-dependent differences were observed. Monolayer cultures responded on nanoparticle incubation with an increase in Akt phosphorylation whereas spheroids on the whole show a decreased Akt activity. This might be due to the differential penetration and distribution of PEI-coated nanoparticles.

Using a 3-d model system to screen for drugs effective on solid tumors

OpenAIRE

Fayad, Walid

2011-01-01

There is a large medical need for the development of effective anticancer agents with minimal side effects. The present thesis represents an attempt to identify potent drugs for treatment of solid tumors. We used a strategy where 3-D multicellular tumor spheroids (cancer cells grown in three dimensional culture) were utilized as in vitro models for solid tumors. Drug libraries were screened using spheroids as targets and using apoptosis induction and loss of cell viability as endpoints. The h...

X-ray studies on a two-dimensional diffusion limited system for cell growth

International Nuclear Information System (INIS)

Hlatky, L.R.; Alpen, E.L.

1985-01-01

X-ray studies were performed on cells grown in a new type of in vitro multicellular system, the ''sandwich'' system. This system is a two-dimensional array of cells, sandwiched between transparent slides which are impermeable to oxygen. The cell system is subject to self-created diffusion gradients of nutrients, metabolic products and, most importantly, oxygen. Sandwiches are analogous to living cross sections of multicellular spheroids or of poorly vascularized tumors. They contain a necrotic center, which the authors show to be due to diffusion limitations, an intermediate region which has a large fraction of quiescent cells and a cycling outer rim. One advantage sandwiches have over three-dimensional tumor models (sheproids) is that can control the amount of cell to cell contact and thereby separate effects due to oxygen or other gradients from effects due to contact. The authors present x-ray survival curves for sandwiches of various cell densities and compare them to x-ray survival curves done for spheroids and monolayers of the same cell line

A Duo of Potassium-Responsive Histidine Kinases Govern the Multicellular Destiny of Bacillus subtilis

Science.gov (United States)

de Oña, Paula; Kunert, Maritta; Leñini, Cecilia; Gallegos-Monterrosa, Ramses; Mhatre, Eisha; Vileta, Darío; Hölscher, Theresa; Kuipers, Oscar P.

2015-01-01

ABSTRACT Multicellular biofilm formation and surface motility are bacterial behaviors considered mutually exclusive. However, the basic decision to move over or stay attached to a surface is poorly understood. Here, we discover that in Bacillus subtilis, the key root biofilm-controlling transcription factor Spo0A~Pi (phosphorylated Spo0A) governs the flagellum-independent mechanism of social sliding motility. A Spo0A-deficient strain was totally unable to slide and colonize plant roots, evidencing the important role that sliding might play in natural settings. Microarray experiments plus subsequent genetic characterization showed that the machineries of sliding and biofilm formation share the same main components (i.e., surfactin, the hydrophobin BslA, exopolysaccharide, and de novo-formed fatty acids). Sliding proficiency was transduced by the Spo0A-phosphorelay histidine kinases KinB and KinC. We discovered that potassium, a previously known inhibitor of KinC-dependent biofilm formation, is the specific sliding-activating signal through a thus-far-unnoticed cytosolic domain of KinB, which resembles the selectivity filter sequence of potassium channels. The differential expression of the Spo0A~Pi reporter abrB gene and the different levels of the constitutively active form of Spo0A, Sad67, in Δspo0A cells grown in optimized media that simultaneously stimulate motile and sessile behaviors uncover the spatiotemporal response of KinB and KinC to potassium and the gradual increase in Spo0A~Pi that orchestrates the sequential activation of sliding, followed by sessile biofilm formation and finally sporulation in the same population. Overall, these results provide insights into how multicellular behaviors formerly believed to be antagonistic are coordinately activated in benefit of the bacterium and its interaction with the host. PMID:26152584

BSim: an agent-based tool for modeling bacterial populations in systems and synthetic biology.

Directory of Open Access Journals (Sweden)

Thomas E Gorochowski

Full Text Available Large-scale collective behaviors such as synchronization and coordination spontaneously arise in many bacterial populations. With systems biology attempting to understand these phenomena, and synthetic biology opening up the possibility of engineering them for our own benefit, there is growing interest in how bacterial populations are best modeled. Here we introduce BSim, a highly flexible agent-based computational tool for analyzing the relationships between single-cell dynamics and population level features. BSim includes reference implementations of many bacterial traits to enable the quick development of new models partially built from existing ones. Unlike existing modeling tools, BSim fully considers spatial aspects of a model allowing for the description of intricate micro-scale structures, enabling the modeling of bacterial behavior in more realistic three-dimensional, complex environments. The new opportunities that BSim opens are illustrated through several diverse examples covering: spatial multicellular computing, modeling complex environments, population dynamics of the lac operon, and the synchronization of genetic oscillators. BSim is open source software that is freely available from http://bsim-bccs.sf.net and distributed under the Open Source Initiative (OSI recognized MIT license. Developer documentation and a wide range of example simulations are also available from the website. BSim requires Java version 1.6 or higher.

Establishment of a rearing system of the extremotolerant tardigrade Ramazzottius varieornatus: a new model animal for astrobiology.

Science.gov (United States)

Horikawa, Daiki D; Kunieda, Takekazu; Abe, Wataru; Watanabe, Masahiko; Nakahara, Yuichi; Yukuhiro, Fumiko; Sakashita, Tetsuya; Hamada, Nobuyuki; Wada, Seiichi; Funayama, Tomoo; Katagiri, Chihiro; Kobayashi, Yasuhiko; Higashi, Seigo; Okuda, Takashi

2008-06-01

Studies on the ability of multicellular organisms to tolerate specific environmental extremes are relatively rare compared to those of unicellular microorganisms in extreme environments. Tardigrades are extremotolerant animals that can enter an ametabolic dry state called anhydrobiosis and have high tolerance to a variety of extreme environmental conditions, particularly while in anhydrobiosis. Although tardigrades have been expected to be a potential model animal for astrobiological studies due to their excellent anhydrobiotic and extremotolerant abilities, few studies of tolerance with cultured tardigrades have been reported, possibly due to the absence of a model species that can be easily maintained under rearing conditions. We report the successful rearing of the herbivorous tardigrade, Ramazzottius varieornatus, by supplying the green alga Chlorella vulgaris as food. The life span was 35 +/- 16.4 d, deposited eggs required 5.7 +/- 1.1 d to hatch, and animals began to deposit eggs 9 d after hatching. The reared individuals of this species had an anhydrobiotic capacity throughout their life cycle in egg, juvenile, and adult stages. Furthermore, the reared adults in an anhydrobiotic state were tolerant of temperatures of 90 degrees C and -196 degrees C, and exposure to 99.8% acetonitrile or irradiation with 4000 Gy (4)He ions. Based on their life history traits and tolerance to extreme stresses, R. varieornatus may be a suitable model for astrobiological studies of multicellular organisms.

Spherical Cancer Models in Tumor Biology

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Louis-Bastien Weiswald

2015-01-01

Full Text Available Three-dimensional (3D in vitro models have been used in cancer research as an intermediate model between in vitro cancer cell line cultures and in vivo tumor. Spherical cancer models represent major 3D in vitro models that have been described over the past 4 decades. These models have gained popularity in cancer stem cell research using tumorospheres. Thus, it is crucial to define and clarify the different spherical cancer models thus far described. Here, we focus on in vitro multicellular spheres used in cancer research. All these spherelike structures are characterized by their well-rounded shape, the presence of cancer cells, and their capacity to be maintained as free-floating cultures. We propose a rational classification of the four most commonly used spherical cancer models in cancer research based on culture methods for obtaining them and on subsequent differences in sphere biology: the multicellular tumor spheroid model, first described in the early 70s and obtained by culture of cancer cell lines under nonadherent conditions; tumorospheres, a model of cancer stem cell expansion established in a serum-free medium supplemented with growth factors; tissue-derived tumor spheres and organotypic multicellular spheroids, obtained by tumor tissue mechanical dissociation and cutting. In addition, we describe their applications to and interest in cancer research; in particular, we describe their contribution to chemoresistance, radioresistance, tumorigenicity, and invasion and migration studies. Although these models share a common 3D conformation, each displays its own intrinsic properties. Therefore, the most relevant spherical cancer model must be carefully selected, as a function of the study aim and cancer type.

Doxorubicin delivery to 3D multicellular spheroids and tumors based on boronic acid-rich chitosan nanoparticles.

Science.gov (United States)

Wang, Xin; Zhen, Xu; Wang, Jing; Zhang, Jialiang; Wu, Wei; Jiang, Xiqun

2013-06-01

Boronic acid-rich chitosan-poly(N-3-acrylamidophenylboronic acid) nanoparticles (CS-PAPBA NPs) with the tunable size were successfully prepared by polymerizing N-3-acrylamidophenylboronic acid in the presence of chitosan in an aqueous solution. The CS-PAPBA NPs were then functionalized by a tumor-penetrating peptide iRGD and loading doxorubicin (DOX). The interaction between boronic acid groups of hydrophobic PAPBA and the amino groups of hydrophilic chitosan inside the nanoparticles was examined by solid-state NMR measurement. The size and morphology of nanoparticles were characterized by dynamic light scattering and electron microscopy. The cellular uptake, tumor penetration, biodistribution and antitumor activity of the nanoparticles were evaluated by using three-dimensional (3-D) multicellular spheroids (MCs) as the in vitro model and H22 tumor-bearing mice as the in vivo model. It was found that the iRGD-conjugated nanoparticles significantly improved the efficiency of DOX penetration in MCs, compared with free DOX and non-conjugated nanoparticles, resulting in the efficient cell killing in the MCs. In vivo antitumor activity examination indicated that iRGD-conjugated CS-PAPBA nanoparticles promoted the accumulation of nanoparticles in tumor tissue and enhanced their penetration in tumor areas, both of which improved the efficiency of DOX-loaded nanoparticles in restraining tumor growth and prolonging the life time of H22 tumor-bearing mice. Copyright © 2013 Elsevier Ltd. All rights reserved.

Hypofractionated radiation induces a decrease in cell proliferation but no histological damage to organotypic multicellular spheroids of human glioblastomas

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Kaaijk, P.; Academic Medical Center, Amsterdam; Troost, D.; Leenstra, S.; Bosch, D.A.; Sminia, P.; Hulshof, M.C.C.M..; Kracht, A.H.W. van der

1997-01-01

The aim of this study was to examine the effect of radiation on glioblastoma, using an organotypic multicellular spheroid (OMS) model. Most glioblastoma cell lines are, in contrast to glioblastomas in vivo, relatively radiosensitive. This limits the value of using cell lines for studying the radiation effect of glioblastomas. The advantage of OMS is maintenance of the characteristics of the original tumour, which is lost in conventional cell cultures. OMS prepared from four glioblastomas were treated with hypofractionated radiation with a radiobiologically equivalent dose to standard radiation treatment for glioblastomas patients. After treatment, the histology as well as the cell proliferation of the OMS was examined. After radiation, a significant decrease in cell proliferation was found, although no histological damage to the OMS was observed. The modest effects of radiation on the OMS are in agreement with the limited therapeutic value of radiotherapy for glioblastoma patients. Therefore, OMS seems to be a good alternative for cell lines to study the radiobiological effect on glioblastomas. (author)

Hypofractionated radiation induces a decrease in cell proliferation but no histological damage to organotypic multicellular spheroids of human glioblastomas

Energy Technology Data Exchange (ETDEWEB)

Kaaijk, P [Academic Medical Center, Amsterdam (Netherlands). Dept. of (Neuro) Pathology; [Academic Medical Center, Amsterdam (Netherlands). Dept. of Neurosurgery; Troost, D [Academic Medical Center, Amsterdam (Netherlands). Dept. of (Neuro) Pathology; Leenstra, S; Bosch, D A [Academic Medical Center, Amsterdam (Netherlands). Dept. of Neurosurgery; Sminia, P; Hulshof, M C.C.M.; Kracht, A.H.W. van der [Academic Medical Center, Amsterdam (Netherlands). Dept. of (Experimental) Radiotherapy

1997-04-01

The aim of this study was to examine the effect of radiation on glioblastoma, using an organotypic multicellular spheroid (OMS) model. Most glioblastoma cell lines are, in contrast to glioblastomas in vivo, relatively radiosensitive. This limits the value of using cell lines for studying the radiation effect of glioblastomas. The advantage of OMS is maintenance of the characteristics of the original tumour, which is lost in conventional cell cultures. OMS prepared from four glioblastomas were treated with hypofractionated radiation with a radiobiologically equivalent dose to standard radiation treatment for glioblastomas patients. After treatment, the histology as well as the cell proliferation of the OMS was examined. After radiation, a significant decrease in cell proliferation was found, although no histological damage to the OMS was observed. The modest effects of radiation on the OMS are in agreement with the limited therapeutic value of radiotherapy for glioblastoma patients. Therefore, OMS seems to be a good alternative for cell lines to study the radiobiological effect on glioblastomas. (author).

The female gametophyte: an emerging model for cell type-specific systems biology in plant development

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Marc William Schmid

2015-11-01

Full Text Available Systems biology, a holistic approach describing a system emerging from the interactions of its molecular components, critically depends on accurate qualitative determination and quantitative measurements of these components. Development and improvement of large-scale profiling methods (omics now facilitates comprehensive measurements of many relevant molecules. For multicellular organisms, such as animals, fungi, algae, and plants, the complexity of the system is augmented by the presence of specialized cell types and organs, and a complex interplay within and between them. Cell type-specific analyses are therefore crucial for the understanding of developmental processes and environmental responses. This review first gives an overview of current methods used for large-scale profiling of specific cell types exemplified by recent advances in plant biology. The focus then lies on suitable model systems to study plant development and cell type specification. We introduce the female gametophyte of flowering plants as an ideal model to study fundamental developmental processes. Moreover, the female reproductive lineage is of importance for the emergence of evolutionary novelties such as an unequal parental contribution to the tissue nurturing the embryo or the clonal production of seeds by asexual reproduction (apomixis. Understanding these processes is not only interesting from a developmental or evolutionary perspective, but bears great potential for further crop improvement and the simplification of breeding efforts. We finally highlight novel methods, which are already available or which will likely soon facilitate large-scale profiling of the specific cell types of the female gametophyte in both model and non-model species. We conclude that it may take only few years until an evolutionary systems biology approach toward female gametogenesis may decipher some of its biologically most interesting and economically most valuable processes.

Respiration control of multicellularity in Bacillus subtilis by a complex of the cytochrome chain with a membrane-embedded histidine kinase

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Kolodkin-Gal, I; Elsholz, AKW; Muth, C; Girguis, PR; Kolter, R; Losick, R

2013-04-29

Bacillus subtilis forms organized multicellular communities known as biofilms wherein the individual cells are held together by a self-produced extracellular matrix. The environmental signals that promote matrix synthesis remain largely unknown. We discovered that one such signal is impaired respiration. Specifically, high oxygen levels suppressed synthesis of the extracellular matrix. In contrast, low oxygen levels, in the absence of an alternative electron acceptor, led to increased matrix production. The response to impaired respiration was blocked in a mutant lacking cytochromes caa(3) and bc and markedly reduced in a mutant lacking kinase KinB. Mass spectrometry of proteins associated with KinB showed that the kinase was in a complex with multiple components of the aerobic respiratory chain. We propose that KinB is activated via a redox switch involving interaction of its second transmembrane segment with one or more cytochromes under conditions of reduced electron transport. In addition, a second kinase (KinA) contributes to the response to impaired respiration. Evidence suggests that KinA is activated by a decrease in the nicotinamide adenine dinucleotide (NAD(+))/NADH ratio via binding of NAD(+) to the kinase in a PAS domain A-dependent manner. Thus, B. subtilis switches from a unicellular to a multicellular state by two pathways that independently respond to conditions of impaired respiration.

Respiration control of multicellularity in Bacillus subtilis by a complex of the cytochrome chain with a membrane-embedded histidine kinase

Science.gov (United States)

Kolodkin-Gal, Ilana; Elsholz, Alexander K.W.; Muth, Christine; Girguis, Peter R.; Kolter, Roberto; Losick, Richard

2013-01-01

Bacillus subtilis forms organized multicellular communities known as biofilms wherein the individual cells are held together by a self-produced extracellular matrix. The environmental signals that promote matrix synthesis remain largely unknown. We discovered that one such signal is impaired respiration. Specifically, high oxygen levels suppressed synthesis of the extracellular matrix. In contrast, low oxygen levels, in the absence of an alternative electron acceptor, led to increased matrix production. The response to impaired respiration was blocked in a mutant lacking cytochromes caa3 and bc and markedly reduced in a mutant lacking kinase KinB. Mass spectrometry of proteins associated with KinB showed that the kinase was in a complex with multiple components of the aerobic respiratory chain. We propose that KinB is activated via a redox switch involving interaction of its second transmembrane segment with one or more cytochromes under conditions of reduced electron transport. In addition, a second kinase (KinA) contributes to the response to impaired respiration. Evidence suggests that KinA is activated by a decrease in the nicotinamide adenine dinucleotide (NAD+)/NADH ratio via binding of NAD+ to the kinase in a PAS domain A-dependent manner. Thus, B. subtilis switches from a unicellular to a multicellular state by two pathways that independently respond to conditions of impaired respiration. PMID:23599347

Image acquisition and planimetry systems to develop wounding techniques in 3D wound model

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Kiefer Ann-Kathrin

2017-09-01

Full Text Available Wound healing represents a complex biological repair process. Established 2D monolayers and wounding techniques investigate cell migration, but do not represent coordinated multi-cellular systems. We aim to use wound surface area measurements obtained from image acquisition and planimetry systems to establish our wounding technique and in vitro organotypic tissue. These systems will be used in our future wound healing treatment studies to assess the rate of wound closure in response to wound healing treatment with light therapy (photobiomodulation. The image acquisition and planimetry systems were developed, calibrated, and verified to measure wound surface area in vitro. The system consists of a recording system (Sony DSC HX60, 20.4 M Pixel, 1/2.3″ CMOS sensor and calibrated with 1mm scale paper. Macro photography with an optical zoom magnification of 2:1 achieves sufficient resolution to evaluate the 3mm wound size and healing growth. The camera system was leveled with an aluminum construction to ensure constant distance and orientation of the images. The JPG-format images were processed with a planimetry system in MATLAB. Edge detection enables definition of the wounded area. Wound area can be calculated with surface integrals. To separate the wounded area from the background, the image was filtered in several steps. Agar models, injured through several test persons with different levels of experience, were used as pilot data to test the planimetry software. These image acquisition and planimetry systems support the development of our wound healing research. The reproducibility of our wounding technique can be assessed by the variability in initial wound surface area. Also, wound healing treatment effects can be assessed by the change in rate of wound closure. These techniques represent the foundations of our wound model, wounding technique, and analysis systems in our ongoing studies in wound healing and therapy.

Oxygenation and response to irradiation of organotypic multicellular spheroids of human glioma.

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Sminia, Peter; Acker, Helmut; Eikesdal, Hans Petter; Kaaijk, Patricia; Enger, Per øvind; Slotman, Ben; Bjerkvig, Rolf

2003-01-01

Investigation of the oxygenation status of organotypic multicellular spheroids (OMS) and their response to irradiation. Tumour specimens of glioblastoma multiforme patients (n = 16) were initiated as OMS. Following 20 Gy gamma-irradiation, the cell migratory capacity was evaluated. Spheroid oxygenation was determined by micro-electrode pO2 measurements and pimonidazole immunostaining. Spheroids prepared from established human glioma cell lines were used as a reference. Irradiation inhibited spheroid outgrowth by 12 to 88% relative to the non-irradiated controls. A large interpatient variation was noticed. Oxygen measurements revealed a gradual decrease in pO2 level from the periphery to the core of the spheroids, but the pO2 values remained within an oxygenated range. However, in the cell line spheroids an intermediate layer of hypoxia surrounding the central core was observed. Cell line spheroids with a hypoxic cell fraction and well-oxygenated OMS both show high resistance to irradiation, indicating that hypoxia may not be the biological factor determining the radioresistance of glioma spheroids in vitro.

Inferring Growth Control Mechanisms in Growing Multi-cellular Spheroids of NSCLC Cells from Spatial-Temporal Image Data.

Science.gov (United States)

Jagiella, Nick; Müller, Benedikt; Müller, Margareta; Vignon-Clementel, Irene E; Drasdo, Dirk

2016-02-01

We develop a quantitative single cell-based mathematical model for multi-cellular tumor spheroids (MCTS) of SK-MES-1 cells, a non-small cell lung cancer (NSCLC) cell line, growing under various nutrient conditions: we confront the simulations performed with this model with data on the growth kinetics and spatial labeling patterns for cell proliferation, extracellular matrix (ECM), cell distribution and cell death. We start with a simple model capturing part of the experimental observations. We then show, by performing a sensitivity analysis at each development stage of the model that its complexity needs to be stepwise increased to account for further experimental growth conditions. We thus ultimately arrive at a model that mimics the MCTS growth under multiple conditions to a great extent. Interestingly, the final model, is a minimal model capable of explaining all data simultaneously in the sense, that the number of mechanisms it contains is sufficient to explain the data and missing out any of its mechanisms did not permit fit between all data and the model within physiological parameter ranges. Nevertheless, compared to earlier models it is quite complex i.e., it includes a wide range of mechanisms discussed in biological literature. In this model, the cells lacking oxygen switch from aerobe to anaerobe glycolysis and produce lactate. Too high concentrations of lactate or too low concentrations of ATP promote cell death. Only if the extracellular matrix density overcomes a certain threshold, cells are able to enter the cell cycle. Dying cells produce a diffusive growth inhibitor. Missing out the spatial information would not permit to infer the mechanisms at work. Our findings suggest that this iterative data integration together with intermediate model sensitivity analysis at each model development stage, provide a promising strategy to infer predictive yet minimal (in the above sense) quantitative models of tumor growth, as prospectively of other tissue

A molecular timescale of eukaryote evolution and the rise of complex multicellular life

Science.gov (United States)

Hedges, S. Blair; Blair, Jaime E.; Venturi, Maria L.; Shoe, Jason L.

2004-01-01

BACKGROUND: The pattern and timing of the rise in complex multicellular life during Earth's history has not been established. Great disparity persists between the pattern suggested by the fossil record and that estimated by molecular clocks, especially for plants, animals, fungi, and the deepest branches of the eukaryote tree. Here, we used all available protein sequence data and molecular clock methods to place constraints on the increase in complexity through time. RESULTS: Our phylogenetic analyses revealed that (i) animals are more closely related to fungi than to plants, (ii) red algae are closer to plants than to animals or fungi, (iii) choanoflagellates are closer to animals than to fungi or plants, (iv) diplomonads, euglenozoans, and alveolates each are basal to plants+animals+fungi, and (v) diplomonads are basal to other eukaryotes (including alveolates and euglenozoans). Divergence times were estimated from global and local clock methods using 20-188 proteins per node, with data treated separately (multigene) and concatenated (supergene). Different time estimation methods yielded similar results (within 5%): vertebrate-arthropod (964 million years ago, Ma), Cnidaria-Bilateria (1,298 Ma), Porifera-Eumetozoa (1,351 Ma), Pyrenomycetes-Plectomycetes (551 Ma), Candida-Saccharomyces (723 Ma), Hemiascomycetes-filamentous Ascomycota (982 Ma), Basidiomycota-Ascomycota (968 Ma), Mucorales-Basidiomycota (947 Ma), Fungi-Animalia (1,513 Ma), mosses-vascular plants (707 Ma), Chlorophyta-Tracheophyta (968 Ma), Rhodophyta-Chlorophyta+Embryophyta (1,428 Ma), Plantae-Animalia (1,609 Ma), Alveolata-plants+animals+fungi (1,973 Ma), Euglenozoa-plants+animals+fungi (1,961 Ma), and Giardia-plants+animals+fungi (2,309 Ma). By extrapolation, mitochondria arose approximately 2300-1800 Ma and plastids arose 1600-1500 Ma. Estimates of the maximum number of cell types of common ancestors, combined with divergence times, showed an increase from two cell types at 2500 Ma to

A molecular timescale of eukaryote evolution and the rise of complex multicellular life

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Venturi Maria L

2004-01-01

Full Text Available Abstract Background The pattern and timing of the rise in complex multicellular life during Earth's history has not been established. Great disparity persists between the pattern suggested by the fossil record and that estimated by molecular clocks, especially for plants, animals, fungi, and the deepest branches of the eukaryote tree. Here, we used all available protein sequence data and molecular clock methods to place constraints on the increase in complexity through time. Results Our phylogenetic analyses revealed that (i animals are more closely related to fungi than to plants, (ii red algae are closer to plants than to animals or fungi, (iii choanoflagellates are closer to animals than to fungi or plants, (iv diplomonads, euglenozoans, and alveolates each are basal to plants+animals+fungi, and (v diplomonads are basal to other eukaryotes (including alveolates and euglenozoans. Divergence times were estimated from global and local clock methods using 20–188 proteins per node, with data treated separately (multigene and concatenated (supergene. Different time estimation methods yielded similar results (within 5%: vertebrate-arthropod (964 million years ago, Ma, Cnidaria-Bilateria (1,298 Ma, Porifera-Eumetozoa (1,351 Ma, Pyrenomycetes-Plectomycetes (551 Ma, Candida-Saccharomyces (723 Ma, Hemiascomycetes-filamentous Ascomycota (982 Ma, Basidiomycota-Ascomycota (968 Ma, Mucorales-Basidiomycota (947 Ma, Fungi-Animalia (1,513 Ma, mosses-vascular plants (707 Ma, Chlorophyta-Tracheophyta (968 Ma, Rhodophyta-Chlorophyta+Embryophyta (1,428 Ma, Plantae-Animalia (1,609 Ma, Alveolata-plants+animals+fungi (1,973 Ma, Euglenozoa-plants+animals+fungi (1,961 Ma, and Giardia-plants+animals+fungi (2,309 Ma. By extrapolation, mitochondria arose approximately 2300-1800 Ma and plastids arose 1600-1500 Ma. Estimates of the maximum number of cell types of common ancestors, combined with divergence times, showed an increase from two cell types at 2500 Ma to ~10

Modeling drug- and chemical- induced hepatotoxicity with systems biology approaches

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Sudin eBhattacharya

2012-12-01

Full Text Available We provide an overview of computational systems biology approaches as applied to the study of chemical- and drug-induced toxicity. The concept of ‘toxicity pathways’ is described in the context of the 2007 US National Academies of Science report, Toxicity testing in the 21st Century: A Vision and A Strategy. Pathway mapping and modeling based on network biology concepts are a key component of the vision laid out in this report for a more biologically-based analysis of dose-response behavior and the safety of chemicals and drugs. We focus on toxicity of the liver (hepatotoxicity – a complex phenotypic response with contributions from a number of different cell types and biological processes. We describe three case studies of complementary multi-scale computational modeling approaches to understand perturbation of toxicity pathways in the human liver as a result of exposure to environmental contaminants and specific drugs. One approach involves development of a spatial, multicellular virtual tissue model of the liver lobule that combines molecular circuits in individual hepatocytes with cell-cell interactions and blood-mediated transport of toxicants through hepatic sinusoids, to enable quantitative, mechanistic prediction of hepatic dose-response for activation of the AhR toxicity pathway. Simultaneously, methods are being developing to extract quantitative maps of intracellular signaling and transcriptional regulatory networks perturbed by environmental contaminants, using a combination of gene expression and genome-wide protein-DNA interaction data. A predictive physiological model (DILIsymTM to understand drug-induced liver injury (DILI, the most common adverse event leading to termination of clinical development programs and regulatory actions on drugs, is also described. The model initially focuses on reactive metabolite-induced DILI in response to administration of acetaminophen, and spans multiple biological scales.

Short and long time effects of low temperature Plasma Activated Media on 3D multicellular tumor spheroids

Science.gov (United States)

Judée, Florian; Fongia, Céline; Ducommun, Bernard; Yousfi, Mohammed; Lobjois, Valérie; Merbahi, Nofel

2016-02-01

This work investigates the regionalized antiproliferative effects of plasma-activated medium (PAM) on colon adenocarcinoma multicellular tumor spheroid (MCTS), a model that mimics 3D organization and regionalization of a microtumor region. PAM was generated by dielectric barrier plasma jet setup crossed by helium carrier gas. MCTS were transferred in PAM at various times after plasma exposure up to 48 hours and effect on MCTS growth and DNA damage were evaluated. We report the impact of plasma exposure duration and delay before transfer on MCTS growth and DNA damage. Local accumulation of DNA damage revealed by histone H2AX phosphorylation is observed on outermost layers and is dependent on plasma exposure. DNA damage is completely reverted by catalase addition indicating that H2O2 plays major role in observed genotoxic effect while growth inhibitory effect is maintained suggesting that it is due to others reactive species. SOD and D-mannitol scavengers also reduced DNA damage by 30% indicating that and OH* are involved in H2O2 formation. Finally, PAM is able to retain its cytotoxic and genotoxic activity upon storage at +4 °C or -80 °C. These results suggest that plasma activated media may be a promising new antitumor strategy for colorectal cancer tumors.

An integrated in vitro imaging platform for characterizing filarial parasite behavior within a multicellular microenvironment.

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Timothy Kassis

2014-11-01

Full Text Available Lymphatic Filariasis, a Neglected Tropical Disease, is caused by thread-like parasitic worms, including B. malayi, which migrate to the human lymphatic system following transmission. The parasites reside in collecting lymphatic vessels and lymph nodes for years, often resulting in lymphedema, elephantiasis or hydrocele. The mechanisms driving worm migration and retention within the lymphatics are currently unknown. We have developed an integrated in vitro imaging platform capable of quantifying B. malayi migration and behavior in a multicellular microenvironment relevant to the initial site of worm injection by incorporating the worm in a Polydimethylsiloxane (PDMS microchannel in the presence of human dermal lymphatic endothelial cells (LECs and human dermal fibroblasts (HDFs. The platform utilizes a motorized controllable microscope with CO2 and temperature regulation to allow for worm tracking experiments with high resolution over large length and time scales. Using post-acquisition algorithms, we quantified four parameters: 1 speed, 2 thrashing intensity, 3 percentage of time spent in a given cell region and 4 persistence ratio. We demonstrated the utility of our system by quantifying these parameters for L3 B. malayi in the presence of LECs and HDFs. Speed and thrashing increased in the presence of both cell types and were altered within minutes upon exposure to the anthelmintic drug, tetramisole. The worms displayed no targeted migration towards either cell type for the time course of this study (3 hours. When cells were not present in the chamber, worm thrashing correlated directly with worm speed. However, this correlation was lost in the presence of cells. The described platform provides the ability to further study B. malayi migration and behavior.

A microfluidic chip with a U-shaped microstructure array for multicellular spheroid formation, culturing and analysis

International Nuclear Information System (INIS)

Fu, Chien-Yu; Chang, Hwan-You; Tseng, Sheng-Yang; Yang, Shih-Mo; Hsu, Long; Liu, Cheng-Hsien

2014-01-01

Multicellular spheroids (MCS), formed by self-assembly of single cells, are commonly used as a three-dimensional cell culture model to bridge the gap between in vitro monolayer culture and in vivo tissues. However, current methods for MCS generation and analysis still suffer drawbacks such as being labor-intensive and of poor controllability, and are not suitable for high-throughput applications. This study demonstrates a novel microfluidic chip to facilitate MCS formation, culturing and analysis. The chip contains an array of U-shaped microstructures fabricated by photopolymerizing the poly(ethylene glycol) diacrylate hydrogel through defining the ultraviolet light exposure pattern with a photomask. The geometry of the U-shaped microstructures allowed trapping cells into the pocket through the actions of fluid flow and the force of gravity. The hydrogel is non-adherent for cells, promoting the formation of MCS. Its permselective property also facilitates exchange of nutrients and waste for MCS, while providing protection of MCS from shearing stress during the medium perfusion. Heterotypic MCS can be formed easily by manipulating the cell trapping steps. Subsequent drug susceptibility analysis and long-term culture could also be achieved within the same chip. This MCS formation and culture platform can be used as a micro-scale bioreactor and applied in many cell biology and drug testing studies. (paper)

Recombination every day: abundant recombination in a virus during a single multi-cellular host infection.

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Remy Froissart

2005-03-01

Full Text Available Viral recombination can dramatically impact evolution and epidemiology. In viruses, the recombination rate depends on the frequency of genetic exchange between different viral genomes within an infected host cell and on the frequency at which such co-infections occur. While the recombination rate has been recently evaluated in experimentally co-infected cell cultures for several viruses, direct quantification at the most biologically significant level, that of a host infection, is still lacking. This study fills this gap using the cauliflower mosaic virus as a model. We distributed four neutral markers along the viral genome, and co-inoculated host plants with marker-containing and wild-type viruses. The frequency of recombinant genomes was evaluated 21 d post-inoculation. On average, over 50% of viral genomes recovered after a single host infection were recombinants, clearly indicating that recombination is very frequent in this virus. Estimates of the recombination rate show that all regions of the genome are equally affected by this process. Assuming that ten viral replication cycles occurred during our experiment-based on data on the timing of coat protein detection-the per base and replication cycle recombination rate was on the order of 2 x 10(-5 to 4 x 10(-5. This first determination of a virus recombination rate during a single multi-cellular host infection indicates that recombination is very frequent in the everyday life of this virus.

Spreading Sequence Design for Multiple Cell Synchronous DS-CDMA Systems under Total Weighted Squared Correlation Criterion

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Cotae Paul

2004-01-01

Full Text Available An algorithm for designing spreading sequences for an overloaded multicellular synchronous DS-CDMA system on uplink is introduced. The criterion used to measure the optimality of the design is the total weighted square correlation (TWSC assuming the channel state information known perfectly at both transmitter and receiver. By using this algorithm it is possible to obtain orthogonal generalized WBE sequences sets for any processing gain. The bandwidth of initial generalized WBE signals of each cell is preserved in the extended signal space associated to multicellular system. Mathematical formalism is illustrated by selected numerical examples.

PhantomNet: Exploring Optimal Multicellular Multiple Antenna Systems

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Foschini Gerard J

2004-01-01

Full Text Available We present a network framework for evaluating the theoretical performance limits of wireless data communication. We address the problem of providing the best possible service to new users joining the system without affecting existing users. Since, interference-wise, new users are required to be invisible to existing users, the network is dubbed PhantomNet. The novelty is the generality obtained in this context. Namely, we can deal with multiple users, multiple antennas, and multiple cells on both the uplink and the downlink. The solution for the uplink is effectively the same as for a single cell system since all the base stations (BSs simply amount to one composite BS with centralized processing. The optimum strategy, following directly from known results, is successive decoding (SD, where the new user is decoded before the existing users so that the new users' signal can be subtracted out to meet its invisibility requirement. Only the BS needs to modify its decoding scheme in the handling of new users, since existing users continue to transmit their data exactly as they did before the new arrivals. The downlink, even with the BSs operating as one composite BS, is more problematic. With multiple antennas at each BS site, the optimal coding scheme and the capacity region for this channel are unsolved problems. SD and dirty paper (DP are two schemes previously reported to achieve capacity in special cases. For PhantomNet, we show that DP coding at the BS is equal to or better than SD. The new user is encoded before the existing users so that the interference caused by his signal to existing users is known to the transmitter. Thus the BS modifies its encoding scheme to accommodate new users so that existing users continue to operate as before: they achieve the same rates as before and they decode their signal in precisely the same way as before. The solutions for the uplink and the downlink are particularly interesting in the way they exhibit a

Computational Model of Secondary Palate Fusion and Disruption

Science.gov (United States)

Morphogenetic events are driven by cell-generated physical forces and complex cellular dynamics. To improve our capacity to predict developmental effects from cellular alterations, we built a multi-cellular agent-based model in CompuCell3D that recapitulates the cellular networks...

Systems biology: From the cell to the brain

Indian Academy of Sciences (India)

on the network of interactions instead of the characteristics of its isolated parts. In this article, we ..... Going up the scale from cellular to multi-cellular systems, we come .... the eight functional cir- cuits for (i) mechanosensation (touch sensitivity),.

Characterization of variants isolated from BCNU-treated 9L multicellular spheroids

International Nuclear Information System (INIS)

Hoff, M.H.B.; Deen, D.F.

1984-01-01

Multicellular spheroids of the 9L rat brain tumor cell line were treated with a single high-dose to produce cells of varying sensitivity. Treatment of 350-450 μm diameter 9L spheroids with 45 μM BCNU for 1 hr at 37 0 C produced 5 log cell kill. Some of the treated spheroids were dissociated immediately after treatment; others were dissociated after 1 wk. From these populations, twenty clones were selected and passaged as monolayers. Each clone was assayed at passage 2 for BCNU-induced damage using colony forming efficiency and sister chromatid exchange. 60% of the clones were resistant to BCNU, 15% were unchanged, and 15% appeared hypersensitive as compared with the control, which were uncloned 9L cells. All of the hypersensitive clones originated from the spheroids that remained in suspension after treatment. Three clones were studied during subsequent passage in monolayer. Two resistant clones maintained their resistance to BCNU over -- 25 passages, while one hypersensitive clone appeared to become progressively more resistant during passage. Thus, as with monolayer and in vivo 9L cells, a single high-dose treatment with BCNU produces a spectrum of sensitivities to BCNU. Some of these phenotypes are stable over many passages and have been used to initiate 9L spheroids having varying sensitivity to BCNU. These spheroids will be used to investigate drug-radiation interactions

Caenorhabditis elegans as a model system for studying non-cell-autonomous mechanisms in protein-misfolding diseases

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Carmen I. Nussbaum-Krammer

2014-01-01

Full Text Available Caenorhabditis elegans has a number of distinct advantages that are useful for understanding the basis for cellular and organismal dysfunction underlying age-associated diseases of protein misfolding. Although protein aggregation, a key feature of human neurodegenerative diseases, has been typically explored in vivo at the single-cell level using cells in culture, there is now increasing evidence that proteotoxicity has a non-cell-autonomous component and is communicated between cells and tissues in a multicellular organism. These discoveries have opened up new avenues for the use of C. elegans as an ideal animal model system to study non-cell-autonomous proteotoxicity, prion-like propagation of aggregation-prone proteins, and the organismal regulation of stress responses and proteostasis. This Review focuses on recent evidence that C. elegans has mechanisms to transmit certain classes of toxic proteins between tissues and a complex stress response that integrates and coordinates signals from single cells and tissues across the organism. These findings emphasize the potential of C. elegans to provide insights into non-cell-autonomous proteotoxic mechanisms underlying age-related protein-misfolding diseases.

Radiation cell survival and growth delay studies in multicellular spheroids of small-cell lung carcinoma

International Nuclear Information System (INIS)

Duchesne, G.M.; Peacock, J.H.

1987-01-01

The radiation sensitivity of two small-cell lung carcinoma cell lines growing as multicellular spheroids in static culture was determined using clonogenic cell survival and growth delay as endpoints. Growth delay determination suggested that clonogenic cell kill was less than was obtained by direct assay of cell survival. Recovery from potentially lethal damage was assayed in one line (HC12) but was not demonstrable, and clonogenic cell survival decreased with time in treated spheroids with diameters greater than 300 μm which contained a hypoxic cell population. Microscopic examination of the treated spheroids showed the emergence of an abnormal giant-cell population, and the progressive clonogenic cell loss that occurred after treatment was thought to be due to oxygen and nutrient deprivation of the remaining viable cells by this doomed cell population. Correction of the growth delay measurements for changes in cell size and clonogenic cell population allowed correlation of the growth delay and cell survival data. (author)

Stem Cell Models: A Guide to Understand and Mitigate Aging?

Science.gov (United States)

Brunauer, Regina; Alavez, Silvestre; Kennedy, Brian K

2017-01-01

Aging is studied either on a systemic level using life span and health span of animal models, or on the cellular level using replicative life span of yeast or mammalian cells. While useful in identifying general and conserved pathways of aging, both approaches provide only limited information about cell-type specific causes and mechanisms of aging. Stem cells are the regenerative units of multicellular life, and stem cell aging might be a major cause for organismal aging. Using the examples of hematopoietic stem cell aging and human pluripotent stem cell models, we propose that stem cell models of aging are valuable for studying tissue-specific causes and mechanisms of aging and can provide unique insights into the mammalian aging process that may be inaccessible in simple model organisms. © 2016 S. Karger AG, Basel.

Antiproliferative Activity and Cellular Uptake of Evodiamine and Rutaecarpine Based on 3D Tumor Models

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Hui Guo

2016-07-01

Full Text Available Evodiamine (EVO and rutaecarpine (RUT are promising anti-tumor drug candidates. The evaluation of the anti-proliferative activity and cellular uptake of EVO and RUT in 3D multicellular spheroids of cancer cells would better recapitulate the native situation and thus better reflect an in vivo response to the treatment. Herein, we employed the 3D culture of MCF-7 and SMMC-7721 cells based on hanging drop method and evaluated the anti-proliferative activity and cellular uptake of EVO and RUT in 3D multicellular spheroids, and compared the results with those obtained from 2D monolayers. The drugs’ IC50 values were significantly increased from the range of 6.4–44.1 μM in 2D monolayers to 21.8–138.0 μM in 3D multicellular spheroids, which may be due to enhanced mass barrier and reduced drug penetration in 3D models. The fluorescence of EVO and RUT was measured via fluorescence spectroscopy and the cellular uptake of both drugs was characterized in 2D tumor models. The results showed that the cellular uptake concentrations of RUT increased with increasing drug concentrations. However, the EVO concentrations uptaken by the cells showed only a small change with increasing drug concentrations, which may be due to the different solubility of EVO and Rut in solvents. Overall, this study provided a new vision of the anti-tumor activity of EVO and RUT via 3D multicellular spheroids and cellular uptake through the fluorescence of compounds.

A bistable model of cell polarity.

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Matteo Semplice

Full Text Available Ultrasensitivity, as described by Goldbeter and Koshland, has been considered for a long time as a way to realize bistable switches in biological systems. It is not as well recognized that when ultrasensitivity and reinforcing feedback loops are present in a spatially distributed system such as the cell plasmamembrane, they may induce bistability and spatial separation of the system into distinct signaling phases. Here we suggest that bistability of ultrasensitive signaling pathways in a diffusive environment provides a basic mechanism to realize cell membrane polarity. Cell membrane polarization is a fundamental process implicated in several basic biological phenomena, such as differentiation, proliferation, migration and morphogenesis of unicellular and multicellular organisms. We describe a simple, solvable model of cell membrane polarization based on the coupling of membrane diffusion with bistable enzymatic dynamics. The model can reproduce a broad range of symmetry-breaking events, such as those observed in eukaryotic directional sensing, the apico-basal polarization of epithelium cells, the polarization of budding and mating yeast, and the formation of Ras nanoclusters in several cell types.

Respiratory hazard assessment of combined exposure to complete gasoline exhaust and respirable volcanic ash in a multicellular human lung model at the air-liquid interface.

Science.gov (United States)

Tomašek, Ines; Horwell, Claire J; Bisig, Christoph; Damby, David E; Comte, Pierre; Czerwinski, Jan; Petri-Fink, Alke; Clift, Martin J D; Drasler, Barbara; Rothen-Rutishauser, Barbara

2018-07-01

Communities resident in urban areas located near active volcanoes can experience volcanic ash exposures during, and following, an eruption, in addition to sustained exposures to high concentrations of anthropogenic air pollutants (e.g., vehicle exhaust emissions). Inhalation of anthropogenic pollution is known to cause the onset of, or exacerbate, respiratory and cardiovascular diseases. It is further postulated similar exposure to volcanic ash can also affect such disease states. Understanding of the impact of combined exposure of volcanic ash and anthropogenic pollution to human health, however, remains limited. The aim of this study was to assess the biological impact of combined exposure to respirable volcanic ash (from Soufrière Hills volcano (SHV), Montserrat and Chaitén volcano (ChV), Chile; representing different magmatic compositions and eruption styles) and freshly-generated complete exhaust from a gasoline vehicle. A multicellular human lung model (an epithelial cell-layer composed of A549 alveolar type II-like cells complemented with human blood monocyte-derived macrophages and dendritic cells cultured at the air-liquid interface) was exposed to diluted exhaust (1:10) continuously for 6 h, followed by immediate exposure to the ash as a dry powder (0.54 ± 0.19 μg/cm 2 and 0.39 ± 0.09 μg/cm 2 for SHV and ChV ash, respectively). After an 18 h incubation, cells were exposed again for 6 h to diluted exhaust, and a final 18 h incubation (at 37 °C and 5% CO 2 ). Cell cultures were then assessed for cytotoxic, oxidative stress and (pro-)inflammatory responses. Results indicate that, at all tested (sub-lethal) concentrations, co-exposures with both ash samples induced no significant expression of genes associated with oxidative stress (HMOX1, NQO1) or production of (pro-)inflammatory markers (IL-1β, IL-8, TNF-α) at the gene and protein levels. In summary, considering the employed experimental conditions, combined exposure of

Respiratory hazard assessment of combined exposure to complete gasoline exhaust and respirable volcanic ash in a multicellular human lung model at the air-liquid interface

Science.gov (United States)

Tomasek, Ines; Horwell, Claire J.; Bisig, Christoph; Damby, David; Comte, Pierre; Czerwinski, Jan; Petri-Fink, Alke; Clift, Martin J D; Drasler, Barbara; Rothen-Rutishauer, Barbara

2018-01-01

Communities resident in urban areas located near active volcanoes can experience volcanic ash exposures during, and following, an eruption, in addition to sustained exposures to high concentrations of anthropogenic air pollutants (e.g., vehicle exhaust emissions). Inhalation of anthropogenic pollution is known to cause the onset of, or exacerbate, respiratory and cardiovascular diseases. It is further postulated similar exposure to volcanic ash can also affect such disease states. Understanding of the impact of combined exposure of volcanic ash and anthropogenic pollution to human health, however, remains limited.The aim of this study was to assess the biological impact of combined exposure to respirable volcanic ash (from Soufrière Hills volcano (SHV), Montserrat and Chaitén volcano (ChV), Chile; representing different magmatic compositions and eruption styles) and freshly-generated complete exhaust from a gasoline vehicle. A multicellular human lung model (an epithelial cell-layer composed of A549 alveolar type II-like cells complemented with human blood monocyte-derived macrophages and dendritic cells cultured at the air-liquid interface) was exposed to diluted exhaust (1:10) continuously for 6 h, followed by immediate exposure to the ash as a dry powder (0.54 ± 0.19 μg/cm2 and 0.39 ± 0.09 μg/cm2 for SHV and ChV ash, respectively). After an 18 h incubation, cells were exposed again for 6 h to diluted exhaust, and a final 18 h incubation (at 37 °C and 5% CO2). Cell cultures were then assessed for cytotoxic, oxidative stress and (pro-)inflammatory responses.Results indicate that, at all tested (sub-lethal) concentrations, co-exposures with both ash samples induced no significant expression of genes associated with oxidative stress (HMOX1, NQO1) or production of (pro-)inflammatory markers (IL-1β, IL-8, TNF-α) at the gene and protein levels. In summary, considering the employed experimental conditions, combined exposure of

The number of cell types, information content, and the evolution of complex multicellularity

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Karl J. Niklas

2014-12-01

Full Text Available The number of different cell types (NCT characterizing an organism is often used to quantify organismic complexity. This method results in the tautology that more complex organisms have a larger number of different kinds of cells, and that organisms with more different kinds of cells are more complex. This circular reasoning can be avoided (and simultaneously tested when NCT is plotted against different measures of organismic information content (e.g., genome or proteome size. This approach is illustrated by plotting the NCT of representative diatoms, green and brown algae, land plants, invertebrates, and vertebrates against data for genome size (number of base-pairs, proteome size (number of amino acids, and proteome functional versatility (number of intrinsically disordered protein domains or residues. Statistical analyses of these data indicate that increases in NCT fail to keep pace with increases in genome size, but exceed a one-to-one scaling relationship with increasing proteome size and with increasing numbers of intrinsically disordered protein residues. We interpret these trends to indicate that comparatively small increases in proteome (and not genome size are associated with disproportionate increases in NCT, and that proteins with intrinsically disordered domains enhance cell type diversity and thus contribute to the evolution of complex multicellularity.

Skin innate immune system

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Berna Aksoy

2013-06-01

Full Text Available All multicellular organisms protect themselves from external universe and microorganisms by innate immune sytem that is constitutively present. Skin innate immune system has several different components composed of epithelial barriers, humoral factors and cellular part. In this review information about skin innate immune system and its components are presented to the reader. Innate immunity, which wasn’t adequately interested in previously, is proven to provide a powerfull early protection system, control many infections before the acquired immunity starts and directs acquired immunity to develop optimally

AlgiMatrix™ based 3D cell culture system as an in-vitro tumor model for anticancer studies.

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Chandraiah Godugu

Full Text Available Three-dimensional (3D in-vitro cultures are recognized for recapitulating the physiological microenvironment and exhibiting high concordance with in-vivo conditions. Taking the advantages of 3D culture, we have developed the in-vitro tumor model for anticancer drug screening.Cancer cells grown in 6 and 96 well AlgiMatrix™ scaffolds resulted in the formation of multicellular spheroids in the size range of 100-300 µm. Spheroids were grown in two weeks in cultures without compromising the growth characteristics. Different marketed anticancer drugs were screened by incubating them for 24 h at 7, 9 and 11 days in 3D cultures and cytotoxicity was measured by AlamarBlue® assay. Effectiveness of anticancer drug treatments were measured based on spheroid number and size distribution. Evaluation of apoptotic and anti-apoptotic markers was done by immunohistochemistry and RT-PCR. The 3D results were compared with the conventional 2D monolayer cultures. Cellular uptake studies for drug (Doxorubicin and nanoparticle (NLC were done using spheroids.IC(50 values for anticancer drugs were significantly higher in AlgiMatrix™ systems compared to 2D culture models. The cleaved caspase-3 expression was significantly decreased (2.09 and 2.47 folds respectively for 5-Fluorouracil and Camptothecin in H460 spheroid cultures compared to 2D culture system. The cytotoxicity, spheroid size distribution, immunohistochemistry, RT-PCR and nanoparticle penetration data suggested that in vitro tumor models show higher resistance to anticancer drugs and supporting the fact that 3D culture is a better model for the cytotoxic evaluation of anticancer drugs in vitro.The results from our studies are useful to develop a high throughput in vitro tumor model to study the effect of various anticancer agents and various molecular pathways affected by the anticancer drugs and formulations.

Unleashing the potential of the root hair cell as a single plant cell type model in root systems biology

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Zhenzhen eQiao

2013-11-01

Full Text Available Plant root is an organ composed of multiple cell types with different functions. This multicellular complexity limits our understanding of root biology because –omics studies performed at the level of the entire root reflect the average responses of all cells composing the organ. To overcome this difficulty and allow a more comprehensive understanding of root cell biology, an approach is needed that would focus on one single cell type in the plant root. Because of its biological functions (i.e. uptake of water and various nutrients; primary site of infection by nitrogen-fixing bacteria in legumes, the root hair cell is an attractive single cell model to study root cell response to various stresses and treatments. To fully study their biology, we have recently optimized procedures in obtaining root hair cell samples. We culture the plants using an ultrasound aeroponic system maximizing root hair cell density on the entire root systems and allowing the homogeneous treatment of the root system. We then isolate the root hair cells in liquid nitrogen. Isolated root hair yields could be up to 800 to 1000 mg of plant cells from 60 root systems. Using soybean as a model, the purity of the root hair was assessed by comparing the expression level of genes previously identified as soybean root hair specific between preparations of isolated root hair cells and stripped roots, roots devoid in root hairs. Enlarging our tests to include other plant species, our results support the isolation of large quantities of highly purified root hair cells which is compatible with a systems biology approach.

Effects of sensitizers on cell respiration. 3. The effects of hypoxic cell radiosensitizers on oxidative metabolism and the radiation response of an in vitro tumour model

Energy Technology Data Exchange (ETDEWEB)

Durand, R E [Wisconsin Clinical Cancer Center, Madison (USA). Dept. of Human Oncology; Biaglow, J E; Greenstock, C L

1978-06-01

Physiological factors are important when considering the effects of radiosensitizers on the radiation response of complex systems such as multi-cellular spheroids. In this system, under conditions of unlimited nutrient supply, cells are rendered hypoxic by metabolism. Thus, using the spheroid system as an in vitro model of the tumour-cell microenvironment, we have determined the relative contribution of radiosensitization and respiratory effects of a number of electron-affinic sensitizers having potential clinical use. These studies are indicative of physiological responses at the cellular level, and suggest optimal drug administration schemes for obtaining maximal radiation response in vivo with hypoxic cell sensitizers.

Radiobiological studies of cells in multicellular spheroids using a sequential trypsinization technique

International Nuclear Information System (INIS)

Giesbrecht, J.L.; Wilson, W.R.; Hill, R.P.

1981-01-01

The radiation response of V79 Chinese hamster cells grown as multicellular spheroids has been investigated by determining survival curves for treatment under a variety of different oxygen concentrations. Spheroids were irradiated under fully oxygenated conditions in air-equilibrated medium at 37 0 C, in medium exposed to lower oxygen tension (5% O 2 ) for times varying from 1 hr to 3 days, or under anoxic conditions. For comparison with the spheroids, using identical treatment conditions, V79 cells were grown in suspension as a subconfluent monolayer attached to Sephadex (microcarrier) beads and irradiated under fully oxygenated or anoxic conditions. The radiation response of cells at different depths within the spheroid was investigated by using a sequential trypsinization technique developed to remove eight or nine shells of cells successively from the spheroid surface. When irradiation was given under fully oxygenated conditions the outer few cell layers were more sensitive than the inner cells, a finding which is not understood. As expected the inner cells in spheroids irradiated in air (at 37 0 C) or in 5% O 2 are more resistant than the outer cells. For an acute exposure to 5% O 2 (1 hr) in the inner cells displayed full radiobiological hypoxia; however, for chronic exposures to low oxygen this was not the case. These results with the sequential trypsinization procedure suggest that the radiation response of cells in spheroids is more complex than anticipted

The swimming polarity of multicellular magnetotactic prokaryotes can change during an isolation process employing magnets: evidence of a relation between swimming polarity and magnetic moment intensity.

Science.gov (United States)

de Melo, Roger Duarte; Acosta-Avalos, Daniel

2017-09-01

Magnetotactic microorganisms are characterized by swimming in the direction of an applied magnetic field. In nature, two types of swimming polarity have been observed: north-seeking microorganisms that swim in the same direction as the magnetic field, and south-seeking microorganisms that swim in the opposite direction. The present work studies the reversal in the swimming polarity of the multicellular magnetotactic prokaryote Candidatus Magnetoglobus multicellularis following an isolation process using high magnetic fields from magnets. The proportion of north- and south-seeking organisms was counted as a function of the magnetic field intensity used during the isolation of the organisms from sediment. It was observed that the proportion of north-seeking organisms increased when the magnetic field was increased. The magnetic moment for north- and south-seeking populations was estimated using the U-turn method. The average magnetic moment was higher for north- than south-seeking organisms. The results suggest that the reversal of swimming polarity must occur during the isolation process in the presence of high magnetic fields and magnetic field gradients. It is shown for the first time that the swimming polarity reversal depends on the magnetic moment intensity of multicellular magnetotactic prokaryotes, and new studies must be undertaken to understand the role of magnetic moment polarity and oxygen gradients in determination of swimming polarity.

Xanthusbase: adapting wikipedia principles to a model organism database

OpenAIRE

Arshinoff, Bradley I.; Suen, Garret; Just, Eric M.; Merchant, Sohel M.; Kibbe, Warren A.; Chisholm, Rex L.; Welch, Roy D.

2006-01-01

xanthusBase () is the official model organism database (MOD) for the social bacterium Myxococcus xanthus. In many respects, M.xanthus represents the pioneer model organism (MO) for studying the genetic, biochemical, and mechanistic basis of prokaryotic multicellularity, a topic that has garnered considerable attention due to the significance of biofilms in both basic and applied microbiology research. To facilitate its utility, the design of xanthusBase incorporates open-source software, leve...

Mathematical model of gluconic acid fermentation by Aspergillus niger

Energy Technology Data Exchange (ETDEWEB)

Takamatsu, T.; Shioya, S.; Furuya, T.

1981-11-01

A mathematical model for the study of gluconic acid fermentation by Aspergillus niger has been developed. The model has been deduced from the basic biological concept of multicellular filamentous microorganisms, i.e. cell population balance. It can be used to explain the behaviour of both batch and continuous cultures, even when in a lag phase. A new characteristic, involving the existence of dual equilibrium stages during fermentation, has been predicted using this mathematical model. (Refs. 6).

Cell-like pressure sensors reveal increase of mechanical stress towards the core of multicellular spheroids under compression.

Science.gov (United States)

Dolega, M E; Delarue, M; Ingremeau, F; Prost, J; Delon, A; Cappello, G

2017-01-27

The surrounding microenvironment limits tumour expansion, imposing a compressive stress on the tumour, but little is known how pressure propagates inside the tumour. Here we present non-destructive cell-like microsensors to locally quantify mechanical stress distribution in three-dimensional tissue. Our sensors are polyacrylamide microbeads of well-defined elasticity, size and surface coating to enable internalization within the cellular environment. By isotropically compressing multicellular spheroids (MCS), which are spherical aggregates of cells mimicking a tumour, we show that the pressure is transmitted in a non-trivial manner inside the MCS, with a pressure rise towards the core. This observed pressure profile is explained by the anisotropic arrangement of cells and our results suggest that such anisotropy alone is sufficient to explain the pressure rise inside MCS composed of a single cell type. Furthermore, such pressure distribution suggests a direct link between increased mechanical stress and previously observed lack of proliferation within the spheroids core.

Population-expression models of immune response

International Nuclear Information System (INIS)

Stromberg, Sean P; Antia, Rustom; Nemenman, Ilya

2013-01-01

The immune response to a pathogen has two basic features. The first is the expansion of a few pathogen-specific cells to form a population large enough to control the pathogen. The second is the process of differentiation of cells from an initial naive phenotype to an effector phenotype which controls the pathogen, and subsequently to a memory phenotype that is maintained and responsible for long-term protection. The expansion and the differentiation have been considered largely independently. Changes in cell populations are typically described using ecologically based ordinary differential equation models. In contrast, differentiation of single cells is studied within systems biology and is frequently modeled by considering changes in gene and protein expression in individual cells. Recent advances in experimental systems biology make available for the first time data to allow the coupling of population and high dimensional expression data of immune cells during infections. Here we describe and develop population-expression models which integrate these two processes into systems biology on the multicellular level. When translated into mathematical equations, these models result in non-conservative, non-local advection-diffusion equations. We describe situations where the population-expression approach can make correct inference from data while previous modeling approaches based on common simplifying assumptions would fail. We also explore how model reduction techniques can be used to build population-expression models, minimizing the complexity of the model while keeping the essential features of the system. While we consider problems in immunology in this paper, we expect population-expression models to be more broadly applicable. (paper)

Cellular and functional specificity among ferritin-like proteins in the multicellular cyanobacterium Nostoc punctiforme.

Science.gov (United States)

Ekman, Martin; Sandh, Gustaf; Nenninger, Anja; Oliveira, Paulo; Stensjö, Karin

2014-03-01

Ferritin-like proteins constitute a remarkably heterogeneous protein family, including ferritins, bacterioferritins and Dps proteins. The genome of the filamentous heterocyst-forming cyanobacterium Nostoc punctiforme encodes five ferritin-like proteins. In the present paper, we report a multidimensional characterization of these proteins. Our phylogenetic and bioinformatics analyses suggest both structural and physiological differences among the ferritin-like proteins. The expression of these five genes responded differently to hydrogen peroxide treatment, with a significantly higher rise in transcript level for Npun_F3730 as compared with the other four genes. A specific role for Npun_F3730 in the cells tolerance against hydrogen peroxide was also supported by the inactivation of Npun_F3730, Npun_R5701 and Npun_R6212; among these, only the ΔNpun_F3730 strain showed an increased sensitivity to hydrogen peroxide compared with wild type. Analysis of promoter-GFP reporter fusions of the ferritin-like genes indicated that Npun_F3730 and Npun_R5701 were expressed in all cell types of a diazotrophic culture, while Npun_F6212 was expressed specifically in heterocysts. Our study provides the first comprehensive analysis combining functional differentiation and cellular specificity within this important group of proteins in a multicellular cyanobacterium. © 2013 John Wiley & Sons Ltd and Society for Applied Microbiology.

Systems Biology of the Fluxome

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Miguel A. Aon

2015-07-01

Full Text Available The advent of high throughput -omics has made the accumulation of comprehensive data sets possible, consisting of changes in genes, transcripts, proteins and metabolites. Systems biology-inspired computational methods for translating metabolomics data into fluxomics provide a direct functional, dynamic readout of metabolic networks. When combined with appropriate experimental design, these methods deliver insightful knowledge about cellular function under diverse conditions. The use of computational models accounting for detailed kinetics and regulatory mechanisms allow us to unravel the control and regulatory properties of the fluxome under steady and time-dependent behaviors. This approach extends the analysis of complex systems from description to prediction, including control of complex dynamic behavior ranging from biological rhythms to catastrophic lethal arrhythmias. The powerful quantitative metabolomics-fluxomics approach will help our ability to engineer unicellular and multicellular organisms evolve from trial-and-error to a more predictable process, and from cells to organ and organisms.

The rapid manufacture of uniform composite multicellular-biomaterial micropellets, their assembly into macroscopic organized tissues, and potential applications in cartilage tissue engineering.

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Betul Kul Babur

Full Text Available We and others have published on the rapid manufacture of micropellet tissues, typically formed from 100-500 cells each. The micropellet geometry enhances cellular biological properties, and in many cases the micropellets can subsequently be utilized as building blocks to assemble complex macrotissues. Generally, micropellets are formed from cells alone, however when replicating matrix-rich tissues such as cartilage it would be ideal if matrix or biomaterials supplements could be incorporated directly into the micropellet during the manufacturing process. Herein we describe a method to efficiently incorporate donor cartilage matrix into tissue engineered cartilage micropellets. We lyophilized bovine cartilage matrix, and then shattered it into microscopic pieces having average dimensions < 10 μm diameter; we termed this microscopic donor matrix "cartilage dust (CD". Using a microwell platform, we show that ~0.83 μg CD can be rapidly and efficiently incorporated into single multicellular aggregates formed from 180 bone marrow mesenchymal stem/stromal cells (MSC each. The microwell platform enabled the rapid manufacture of thousands of replica composite micropellets, with each micropellet having a material/CD core and a cellular surface. This micropellet organization enabled the rapid bulking up of the micropellet core matrix content, and left an adhesive cellular outer surface. This morphological organization enabled the ready assembly of the composite micropellets into macroscopic tissues. Generically, this is a versatile method that enables the rapid and uniform integration of biomaterials into multicellular micropellets that can then be used as tissue building blocks. In this study, the addition of CD resulted in an approximate 8-fold volume increase in the micropellets, with the donor matrix functioning to contribute to an increase in total cartilage matrix content. Composite micropellets were readily assembled into macroscopic cartilage

Visualizing the effect of tumor microenvironments on radiation-induced cell kinetics in multicellular spheroids consisting of HeLa cells

International Nuclear Information System (INIS)

Kaida, Atsushi; Miura, Masahiko

2013-01-01

Highlights: •We visualized radiation-induced cell kinetics in spheroids. •HeLa-Fucci cells were used for detection of cell-cycle changes. •Radiation-induced G2 arrest was prolonged in the spheroid. •The inner and outer cell fractions behaved differently. -- Abstract: In this study, we visualized the effect of tumor microenvironments on radiation-induced tumor cell kinetics. For this purpose, we utilized a multicellular spheroid model, with a diameter of ∼500 μm, consisting of HeLa cells expressing the fluorescent ubiquitination-based cell-cycle indicator (Fucci). In live spheroids, a confocal laser scanning microscope allowed us to clearly monitor cell kinetics at depths of up to 60 μm. Surprisingly, a remarkable prolongation of G2 arrest was observed in the outer region of the spheroid relative to monolayer-cultured cells. Scale, an aqueous reagent that renders tissues optically transparent, allowed visualization deeper inside spheroids. About 16 h after irradiation, a red fluorescent cell fraction, presumably a quiescent G0 cell fraction, became distinct from the outer fraction consisting of proliferating cells, most of which exhibited green fluorescence indicative of G2 arrest. Thereafter, the red cell fraction began to emit green fluorescence and remained in prolonged G2 arrest. Thus, for the first time, we visualized the prolongation of radiation-induced G2 arrest in spheroids and the differences in cell kinetics between the outer and inner fractions

A Preliminary Study of the Application of a Model Animal-Caenorhabidity elegans' Exposure to a Low-Energy Ion Irradiation System

International Nuclear Information System (INIS)

Liu Xuelan; Cai Kezhou; Feng Huiyun; Xu An; Yuan Hang; Yu Zengliang

2007-01-01

Because of the lack of suitable animal models adapted to high vacuum stress in the low-energy ion implantation system, the bio-effects ion irradiation with an energy less than 50 keV on multi-cellular animal individuals have never been investigated so far. The nematode Caenorhabditis elegans has proved to be an excellent animal model used for the study of a broad spectrum of biological issues. The purpose of this work was to investigate the viability of this animal under ion irradiation. We studied the protection effects of glycerol and trehalose on the enhancement of nematodes' ability to bear the vacuum stress. The results showed that the survival of the nematodes was enhanced remarkably under long and slow desiccation, even without glycerol and trehalose. 15% glycerol showed a better anti-vacuum stress effect on the nematodes than trehalose did under short-time desiccation. Low-temperature pre-treatment or post-treatment of the samples had no obvious effect on the survival scored after argon ion irradiation. Moreover, little effect was induced by 15% glycerol- and vacuum-exposure on germ cell apoptosis, compared to the untreated control sample. It issuggested that such treatment would provide relatively low background for genotoxic evaluations with ion irradiation

Modeling the fusion of cylindrical bioink particles in post bioprinting structure formation

Science.gov (United States)

McCune, Matt; Shafiee, Ashkan; Forgacs, Gabor; Kosztin, Ioan

2015-03-01

Cellular Particle Dynamics (CPD) is an effective computational method to describe the shape evolution and biomechanical relaxation processes in multicellular systems. Thus, CPD is a useful tool to predict the outcome of post-printing structure formation in bioprinting. The predictive power of CPD has been demonstrated for multicellular systems composed of spherical bioink units. Experiments and computer simulations were related through an independently developed theoretical formalism based on continuum mechanics. Here we generalize the CPD formalism to (i) include cylindrical bioink particles often used in specific bioprinting applications, (ii) describe the more realistic experimental situation in which both the length and the volume of the cylindrical bioink units decrease during post-printing structure formation, and (iii) directly connect CPD simulations to the corresponding experiments without the need of the intermediate continuum theory inherently based on simplifying assumptions. Work supported by NSF [PHY-0957914]. Computer time provided by the University of Missouri Bioinformatics Consortium.

Mutation in SUMO E3 ligase, SIZ1, disrupts the mature female gametophyte in Arabidopsis

KAUST Repository

Ling, Yu; Zhang, Chunyu; Chen, Tong; Hao, Huaiqing; Liu, Peng; Bressan, Ray A.; Hasegawa, Paul M.; Jin, Jing Bo; Lin, Jinxing

2012-01-01

Female gametophyte is the multicellular haploid structure that can produce embryo and endosperm after fertilization, which has become an attractive model system for investigating molecular mechanisms in nuclei migration, cell specification, cell

Multimodal sensorimotor system in unicellular zoospores of a fungus.

Science.gov (United States)

Swafford, Andrew J M; Oakley, Todd H

2018-01-19

Complex sensory systems often underlie critical behaviors, including avoiding predators and locating prey, mates and shelter. Multisensory systems that control motor behavior even appear in unicellular eukaryotes, such as Chlamydomonas , which are important laboratory models for sensory biology. However, we know of no unicellular opisthokonts that control motor behavior using a multimodal sensory system. Therefore, existing single-celled models for multimodal sensorimotor integration are very distantly related to animals. Here, we describe a multisensory system that controls the motor function of unicellular fungal zoospores. We found that zoospores of Allomyces arbusculus exhibit both phototaxis and chemotaxis. Furthermore, we report that closely related Allomyces species respond to either the chemical or the light stimuli presented in this study, not both, and likely do not share this multisensory system. This diversity of sensory systems within Allomyces provides a rare example of a comparative framework that can be used to examine the evolution of sensory systems following the gain/loss of available sensory modalities. The tractability of Allomyces and related fungi as laboratory organisms will facilitate detailed mechanistic investigations into the genetic underpinnings of novel photosensory systems, and how multisensory systems may have functioned in early opisthokonts before multicellularity allowed for the evolution of specialized cell types. © 2018. Published by The Company of Biologists Ltd.

The Evolution of COP9 Signalosome in Unicellular and Multicellular Organisms.

Science.gov (United States)

Barth, Emanuel; Hübler, Ron; Baniahmad, Aria; Marz, Manja

2016-05-02

The COP9 signalosome (CSN) is a highly conserved protein complex, recently being crystallized for human. In mammals and plants the COP9 complex consists of nine subunits, CSN 1-8 and CSNAP. The CSN regulates the activity of culling ring E3 ubiquitin and plays central roles in pleiotropy, cell cycle, and defense of pathogens. Despite the interesting and essential functions, a thorough analysis of the CSN subunits in evolutionary comparative perspective is missing. Here we compared 61 eukaryotic genomes including plants, animals, and yeasts genomes and show that the most conserved subunits of eukaryotes among the nine subunits are CSN2 and CSN5. This may indicate a strong evolutionary selection for these two subunits. Despite the strong conservation of the protein sequence, the genomic structures of the intron/exon boundaries indicate no conservation at genomic level. This suggests that the gene structure is exposed to a much less selection compared with the protein sequence. We also show the conservation of important active domains, such as PCI (proteasome lid-CSN-initiation factor) and MPN (MPR1/PAD1 amino-terminal). We identified novel exons and alternative splicing variants for all CSN subunits. This indicates another level of complexity of the CSN. Notably, most COP9-subunits were identified in all multicellular and unicellular eukaryotic organisms analyzed, but not in prokaryotes or archaeas. Thus, genes encoding CSN subunits present in all analyzed eukaryotes indicate the invention of the signalosome at the root of eukaryotes. The identification of alternative splice variants indicates possible "mini-complexes" or COP9 complexes with independent subunits containing potentially novel and not yet identified functions. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Developing a System Architecture for Holonic Shop Floor Control

DEFF Research Database (Denmark)

Sørensen, Christian; Langer, Gilad; Alting, Leo

1998-01-01

This paper describes the results of research regarding the emerging theory of Holonic Manufacturing Systems. This theory and in particular its corresponding reference architecture serves as the basis for the development of a system-architecture for shop floor control systems in a multi-cellular c......This paper describes the results of research regarding the emerging theory of Holonic Manufacturing Systems. This theory and in particular its corresponding reference architecture serves as the basis for the development of a system-architecture for shop floor control systems in a multi...

A cellular automata model of bone formation.

Science.gov (United States)

Van Scoy, Gabrielle K; George, Estee L; Opoku Asantewaa, Flora; Kerns, Lucy; Saunders, Marnie M; Prieto-Langarica, Alicia

2017-04-01

Bone remodeling is an elegantly orchestrated process by which osteocytes, osteoblasts and osteoclasts function as a syncytium to maintain or modify bone. On the microscopic level, bone consists of cells that create, destroy and monitor the bone matrix. These cells interact in a coordinated manner to maintain a tightly regulated homeostasis. It is this regulation that is responsible for the observed increase in bone gain in the dominant arm of a tennis player and the observed increase in bone loss associated with spaceflight and osteoporosis. The manner in which these cells interact to bring about a change in bone quality and quantity has yet to be fully elucidated. But efforts to understand the multicellular complexity can ultimately lead to eradication of metabolic bone diseases such as osteoporosis and improved implant longevity. Experimentally validated mathematical models that simulate functional activity and offer eventual predictive capabilities offer tremendous potential in understanding multicellular bone remodeling. Here we undertake the initial challenge to develop a mathematical model of bone formation validated with in vitro data obtained from osteoblastic bone cells induced to mineralize and quantified at 26 days of culture. A cellular automata model was constructed to simulate the in vitro characterization. Permutation tests were performed to compare the distribution of the mineralization in the cultures and the distribution of the mineralization in the mathematical models. The results of the permutation test show the distribution of mineralization from the characterization and mathematical model come from the same probability distribution, therefore validating the cellular automata model. Copyright © 2017 Elsevier Inc. All rights reserved.

In-silico analysis on biofabricating vascular networks using kinetic Monte Carlo simulations

International Nuclear Information System (INIS)

Sun, Yi; Yang, Xiaofeng; Wang, Qi

2014-01-01

We present a computational modeling approach to study the fusion of multicellular aggregate systems in a novel scaffold-less biofabrication process, known as ‘bioprinting’. In this novel technology, live multicellular aggregates are used as fundamental building blocks to make tissues or organs (collectively known as the bio-constructs,) via the layer-by-layer deposition technique or other methods; the printed bio-constructs embedded in maturogens, consisting of nutrient-rich bio-compatible hydrogels, are then placed in bioreactors to undergo the cellular aggregate fusion process to form the desired functional bio-structures. Our approach reported here is an agent-based modeling method, which uses the kinetic Monte Carlo (KMC) algorithm to evolve the cellular system on a lattice. In this method, the cells and the hydrogel media, in which cells are embedded, are coarse-grained to material’s points on a three-dimensional (3D) lattice, where the cell–cell and cell–medium interactions are quantified by adhesion and cohesion energies. In a multicellular aggregate system with a fixed number of cells and fixed amount of hydrogel media, where the effect of cell differentiation, proliferation and death are tactically neglected, the interaction energy is primarily dictated by the interfacial energy between cell and cell as well as between cell and medium particles on the lattice, respectively, based on the differential adhesion hypothesis. By using the transition state theory to track the time evolution of the multicellular system while minimizing the interfacial energy, KMC is shown to be an efficient time-dependent simulation tool to study the evolution of the multicellular aggregate system. In this study, numerical experiments are presented to simulate fusion and cell sorting during the biofabrication process of vascular networks, in which the bio-constructs are fabricated via engineering designs. The results predict the feasibility of fabricating the vascular

In-silico analysis on biofabricating vascular networks using kinetic Monte Carlo simulations.

Science.gov (United States)

Sun, Yi; Yang, Xiaofeng; Wang, Qi

2014-03-01

We present a computational modeling approach to study the fusion of multicellular aggregate systems in a novel scaffold-less biofabrication process, known as 'bioprinting'. In this novel technology, live multicellular aggregates are used as fundamental building blocks to make tissues or organs (collectively known as the bio-constructs,) via the layer-by-layer deposition technique or other methods; the printed bio-constructs embedded in maturogens, consisting of nutrient-rich bio-compatible hydrogels, are then placed in bioreactors to undergo the cellular aggregate fusion process to form the desired functional bio-structures. Our approach reported here is an agent-based modeling method, which uses the kinetic Monte Carlo (KMC) algorithm to evolve the cellular system on a lattice. In this method, the cells and the hydrogel media, in which cells are embedded, are coarse-grained to material's points on a three-dimensional (3D) lattice, where the cell-cell and cell-medium interactions are quantified by adhesion and cohesion energies. In a multicellular aggregate system with a fixed number of cells and fixed amount of hydrogel media, where the effect of cell differentiation, proliferation and death are tactically neglected, the interaction energy is primarily dictated by the interfacial energy between cell and cell as well as between cell and medium particles on the lattice, respectively, based on the differential adhesion hypothesis. By using the transition state theory to track the time evolution of the multicellular system while minimizing the interfacial energy, KMC is shown to be an efficient time-dependent simulation tool to study the evolution of the multicellular aggregate system. In this study, numerical experiments are presented to simulate fusion and cell sorting during the biofabrication process of vascular networks, in which the bio-constructs are fabricated via engineering designs. The results predict the feasibility of fabricating the vascular structures

Chemosensitivity of irradiated resistant cells of multicellular spheroids in A549 lung adenocarcinoma

International Nuclear Information System (INIS)

Shi Degang; Shi Genming; Huang Gang

2006-01-01

Objective: To investigate the chemosensitivity of irradiated resistant cells of multicellular spheroids in A549 lung adenocarcinoma. Methods: The A549 irradiated resistant cells were the 10th regrowth generations after irradiated with 2.5 Gy of 6 MV X-ray, the control groups were A549 parent cells and MCFY/VCR resistant cells. The 6 kinds of chemotherapeutic drugs were DDP, VDS, 5-FU, HCP, MMC and ADM respectively, with verapamil (VPL) as reverse agent. The treatment effect was compared with MTT assay, and the multidrug resistant gene expressions of mdrl and MRP were measured with RT-PCR method. Results: A549 cells and irradiated resistant cells were resistant to DDP, but sensitivity to VDS,5-FU, HCP, MMC and ADM. The inhibitory rates of VPL to the above two cells were 98% and 25% respectively(P 2 -MG and MRP/β 2 -MG of all A549 cells were about 0 and 0.7 respectively, and those of MCFT/VCR cells were 35 and 4.36. Conclusion: The chemosensitivity of A549 irradiated resistant cells had not changed markedly, the decreased sensitivity to VPL could not be explained by the gene expression of mdrl and MRP. It is conferred that some kinds of changes in the cell membrane and decreased regrowth ability to result in resistance. Unlike multidrug resistance induced by chemotherapy, VPL may be not an ideal reverser to irradiated resistant cells. The new kinds of biological preparation should be sought to combine chemotherapy to treat recurring tumor with irradiated resistance. (authors)

An oscillating dynamic model of collective cells in a monolayer

Science.gov (United States)

Lin, Shao-Zhen; Xue, Shi-Lei; Li, Bo; Feng, Xi-Qiao

2018-03-01

Periodic oscillations of collective cells occur in the morphogenesis and organogenesis of various tissues and organs. In this paper, an oscillating cytodynamic model is presented by integrating the chemomechanical interplay between the RhoA effector signaling pathway and cell deformation. We show that both an isolated cell and a cell aggregate can undergo spontaneous oscillations as a result of Hopf bifurcation, upon which the system evolves into a limit cycle of chemomechanical oscillations. The dynamic characteristics are tailored by the mechanical properties of cells (e.g., elasticity, contractility, and intercellular tension) and the chemical reactions involved in the RhoA effector signaling pathway. External forces are found to modulate the oscillation intensity of collective cells in the monolayer and to polarize their oscillations along the direction of external tension. The proposed cytodynamic model can recapitulate the prominent features of cell oscillations observed in a variety of experiments, including both isolated cells (e.g., spreading mouse embryonic fibroblasts, migrating amoeboid cells, and suspending 3T3 fibroblasts) and multicellular systems (e.g., Drosophila embryogenesis and oogenesis).

Transient selection in multicellular immune networks

Science.gov (United States)

Ivanchenko, M. V.

2011-03-01

We analyze the dynamics of a multi-clonotype naive T-cell population competing for survival signals from antigen-presenting cells. We find that this competition provides with an efficacious selection of clonotypes, making the less able and more repetitive get extinct. We uncover the scaling principles for large systems the extinction rate obeys and calibrate the model parameters to their experimental counterparts. For the first time, we estimate the physiological values of the T-cell receptor-antigen presentation profile recognition probability and T-cell clonotypes niche overlap. We demonstrate that, while the ultimate state is a stable fixed point, sequential transients dominate the dynamics over large timescales that may span over years, if not decades, in real time. We argue that what is currently viewed as "homeostasis" is a complex sequential transient process, while being quasi-stationary in the total number of T-cells only. The discovered type of sequential transient dynamics in large random networks is a novel alternative to the stable heteroclinic channel mechanism.

Systems Biology for Organotypic Cell Cultures

Energy Technology Data Exchange (ETDEWEB)

Grego, Sonia [RTI International, Research Triangle Park, NC (United States); Dougherty, Edward R. [Texas A & M Univ., College Station, TX (United States); Alexander, Francis J. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Auerbach, Scott S. [National Inst. of Environmental Health Sciences, Research Triangle Park, NC (United States); Berridge, Brian R. [GlaxoSmithKline, Research Triangle Park, NC (United States); Bittner, Michael L. [Translational Genomics Research Inst., Phoenix, AZ (United States); Casey, Warren [National Inst. of Environmental Health Sciences, Research Triangle Park, NC (United States); Cooley, Philip C. [RTI International, Research Triangle Park, NC (United States); Dash, Ajit [HemoShear Therapeutics, Charlottesville, VA (United States); Ferguson, Stephen S. [National Inst. of Environmental Health Sciences, Research Triangle Park, NC (United States); Fennell, Timothy R. [RTI International, Research Triangle Park, NC (United States); Hawkins, Brian T. [RTI International, Research Triangle Park, NC (United States); Hickey, Anthony J. [RTI International, Research Triangle Park, NC (United States); Kleensang, Andre [Johns Hopkins Univ., Baltimore, MD (United States). Center for Alternatives to Animal Testing; Liebman, Michael N. [IPQ Analytics, Kennett Square, PA (United States); Martin, Florian [Phillip Morris International, Neuchatel (Switzerland); Maull, Elizabeth A. [National Inst. of Environmental Health Sciences, Research Triangle Park, NC (United States); Paragas, Jason [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Qiao, Guilin [Defense Threat Reduction Agency, Ft. Belvoir, VA (United States); Ramaiahgari, Sreenivasa [National Inst. of Environmental Health Sciences, Research Triangle Park, NC (United States); Sumner, Susan J. [RTI International, Research Triangle Park, NC (United States); Yoon, Miyoung [The Hamner Inst. for Health Sciences, Research Triangle Park, NC (United States); ScitoVation, Research Triangle Park, NC (United States)

2016-08-04

Translating in vitro biological data into actionable information related to human health holds the potential to improve disease treatment and risk assessment of chemical exposures. While genomics has identified regulatory pathways at the cellular level, translation to the organism level requires a multiscale approach accounting for intra-cellular regulation, inter-cellular interaction, and tissue/organ-level effects. Tissue-level effects can now be probed in vitro thanks to recently developed systems of three-dimensional (3D), multicellular, “organotypic” cell cultures, which mimic functional responses of living tissue. However, there remains a knowledge gap regarding interactions across different biological scales, complicating accurate prediction of health outcomes from molecular/genomic data and tissue responses. Systems biology aims at mathematical modeling of complex, non-linear biological systems. We propose to apply a systems biology approach to achieve a computational representation of tissue-level physiological responses by integrating empirical data derived from organotypic culture systems with computational models of intracellular pathways to better predict human responses. Successful implementation of this integrated approach will provide a powerful tool for faster, more accurate and cost-effective screening of potential toxicants and therapeutics. On September 11, 2015, an interdisciplinary group of scientists, engineers, and clinicians gathered for a workshop in Research Triangle Park, North Carolina, to discuss this ambitious goal. Participants represented laboratory-based and computational modeling approaches to pharmacology and toxicology, as well as the pharmaceutical industry, government, non-profits, and academia. Discussions focused on identifying critical system perturbations to model, the computational tools required, and the experimental approaches best suited to generating key data. This consensus report summarizes the discussions held.

The sensitivity of Turing self-organization to biological feedback delays: 2D models of fish pigmentation

KAUST Repository

Gaffney, E. A.

2013-10-01

© The authors 2013. Turing morphogen models have been extensively explored in the context of large-scale self-organization in multicellular biological systems. However, reconciling the detailed biology of morphogen dynamics, while accounting for time delays associated with gene expression, reveals aberrant behaviours that are not consistent with early developmental self-organization, especially the requirement for exquisite temporal control. Attempts to reconcile the interpretation of Turing\\'s ideas with an increasing understanding of the mechanisms driving zebrafish pigmentation suggests that one should reconsider Turing\\'s model in terms of pigment cells rather than morphogens (Nakamasu et al., 2009, PNAS, 106, 8429-8434; Yamaguchi et al., 2007, PNAS, 104, 4790-4793). Here the dynamics of pigment cells is subject to response delays implicit in the cell cycle and apoptosis. Hence we explore simulations of fish skin patterning, focussing on the dynamical influence of gene expression delays in morphogen-based Turing models and response delays for cell-based Turing models. We find that reconciling the mechanisms driving the behaviour of Turing systems with observations of fish skin patterning remains a fundamental challenge.

Being human: The role of pluripotent stem cells in regenerative medicine and humanizing Alzheimer's disease models.

Science.gov (United States)

Sproul, Andrew A

2015-01-01

Human pluripotent stem cells (PSCs) have the capacity to revolutionize medicine by allowing the generation of functional cell types such as neurons for cell replacement therapy. However, the more immediate impact of PSCs on treatment of Alzheimer's disease (AD) will be through improved human AD model systems for mechanistic studies and therapeutic screening. This review will first briefly discuss different types of PSCs and genome-editing techniques that can be used to modify PSCs for disease modeling or for personalized medicine. This will be followed by a more in depth analysis of current AD iPSC models and a discussion of the need for more complex multicellular models, including cell types such as microglia. It will finish with a discussion on current clinical trials using PSC-derived cells and the long-term potential of such strategies for treating AD. Copyright © 2015 Elsevier Ltd. All rights reserved.

Pramana – Journal of Physics | Indian Academy of Sciences

Indian Academy of Sciences (India)

We have studied the collective behaviour of a one-dimensional ring of cells for conditions when the individual uncoupled cells show stable, bistable and oscillatory dynamics. We show that the global dynamics of this model multicellular system depends on the system size, coupling strength and the intrinsic dynamics of the ...

A Primer on Mathematical Modeling in the Study of Organisms and Their Parts.

Science.gov (United States)

Montévil, Maël

2018-01-01

Mathematical modeling is a very powerful tool for understanding natural phenomena. Such a tool carries its own assumptions and should always be used critically. In this chapter, we highlight the key ingredients and steps of modeling and focus on their biological interpretation. In particular, we discuss the role of theoretical principles in writing models. We also highlight the meaning and interpretation of equations. The main aim of this chapter is to facilitate the interaction between biologists and mathematical modelers. We focus on the case of cell proliferation and motility in the context of multicellular organisms.

[MiRNA system in unicellular eukaryotes and its evolutionary implications].

Science.gov (United States)

Zhang, Yan-Qiong; Wen, Jian-Fan

2010-02-01

microRNAs (miRNAs) in higher multicellular eukaryotes have been extensively studied in recent years. Great progresses have also been achieved for miRNAs in unicellular eukaryotes. All these studies not only enrich our knowledge about the complex expression regulation system in diverse organisms, but also have evolutionary significance for understanding the origin of this system. In this review, Authors summarize the recent advance in the studies of miRNA in unicellular eukaryotes, including that on the most primitive unicellular eukaryote--Giardia. The origin and evolution of miRNA system is also discussed.

Endothelial network formed with human dermal microvascular endothelial cells in autologous multicellular skin substitutes.

Science.gov (United States)

Ponec, Maria; El Ghalbzouri, Abdoelwaheb; Dijkman, Remco; Kempenaar, Johanna; van der Pluijm, Gabri; Koolwijk, Pieter

2004-01-01

A human skin equivalent from a single skin biopsy harboring keratinocytes and melanocytes in the epidermal compartment, and fibroblasts and microvascular dermal endothelial cells in the dermal compartment was developed. The results of the study revealed that the nature of the extracellular matrix of the dermal compartments plays an important role in establishment of endothelial network in vitro. With rat-tail type I collagen matrices only lateral but not vertical expansion of endothelial networks was observed. In contrast, the presence of extracellular matrix of entirely human origin facilitated proper spatial organization of the endothelial network. Namely, when human dermal fibroblasts and microvascular endothelial cells were seeded on the bottom of an inert filter and subsequently epidermal cells were seeded on top of it, fibroblasts produced extracellular matrix throughout which numerous branched tubes were spreading three-dimensionally. Fibroblasts also facilitated the formation of basement membrane at the epidermal/matrix interface. Under all culture conditions, fully differentiated epidermis was formed with numerous melanocytes present in the basal epidermal cell layer. The results of the competitive RT-PCR revealed that both keratinocytes and fibroblasts expressed VEGF-A, -B, -C, aFGF and bFGF mRNA, whereas fibroblasts also expressed VEGF-D mRNA. At protein level, keratinocytes produced 10 times higher amounts of VEGF-A than fibroblasts did. The generation of multicellular skin equivalent from a single human skin biopsy will stimulate further developments for its application in the treatment of full-thickness skin defects. The potential development of biodegradable, biocompatible material suitable for these purposes is a great challenge for future research.

Assessment of lung cell toxicity of various gasoline engine exhausts using a versatile in vitro exposure system.

Science.gov (United States)

Bisig, Christoph; Comte, Pierre; Güdel, Martin; Czerwinski, Jan; Mayer, Andreas; Müller, Loretta; Petri-Fink, Alke; Rothen-Rutishauser, Barbara

2018-04-01

Adverse effect studies of gasoline exhaust are scarce, even though gasoline direct injection (GDI) vehicles can emit a high number of particles. The aim of this study was to conduct an in vitro hazard assessment of different GDI exhausts using two different cell culture models mimicking the human airway. In addition to gasoline particle filters (GPF), the effects of two lubrication oils with low and high ash content were assessed, since it is known that oils are important contributors to exhaust emissions. Complete exhausts from two gasoline driven cars (GDI1 and GDI2) were applied for 6 h (acute exposure) to a multi-cellular human lung model (16HBE14o-cell line, macrophages, and dendritic cells) and a primary human airway model (MucilAir™). GDI1 vehicle was driven unfiltered and filtered with an uncoated and a coated GPF. GDI2 vehicle was driven under four settings with different fuels: normal unleaded gasoline, 2% high and low ash oil in gasoline, and 2% high ash oil in gasoline with a GPF. GDI1 unfiltered was also used for a repeated exposure (3 times 6 h) to assess possible adverse effects. After 6 h exposure, no genes or proteins for oxidative stress or pro-inflammation were upregulated compared to the filtered air control in both cell systems, neither in GDI1 with GPFs nor in GDI2 with the different fuels. However, the repeated exposure led to a significant increase in HMOX1 and TNFa gene expression in the multi-cellular model, showing the responsiveness of the system towards gasoline engine exhaust upon prolonged exposure. The reduction of particles by GPFs is significant and no adverse effects were observed in vitro during a short-term exposure. On the other hand, more data comparing different lubrication oils and their possible adverse effects are needed. Future experiments also should, as shown here, focus on repeated exposures. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Age-Dependent Differences in Systemic and Cell-Autonomous Immunity to L. monocytogenes

Directory of Open Access Journals (Sweden)

Ashley M. Sherrid

2013-01-01

Full Text Available Host defense against infection can broadly be categorized into systemic immunity and cell-autonomous immunity. Systemic immunity is crucial for all multicellular organisms, increasing in importance with increasing cellular complexity of the host. The systemic immune response to Listeria monocytogenes has been studied extensively in murine models; however, the clinical applicability of these findings to the human newborn remains incompletely understood. Furthermore, the ability to control infection at the level of an individual cell, known as “cell-autonomous immunity,” appears most relevant following infection with L. monocytogenes; as the main target, the monocyte is centrally important to innate as well as adaptive systemic immunity to listeriosis. We thus suggest that the overall increased risk to suffer and die from L. monocytogenes infection in the newborn period is a direct consequence of age-dependent differences in cell-autonomous immunity of the monocyte to L. monocytogenes. We here review what is known about age-dependent differences in systemic innate and adaptive as well as cell-autonomous immunity to infection with Listeria monocytogenes.

Systemic resilience model

International Nuclear Information System (INIS)

Lundberg, Jonas; Johansson, Björn JE

2015-01-01

It has been realized that resilience as a concept involves several contradictory definitions, both for instance resilience as agile adjustment and as robust resistance to situations. Our analysis of resilience concepts and models suggest that beyond simplistic definitions, it is possible to draw up a systemic resilience model (SyRes) that maintains these opposing characteristics without contradiction. We outline six functions in a systemic model, drawing primarily on resilience engineering, and disaster response: anticipation, monitoring, response, recovery, learning, and self-monitoring. The model consists of four areas: Event-based constraints, Functional Dependencies, Adaptive Capacity and Strategy. The paper describes dependencies between constraints, functions and strategies. We argue that models such as SyRes should be useful both for envisioning new resilience methods and metrics, as well as for engineering and evaluating resilient systems. - Highlights: • The SyRes model resolves contradictions between previous resilience definitions. • SyRes is a core model for envisioning and evaluating resilience metrics and models. • SyRes describes six functions in a systemic model. • They are anticipation, monitoring, response, recovery, learning, self-monitoring. • The model describes dependencies between constraints, functions and strategies

Stochastic models of cell motility

DEFF Research Database (Denmark)

Gradinaru, Cristian

2012-01-01

Cell motility and migration are central to the development and maintenance of multicellular organisms, and errors during this process can lead to major diseases. Consequently, the mechanisms and phenomenology of cell motility are currently under intense study. In recent years, a new...... interdisciplinary field focusing on the study of biological processes at the nanoscale level, with a range of technological applications in medicine and biological research, has emerged. The work presented in this thesis is at the interface of cell biology, image processing, and stochastic modeling. The stochastic...... models introduced here are based on persistent random motion, which I apply to real-life studies of cell motility on flat and nanostructured surfaces. These models aim to predict the time-dependent position of cell centroids in a stochastic manner, and conversely determine directly from experimental...

Anaerobic Respiration Using a Complete Oxidative TCA Cycle Drives Multicellular Swarming in Proteus mirabilis

Science.gov (United States)

Alteri, Christopher J.; Himpsl, Stephanie D.; Engstrom, Michael D.; Mobley, Harry L. T.

2012-01-01

ABSTRACT Proteus mirabilis rapidly migrates across surfaces using a periodic developmental process of differentiation alternating between short swimmer cells and elongated hyperflagellated swarmer cells. To undergo this vigorous flagellum-mediated motility, bacteria must generate a substantial proton gradient across their cytoplasmic membranes by using available energy pathways. We sought to identify the link between energy pathways and swarming differentiation by examining the behavior of defined central metabolism mutants. Mutations in the tricarboxylic acid (TCA) cycle (fumC and sdhB mutants) caused altered patterns of swarming periodicity, suggesting an aerobic pathway. Surprisingly, the wild-type strain swarmed on agar containing sodium azide, which poisons aerobic respiration; the fumC TCA cycle mutant, however, was unable to swarm on azide. To identify other contributing energy pathways, we screened transposon mutants for loss of swarming on sodium azide and found insertions in the following genes that involved fumarate metabolism or respiration: hybB, encoding hydrogenase; fumC, encoding fumarase; argH, encoding argininosuccinate lyase (generates fumarate); and a quinone hydroxylase gene. These findings validated the screen and suggested involvement of anaerobic electron transport chain components. Abnormal swarming periodicity of fumC and sdhB mutants was associated with the excretion of reduced acidic fermentation end products. Bacteria lacking SdhB were rescued to wild-type pH and periodicity by providing fumarate, independent of carbon source but dependent on oxygen, while fumC mutants were rescued by glycerol, independent of fumarate only under anaerobic conditions. These findings link multicellular swarming patterns with fumarate metabolism and membrane electron transport using a previously unappreciated configuration of both aerobic and anaerobic respiratory chain components. PMID:23111869

The sensitivity of Turing self-organization to biological feedback delays: 2D models of fish pigmentation.

Science.gov (United States)

Gaffney, E A; Lee, S Seirin

2015-03-01

Turing morphogen models have been extensively explored in the context of large-scale self-organization in multicellular biological systems. However, reconciling the detailed biology of morphogen dynamics, while accounting for time delays associated with gene expression, reveals aberrant behaviours that are not consistent with early developmental self-organization, especially the requirement for exquisite temporal control. Attempts to reconcile the interpretation of Turing's ideas with an increasing understanding of the mechanisms driving zebrafish pigmentation suggests that one should reconsider Turing's model in terms of pigment cells rather than morphogens (Nakamasu et al., 2009, PNAS, 106: , 8429-8434; Yamaguchi et al., 2007, PNAS, 104: , 4790-4793). Here the dynamics of pigment cells is subject to response delays implicit in the cell cycle and apoptosis. Hence we explore simulations of fish skin patterning, focussing on the dynamical influence of gene expression delays in morphogen-based Turing models and response delays for cell-based Turing models. We find that reconciling the mechanisms driving the behaviour of Turing systems with observations of fish skin patterning remains a fundamental challenge. © The Authors 2013. Published by Oxford University Press on behalf of the Institute of Mathematics and its Applications. All rights reserved.

Magnetically levitated mesenchymal stem cell spheroids cultured with a collagen gel maintain phenotype and quiescence

Directory of Open Access Journals (Sweden)

Natasha S Lewis

2017-04-01

Full Text Available Multicellular spheroids are an established system for three-dimensional cell culture. Spheroids are typically generated using hanging drop or non-adherent culture; however, an emerging technique is to use magnetic levitation. Herein, mesenchymal stem cell spheroids were generated using magnetic nanoparticles and subsequently cultured within a type I collagen gel, with a view towards developing a bone marrow niche environment. Cells were loaded with magnetic nanoparticles, and suspended beneath an external magnet, inducing self-assembly of multicellular spheroids. Cells in spheroids were viable and compared to corresponding monolayer controls, maintained stem cell phenotype and were quiescent. Interestingly, core spheroid necrosis was not observed, even with increasing spheroid size, in contrast to other commonly used spheroid systems. This mesenchymal stem cell spheroid culture presents a potential platform for modelling in vitro bone marrow stem cell niches, elucidating interactions between cells, as well as a useful model for drug delivery studies.

RSMASS system model development

International Nuclear Information System (INIS)

Marshall, A.C.; Gallup, D.R.

1998-01-01

RSMASS system mass models have been used for more than a decade to make rapid estimates of space reactor power system masses. This paper reviews the evolution of the RSMASS models and summarizes present capabilities. RSMASS has evolved from a simple model used to make rough estimates of space reactor and shield masses to a versatile space reactor power system model. RSMASS uses unique reactor and shield models that permit rapid mass optimization calculations for a variety of space reactor power and propulsion systems. The RSMASS-D upgrade of the original model includes algorithms for the balance of the power system, a number of reactor and shield modeling improvements, and an automatic mass optimization scheme. The RSMASS-D suite of codes cover a very broad range of reactor and power conversion system options as well as propulsion and bimodal reactor systems. Reactor choices include in-core and ex-core thermionic reactors, liquid metal cooled reactors, particle bed reactors, and prismatic configuration reactors. Power conversion options include thermoelectric, thermionic, Stirling, Brayton, and Rankine approaches. Program output includes all major component masses and dimensions, efficiencies, and a description of the design parameters for a mass optimized system. In the past, RSMASS has been used as an aid to identify and select promising concepts for space power applications. The RSMASS modeling approach has been demonstrated to be a valuable tool for guiding optimization of the power system design; consequently, the model is useful during system design and development as well as during the selection process. An improved in-core thermionic reactor system model RSMASS-T is now under development. The current development of the RSMASS-T code represents the next evolutionary stage of the RSMASS models. RSMASS-T includes many modeling improvements and is planned to be more user-friendly. RSMASS-T will be released as a fully documented, certified code at the end of

The Earth System Model

Science.gov (United States)

Schoeberl, Mark; Rood, Richard B.; Hildebrand, Peter; Raymond, Carol

2003-01-01

The Earth System Model is the natural evolution of current climate models and will be the ultimate embodiment of our geophysical understanding of the planet. These models are constructed from components - atmosphere, ocean, ice, land, chemistry, solid earth, etc. models and merged together through a coupling program which is responsible for the exchange of data from the components. Climate models and future earth system models will have standardized modules, and these standards are now being developed by the ESMF project funded by NASA. The Earth System Model will have a variety of uses beyond climate prediction. The model can be used to build climate data records making it the core of an assimilation system, and it can be used in OSSE experiments to evaluate. The computing and storage requirements for the ESM appear to be daunting. However, the Japanese ES theoretical computing capability is already within 20% of the minimum requirements needed for some 2010 climate model applications. Thus it seems very possible that a focused effort to build an Earth System Model will achieve succcss.

Biomaterials in co-culture systems: towards optimizing tissue integration and cell signaling within scaffolds.

Science.gov (United States)

Battiston, Kyle G; Cheung, Jane W C; Jain, Devika; Santerre, J Paul

2014-05-01

Most natural tissues consist of multi-cellular systems made up of two or more cell types. However, some of these tissues may not regenerate themselves following tissue injury or disease without some form of intervention, such as from the use of tissue engineered constructs. Recent studies have increasingly used co-cultures in tissue engineering applications as these systems better model the natural tissues, both physically and biologically. This review aims to identify the challenges of using co-culture systems and to highlight different approaches with respect to the use of biomaterials in the use of such systems. The application of co-culture systems to stimulate a desired biological response and examples of studies within particular tissue engineering disciplines are summarized. A description of different analytical co-culture systems is also discussed and the role of biomaterials in the future of co-culture research are elaborated on. Understanding the complex cell-cell and cell-biomaterial interactions involved in co-culture systems will ultimately lead the field towards biomaterial concepts and designs with specific biochemical, electrical, and mechanical characteristics that are tailored towards the needs of distinct co-culture systems. Copyright © 2014 Elsevier Ltd. All rights reserved.

Human performance modeling for system of systems analytics.

Energy Technology Data Exchange (ETDEWEB)

Dixon, Kevin R.; Lawton, Craig R.; Basilico, Justin Derrick; Longsine, Dennis E. (INTERA, Inc., Austin, TX); Forsythe, James Chris; Gauthier, John Henry; Le, Hai D.

2008-10-01

A Laboratory-Directed Research and Development project was initiated in 2005 to investigate Human Performance Modeling in a System of Systems analytic environment. SAND2006-6569 and SAND2006-7911 document interim results from this effort; this report documents the final results. The problem is difficult because of the number of humans involved in a System of Systems environment and the generally poorly defined nature of the tasks that each human must perform. A two-pronged strategy was followed: one prong was to develop human models using a probability-based method similar to that first developed for relatively well-understood probability based performance modeling; another prong was to investigate more state-of-art human cognition models. The probability-based modeling resulted in a comprehensive addition of human-modeling capability to the existing SoSAT computer program. The cognitive modeling resulted in an increased understanding of what is necessary to incorporate cognition-based models to a System of Systems analytic environment.

The biomechanical role of overall-shape transformation in a primitive multicellular organism: A case study of dimorphism in the filamentous cyanobacterium Arthrospira platensis.

Science.gov (United States)

Chaiyasitdhi, Atitheb; Miphonpanyatawichok, Wirat; Riehle, Mathis Oliver; Phatthanakun, Rungrueang; Surareungchai, Werasak; Kundhikanjana, Worasom; Kuntanawat, Panwong

2018-01-01

Morphological transformations in primitive organisms have long been observed; however, its biomechanical roles are largely unexplored. In this study, we investigate the structural advantages of dimorphism in Arthrospira platensis, a filamentous multicellular cyanobacterium. We report that helical trichomes, the default shape, have a higher persistence length (Lp), indicating a higher resistance to bending or a large value of flexural rigidity (kf), the product of the local cell stiffness (E) and the moment of inertia of the trichomes' cross-section (I). Through Atomic Force Microscopy (AFM), we determined that the E of straight and helical trichomes were the same. In contrast, our computational model shows that I is greatly dependent on helical radii, implying that trichome morphology is the major contributor to kf variation. According to our estimation, increasing the helical radii alone can increase kf by 2 orders of magnitude. We also observe that straight trichomes have improved gliding ability, due to its structure and lower kf. Our study shows that dimorphism provides mechanical adjustability to the organism and may allow it to thrive in different environmental conditions. The higher kf provides helical trichomes a better nutrient uptake through advection in aquatic environments. On the other hand, the lower kf improves the gliding ability of straight trichomes in aquatic environments, enabling it to chemotactically relocate to more favorable territories when it encounters certain environmental stresses. When more optimal conditions are encountered, straight trichomes can revert to their original helical form. Our study is one of the first to highlight the biomechanical role of an overall-shape transformation in cyanobacteria.

Optimization of large-scale heterogeneous system-of-systems models.

Energy Technology Data Exchange (ETDEWEB)

Parekh, Ojas; Watson, Jean-Paul; Phillips, Cynthia Ann; Siirola, John; Swiler, Laura Painton; Hough, Patricia Diane (Sandia National Laboratories, Livermore, CA); Lee, Herbert K. H. (University of California, Santa Cruz, Santa Cruz, CA); Hart, William Eugene; Gray, Genetha Anne (Sandia National Laboratories, Livermore, CA); Woodruff, David L. (University of California, Davis, Davis, CA)

2012-01-01

Decision makers increasingly rely on large-scale computational models to simulate and analyze complex man-made systems. For example, computational models of national infrastructures are being used to inform government policy, assess economic and national security risks, evaluate infrastructure interdependencies, and plan for the growth and evolution of infrastructure capabilities. A major challenge for decision makers is the analysis of national-scale models that are composed of interacting systems: effective integration of system models is difficult, there are many parameters to analyze in these systems, and fundamental modeling uncertainties complicate analysis. This project is developing optimization methods to effectively represent and analyze large-scale heterogeneous system of systems (HSoS) models, which have emerged as a promising approach for describing such complex man-made systems. These optimization methods enable decision makers to predict future system behavior, manage system risk, assess tradeoffs between system criteria, and identify critical modeling uncertainties.

Selected System Models

Science.gov (United States)

Schmidt-Eisenlohr, F.; Puñal, O.; Klagges, K.; Kirsche, M.

Apart from the general issue of modeling the channel, the PHY and the MAC of wireless networks, there are specific modeling assumptions that are considered for different systems. In this chapter we consider three specific wireless standards and highlight modeling options for them. These are IEEE 802.11 (as example for wireless local area networks), IEEE 802.16 (as example for wireless metropolitan networks) and IEEE 802.15 (as example for body area networks). Each section on these three systems discusses also at the end a set of model implementations that are available today.

Development of three-dimensional lung multicellular spheroids in air- and liquid-interface culture for the evaluation of anticancer therapeutics.

Science.gov (United States)

Meenach, Samantha A; Tsoras, Alexandra N; McGarry, Ronald C; Mansour, Heidi M; Hilt, J Zach; Anderson, Kimberly W

2016-04-01

Three-dimensional (3D) lung multicellular spheroids (MCS) in liquid-covered culture (LCC) and air-interface culture (AIC) conditions have both been developed for the evaluation of aerosol anticancer therapeutics in solution and aerosols, respectively. The MCS were formed by seeding lung cancer cells on top of collagen where they formed spheroids due to the prevalence of cell-to-cell interactions. LCC MCS were exposed to paclitaxel (PTX) in media whereas AIC MCS were exposed to dry powder PEGylated phospholipid aerosol microparticles containing paclitaxel. The difference in viability for 2D versus 3D culture for both LCC and AIC was evaluated along with the effects of the particles on lung epithelium via transepithelial electrical resistance (TEER) measurements. For LCC and AIC conditions, the 3D spheroids were more resistant to treatment with higher IC50 values for A549 and H358 cell lines. TEER results initially indicated a decrease in resistance upon drug or particle exposure, however, these values increased over the course of several days indicating the ability of the cells to recover. Overall, these studies offer a comprehensive in vitro evaluation of aerosol particles used in the treatment of lung cancer while introducing a new method for culturing lung cancer MCS in both LCC and AIC conditions.

Modeller af komplicerede systemer

DEFF Research Database (Denmark)

Mortensen, J.

emphasizes their use in relation to technical systems. All the presented models, with the exception of the types presented in chapter 2, are non-theoretical non-formal conceptual network models. Two new model types are presented: 1) The System-Environment model, which describes the environments interaction...... with conceptual modeling in relation to process control. It´s purpose is to present classify and exemplify the use of a set of qualitative model types. Such model types are useful in the early phase of modeling, where no structured methods are at hand. Although the models are general in character, this thesis......This thesis, "Modeller af komplicerede systemer", represents part of the requirements for the Danish Ph.D.degree. Assisting professor John Nørgaard-Nielsen, M.Sc.E.E.Ph.D. has been principal supervisor and professor Morten Lind, M.Sc.E.E.Ph.D. has been assisting supervisor. The thesis is concerned...

Modeling Novo Nordisk Production Systems

DEFF Research Database (Denmark)

Miller, Thomas Dedenroth

1997-01-01

This report describes attributes of models and systems, and how models can be used for description of production systems. There are special attention on the 'Theory of Domains'.......This report describes attributes of models and systems, and how models can be used for description of production systems. There are special attention on the 'Theory of Domains'....

Impact of jamming on collective cell migration

Science.gov (United States)

Nnetu, Kenechukwu David; Knorr, Melanie; Pawlizak, Steve; Fuhs, Thomas; Zink, Mareike; KäS, Josef A.

2012-02-01

Multi-cellular migration plays an important role in physiological processes such as embryogenesis, cancer metastasis and tissue repair. During migration, single cells undergo cycles of extension, adhesion and retraction resulting in morphological changes. In a confluent monolayer, there are inter-cellular interactions and crowding, however, the impact of these interactions on the dynamics and elasticity of the monolayer at the multi-cellular and single cell level is not well understood. Here we study the dynamics of a confluent epithelial monolayer by simultaneously measuring cell motion at the multi-cellular and single cell level for various cell densities and tensile elasticity. At the multi-cellular level, the system exhibited spatial kinetic transitions from isotropic to anisotropic migration on long times and the velocity of the monolayer decreased with increasing cell density. Moreover, the dynamics was spatially and temporally heterogeneous. Interestingly, the dynamics was also heterogeneous in wound-healing assays and the correlation length was fitted by compressed exponential. On the single cell scale, we observed transient caging effects with increasing cage rearrangement times as the system age due to an increase in density. Also, the density dependent elastic modulus of the monolayer scaled as a weak power law. Together, these findings suggest that caging effects at the single cell level initiates a slow and heterogeneous dynamics at the multi-cellular level which is similar to the glassy dynamics of deformable colloidal systems.

Treatment Analysis in a Cancer Stem Cell Context Using a Tumor Growth Model Based on Cellular Automata.

Science.gov (United States)

Monteagudo, Ángel; Santos, José

2015-01-01

Cancer can be viewed as an emergent behavior in terms of complex system theory and artificial life, Cellular Automata (CA) being the tool most used for studying and characterizing the emergent behavior. Different approaches with CA models were used to model cancer growth. The use of the abstract model of acquired cancer hallmarks permits the direct modeling at cellular level, where a cellular automaton defines the mitotic and apoptotic behavior of cells, and allows for an analysis of different dynamics of the cellular system depending on the presence of the different hallmarks. A CA model based on the presence of hallmarks in the cells, which includes a simulation of the behavior of Cancer Stem Cells (CSC) and their implications for the resultant growth behavior of the multicellular system, was employed. This modeling of cancer growth, in the avascular phase, was employed to analyze the effect of cancer treatments in a cancer stem cell context. The model clearly explains why, after treatment against non-stem cancer cells, the regrowth capability of CSCs generates a faster regrowth of tumor behavior, and also shows that a continuous low-intensity treatment does not favor CSC proliferation and differentiation, thereby allowing an unproblematic control of future tumor regrowth. The analysis performed indicates that, contrary to the current attempts at CSC control, trying to make CSC proliferation more difficult is an important point to consider, especially in the immediate period after a standard treatment for controlling non-stem cancer cell proliferation.

Report on the Imaging Workshop for the Genomes to Life Program, April 16-18, 2002

Energy Technology Data Exchange (ETDEWEB)

Colson, STEVEN

2003-08-04

This report is a result of the Imaging Workshop for the Genomes to Life (GTL) program held April 16-19, 2002, in Charlotte, North Carolina. The meeting was sponsored by the Office of Biological and Environmental Research and the Office of Advanced Scientific Computing Research of the U.S. Department of Energy's (DOE) Office of Science. The purpose of the workshop was to project a broad vision for future needs and determine the value of imaging to GTL program research. The workshop included four technical sessions with plenary lectures on biology and technology perspectives and technical presentations on needs and approaches as they related to the following areas of the GTL program: (1) Molecular machines (protein complexes); (2) Intracellular and cellular structure, function, and processes; (3) Multicellular: Monoclonal and heterogeneous multicellular systems, cell-cell signaling, and model systems; and (4) Cells in situ and in vivo: Bacteria in the natural environment, microenvironment, and in vivo systems.

Modeling Complex Systems

International Nuclear Information System (INIS)

Schreckenberg, M

2004-01-01

This book by Nino Boccara presents a compilation of model systems commonly termed as 'complex'. It starts with a definition of the systems under consideration and how to build up a model to describe the complex dynamics. The subsequent chapters are devoted to various categories of mean-field type models (differential and recurrence equations, chaos) and of agent-based models (cellular automata, networks and power-law distributions). Each chapter is supplemented by a number of exercises and their solutions. The table of contents looks a little arbitrary but the author took the most prominent model systems investigated over the years (and up until now there has been no unified theory covering the various aspects of complex dynamics). The model systems are explained by looking at a number of applications in various fields. The book is written as a textbook for interested students as well as serving as a comprehensive reference for experts. It is an ideal source for topics to be presented in a lecture on dynamics of complex systems. This is the first book on this 'wide' topic and I have long awaited such a book (in fact I planned to write it myself but this is much better than I could ever have written it!). Only section 6 on cellular automata is a little too limited to the author's point of view and one would have expected more about the famous Domany-Kinzel model (and more accurate citation!). In my opinion this is one of the best textbooks published during the last decade and even experts can learn a lot from it. Hopefully there will be an actualization after, say, five years since this field is growing so quickly. The price is too high for students but this, unfortunately, is the normal case today. Nevertheless I think it will be a great success! (book review)

Fibroblast spheroids as a model to study sustained fibroblast quiescence and their crosstalk with tumor cells

Energy Technology Data Exchange (ETDEWEB)

Salmenperä, Pertteli, E-mail: pertteli.salmenpera@helsinki.fi [Department of Virology, Medicum, Faculty of Medicine, University of Helsinki, P.O. Box 21, FIN-00014 (Finland); Karhemo, Piia-Riitta [Research Programs Unit, Translational Cancer Biology, and Institute of Biomedicine, University of Helsinki, P.O. Box 63, FIN-00014 (Finland); Räsänen, Kati [Department of Virology, Medicum, Faculty of Medicine, University of Helsinki, P.O. Box 21, FIN-00014 (Finland); Laakkonen, Pirjo [Research Programs Unit, Translational Cancer Biology, and Institute of Biomedicine, University of Helsinki, P.O. Box 63, FIN-00014 (Finland); Vaheri, Antti [Department of Virology, Medicum, Faculty of Medicine, University of Helsinki, P.O. Box 21, FIN-00014 (Finland)

2016-07-01

Stromal fibroblasts have an important role in regulating tumor progression. Normal and quiescent fibroblasts have been shown to restrict and control cancer cell growth, while cancer-associated, i. e. activated fibroblasts have been shown to enhance proliferation and metastasis of cancer cells. In this study we describe generation of quiescent fibroblasts in multicellular spheroids and their effects on squamous cell carcinoma (SCC) growth in soft-agarose and xenograft models. Quiescent phenotype of fibroblasts was determined by global down-regulation of expression of genes related to cell cycle and increased expression of p27. Interestingly, microarray analysis showed that fibroblast quiescence was associated with similar secretory phenotype as seen in senescence and they expressed senescence-associated-β-galactosidase. Quiescent fibroblasts spheroids also restricted the growth of RT3 SCC cells both in soft-agarose and xenograft models unlike proliferating fibroblasts. Restricted tumor growth was associated with marginally increased tumor cell senescence and cellular differentiation, showed with senescence-associated-β-galactosidase and cytokeratin 7 staining. Our results show that the fibroblasts spheroids can be used as a model to study cellular quiescence and their effects on cancer cell progression. - Highlights: • Fibroblasts acquire a sustained quiescence when grown as multicellular spheroids. • This quiescence is associated with drastic change in gene expression. • Fibroblasts spheroids secrete various inflammation-linked cytokines and chemokines. • Fibroblasts spheroids reduced growth of RT3 SCC cells in xenograft model.

An online model composition tool for system biology models.

Science.gov (United States)

Coskun, Sarp A; Cicek, A Ercument; Lai, Nicola; Dash, Ranjan K; Ozsoyoglu, Z Meral; Ozsoyoglu, Gultekin

2013-09-05

There are multiple representation formats for Systems Biology computational models, and the Systems Biology Markup Language (SBML) is one of the most widely used. SBML is used to capture, store, and distribute computational models by Systems Biology data sources (e.g., the BioModels Database) and researchers. Therefore, there is a need for all-in-one web-based solutions that support advance SBML functionalities such as uploading, editing, composing, visualizing, simulating, querying, and browsing computational models. We present the design and implementation of the Model Composition Tool (Interface) within the PathCase-SB (PathCase Systems Biology) web portal. The tool helps users compose systems biology models to facilitate the complex process of merging systems biology models. We also present three tools that support the model composition tool, namely, (1) Model Simulation Interface that generates a visual plot of the simulation according to user's input, (2) iModel Tool as a platform for users to upload their own models to compose, and (3) SimCom Tool that provides a side by side comparison of models being composed in the same pathway. Finally, we provide a web site that hosts BioModels Database models and a separate web site that hosts SBML Test Suite models. Model composition tool (and the other three tools) can be used with little or no knowledge of the SBML document structure. For this reason, students or anyone who wants to learn about systems biology will benefit from the described functionalities. SBML Test Suite models will be a nice starting point for beginners. And, for more advanced purposes, users will able to access and employ models of the BioModels Database as well.

Introducing Model-Based System Engineering Transforming System Engineering through Model-Based Systems Engineering

Science.gov (United States)

2014-03-31

Web  Presentation...Software  .....................................................  20   Figure  6.  Published   Web  Page  from  Data  Collection...the  term  Model  Based  Engineering  (MBE),  Model  Driven  Engineering  ( MDE ),  or  Model-­‐Based  Systems  

Compact plane illumination plugin device to enable light sheet fluorescence imaging of multi-cellular organisms on an inverted wide-field microscope.

Science.gov (United States)

Guan, Zeyi; Lee, Juhyun; Jiang, Hao; Dong, Siyan; Jen, Nelson; Hsiai, Tzung; Ho, Chih-Ming; Fei, Peng

2016-01-01

We developed a compact plane illumination plugin (PIP) device which enabled plane illumination and light sheet fluorescence imaging on a conventional inverted microscope. The PIP device allowed the integration of microscope with tunable laser sheet profile, fast image acquisition, and 3-D scanning. The device is both compact, measuring approximately 15 by 5 by 5 cm, and cost-effective, since we employed consumer electronics and an inexpensive device molding method. We demonstrated that PIP provided significant contrast and resolution enhancement to conventional microscopy through imaging different multi-cellular fluorescent structures, including 3-D branched cells in vitro and live zebrafish embryos. Imaging with the integration of PIP greatly reduced out-of-focus contamination and generated sharper contrast in acquired 2-D plane images when compared with the stand-alone inverted microscope. As a result, the dynamic fluid domain of the beating zebrafish heart was clearly segmented and the functional monitoring of the heart was achieved. Furthermore, the enhanced axial resolution established by thin plane illumination of PIP enabled the 3-D reconstruction of the branched cellular structures, which leads to the improvement on the functionality of the wide field microscopy.

Particle Tracking Model (PTM) with Coastal Modeling System (CMS)

Science.gov (United States)

2015-11-04

Coastal Inlets Research Program Particle Tracking Model (PTM) with Coastal Modeling System ( CMS ) The Particle Tracking Model (PTM) is a Lagrangian...currents and waves. The Coastal Inlets Research Program (CIRP) supports the PTM with the Coastal Modeling System ( CMS ), which provides coupled wave...and current forcing for PTM simulations. CMS -PTM is implemented in the Surface-water Modeling System, a GUI environment for input development

Using the Model Coupling Toolkit to couple earth system models

Science.gov (United States)

Warner, J.C.; Perlin, N.; Skyllingstad, E.D.

2008-01-01

Continued advances in computational resources are providing the opportunity to operate more sophisticated numerical models. Additionally, there is an increasing demand for multidisciplinary studies that include interactions between different physical processes. Therefore there is a strong desire to develop coupled modeling systems that utilize existing models and allow efficient data exchange and model control. The basic system would entail model "1" running on "M" processors and model "2" running on "N" processors, with efficient exchange of model fields at predetermined synchronization intervals. Here we demonstrate two coupled systems: the coupling of the ocean circulation model Regional Ocean Modeling System (ROMS) to the surface wave model Simulating WAves Nearshore (SWAN), and the coupling of ROMS to the atmospheric model Coupled Ocean Atmosphere Prediction System (COAMPS). Both coupled systems use the Model Coupling Toolkit (MCT) as a mechanism for operation control and inter-model distributed memory transfer of model variables. In this paper we describe requirements and other options for model coupling, explain the MCT library, ROMS, SWAN and COAMPS models, methods for grid decomposition and sparse matrix interpolation, and provide an example from each coupled system. Methods presented in this paper are clearly applicable for coupling of other types of models. ?? 2008 Elsevier Ltd. All rights reserved.

Oxygen consumption rate and mitochondrial density in human melanoma monolayer cultures and multicellular spheroids.

Science.gov (United States)

Hystad, M E; Rofstad, E K

1994-05-15

Rate of oxygen consumption per cell has been shown in previous studies to decrease with increasing depth in the viable rim of multicellular spheroids initiated from rodent cells, human colon-carcinoma cells, and human glioma cells, due to progressive accumulation of quiescent cells during spheroid growth. The purpose of our work was to determine oxygen-consumption profiles in human melanoma spheroids. Monolayer cultures of 4 lines (BEX-c, COX-c, SAX-c, and WIX-c) and spheroid cultures of 2 lines (BEX-c and WIX-c) were subjected to investigation. Spheroids were initiated from monolayer cell cultures and grown in spinner flasks. Rate of oxygen consumption was measured with a Clarke-type electrode. Mitochondrial density was determined by stereological analysis of transmission electron micrographs. Thickness of viable rim and cell packing density were assessed by light microscopy of central spheroid sections. Cell-cycle distribution was determined by analysis of DNA histograms measured by flow cytometry. Cell volume was measured by an electronic particle counter. Rate of oxygen consumption per cell differed by a factor of approximately 1.8 between the 4 cell lines and was positively correlated to total volume of mitochondria per cell. Rate of oxygen consumption per cell and total volume of mitochondria per cell were equal for monolayer cell cultures, 600-microns spheroids and 1,200-microns spheroids of the same line. Mitochondrial density and location in the cell did not differ between cells at the spheroid surface, in the middle of the viable rim and adjacent to the central necrosis. Cell-cycle distribution, cell volume, and cell-packing density in the outer and inner halves of the viable rim were not significantly different. Consequently, the rate of oxygen consumption per cell in inner regions of the viable rim was probably equal to that at the spheroid surface, suggesting that oxygen diffusion distances may be shorter in some melanomas than in many other tumor

A stream-based mathematical model for distributed information processing systems - SysLab system model

OpenAIRE

Klein, Cornel; Rumpe, Bernhard; Broy, Manfred

2014-01-01

In the SysLab project we develop a software engineering method based on a mathematical foundation. The SysLab system model serves as an abstract mathematical model for information systems and their components. It is used to formalize the semantics of all used description techniques such as object diagrams state automata sequence charts or data-flow diagrams. Based on the requirements for such a reference model, we define the system model including its different views and their relationships.

A new source of elemol rich essential oil and existence of multicellular oil glands in leaves of the Dioscorea species.

Science.gov (United States)

Odimegwu, Joy I; Odukoya, Olukemi; Yadav, Ritesh K; Chanotiya, C S; Ogbonnia, Steve; Sangwan, Neelam S

2013-01-01

Dioscorea species is a very important food and drug plant. The tubers of the plant are extensively used in food and drug purposes owing to the presence of steroidal constituent's diosgenin in the tubers. In the present study, we report for the first time that the leaves of Dioscorea composita and Dioscorea floribunda grown under the field conditions exhibited the presence of multicellular oil glands on the epidermal layers of the plants using stereomicroscopy (SM) and scanning electron microscopy (SEM). Essential oil was also isolated from the otherwise not useful herbage of the plant, and gas chromatographic-mass spectroscopy analysis revealed confirmation of the essential oil constituents. Out of the 76 compounds detected in D. floribunda and 37 from D. composita essential oil, major terpenoids which are detected and reported for Dioscorea leaf essential oil are α -terpinene, nerolidol, citronellyl acetate, farnesol, elemol, α -farnesene, valerenyl acetate, and so forth. Elemol was detected as the major constituent of both the Dioscorea species occupying 41% and 22% of D. Floribunda and D. composita essential oils, respectively. In this paper, we report for the first time Dioscorea as a possible novel bioresource for the essential oil besides its well-known importance for yielding diosgenin.

A New Source of Elemol Rich Essential Oil and Existence of Multicellular Oil Glands in Leaves of the Dioscorea Species

Directory of Open Access Journals (Sweden)

Joy I. Odimegwu

2013-01-01

Full Text Available Dioscorea species is a very important food and drug plant. The tubers of the plant are extensively used in food and drug purposes owing to the presence of steroidal constituent’s diosgenin in the tubers. In the present study, we report for the first time that the leaves of Dioscorea composita and Dioscorea floribunda grown under the field conditions exhibited the presence of multicellular oil glands on the epidermal layers of the plants using stereomicroscopy (SM and scanning electron microscopy (SEM. Essential oil was also isolated from the otherwise not useful herbage of the plant, and gas chromatographic-mass spectroscopy analysis revealed confirmation of the essential oil constituents. Out of the 76 compounds detected in D. floribunda and 37 from D. composita essential oil, major terpenoids which are detected and reported for Dioscorea leaf essential oil are α-terpinene, nerolidol, citronellyl acetate, farnesol, elemol, α-farnesene, valerenyl acetate, and so forth. Elemol was detected as the major constituent of both the Dioscorea species occupying 41% and 22% of D. Floribunda and D. composita essential oils, respectively. In this paper, we report for the first time Dioscorea as a possible novel bioresource for the essential oil besides its well-known importance for yielding diosgenin.

Modeling aluminum-air battery systems

Science.gov (United States)

Savinell, R. F.; Willis, M. S.

The performance of a complete aluminum-air battery system was studied with a flowsheet model built from unit models of each battery system component. A plug flow model for heat transfer was used to estimate the amount of heat transferred from the electrolyte to the air stream. The effect of shunt currents on battery performance was found to be insignificant. Using the flowsheet simulator to analyze a 100 cell battery system now under development demonstrated that load current, aluminate concentration, and electrolyte temperature are dominant variables controlling system performance. System efficiency was found to decrease as both load current and aluminate concentration increases. The flowsheet model illustrates the interdependence of separate units on overall system performance.

Modeling Complex Systems

CERN Document Server

Boccara, Nino

2010-01-01

Modeling Complex Systems, 2nd Edition, explores the process of modeling complex systems, providing examples from such diverse fields as ecology, epidemiology, sociology, seismology, and economics. It illustrates how models of complex systems are built and provides indispensable mathematical tools for studying their dynamics. This vital introductory text is useful for advanced undergraduate students in various scientific disciplines, and serves as an important reference book for graduate students and young researchers. This enhanced second edition includes: . -recent research results and bibliographic references -extra footnotes which provide biographical information on cited scientists who have made significant contributions to the field -new and improved worked-out examples to aid a student’s comprehension of the content -exercises to challenge the reader and complement the material Nino Boccara is also the author of Essentials of Mathematica: With Applications to Mathematics and Physics (Springer, 2007).

Intravital multiphoton imaging reveals multicellular streaming as a crucial component of in vivo cell migration in human breast tumors

Science.gov (United States)

Patsialou, Antonia; Bravo-Cordero, Jose Javier; Wang, Yarong; Entenberg, David; Liu, Huiping; Clarke, Michael; Condeelis, John S.

2014-01-01

Metastasis is the main cause of death in breast cancer patients. Cell migration is an essential component of almost every step of the metastatic cascade, especially the early step of invasion inside the primary tumor. In this report, we have used intravital multiphoton microscopy to visualize the different migration patterns of human breast tumor cells in live primary tumors. We used xenograft tumors of MDA-MB-231 cells as well as a low passage xenograft tumor from orthotopically injected patient-derived breast tumor cells. Direct visualization of human tumor cells in vivo shows two patterns of high-speed migration inside primary tumors: a. single cells and b. multicellular streams (i.e., cells following each other in a single file but without cohesive cell junctions). Critically, we found that only streaming and not random migration of single cells was significantly correlated with proximity to vessels, with intravasation and with numbers of elevated circulating tumor cells in the bloodstream. Finally, although the two human tumors were derived from diverse genetic backgrounds, we found that their migratory tumor cells exhibited coordinated gene expression changes that led to the same end-phenotype of enhanced migration involving activating actin polymerization and myosin contraction. Our data are the first direct visualization and assessment of in vivo migration within a live patient-derived breast xenograft tumor. PMID:25013744

Watershed System Model: The Essentials to Model Complex Human-Nature System at the River Basin Scale

Science.gov (United States)

Li, Xin; Cheng, Guodong; Lin, Hui; Cai, Ximing; Fang, Miao; Ge, Yingchun; Hu, Xiaoli; Chen, Min; Li, Weiyue

2018-03-01

Watershed system models are urgently needed to understand complex watershed systems and to support integrated river basin management. Early watershed modeling efforts focused on the representation of hydrologic processes, while the next-generation watershed models should represent the coevolution of the water-land-air-plant-human nexus in a watershed and provide capability of decision-making support. We propose a new modeling framework and discuss the know-how approach to incorporate emerging knowledge into integrated models through data exchange interfaces. We argue that the modeling environment is a useful tool to enable effective model integration, as well as create domain-specific models of river basin systems. The grand challenges in developing next-generation watershed system models include but are not limited to providing an overarching framework for linking natural and social sciences, building a scientifically based decision support system, quantifying and controlling uncertainties, and taking advantage of new technologies and new findings in the various disciplines of watershed science. The eventual goal is to build transdisciplinary, scientifically sound, and scale-explicit watershed system models that are to be codesigned by multidisciplinary communities.

Modeling the earth system

Energy Technology Data Exchange (ETDEWEB)

Ojima, D. [ed.

1992-12-31

The 1990 Global Change Institute (GCI) on Earth System Modeling is the third of a series organized by the Office for Interdisciplinary Earth Studies to look in depth at particular issues critical to developing a better understanding of the earth system. The 1990 GCI on Earth System Modeling was organized around three themes: defining critical gaps in the knowledge of the earth system, developing simplified working models, and validating comprehensive system models. This book is divided into three sections that reflect these themes. Each section begins with a set of background papers offering a brief tutorial on the subject, followed by working group reports developed during the institute. These reports summarize the joint ideas and recommendations of the participants and bring to bear the interdisciplinary perspective that imbued the institute. Since the conclusion of the 1990 Global Change Institute, research programs, nationally and internationally, have moved forward to implement a number of the recommendations made at the institute, and many of the participants have maintained collegial interactions to develop research projects addressing the needs identified during the two weeks in Snowmass.

Modeling cellular systems

CERN Document Server

Matthäus, Franziska; Pahle, Jürgen

2017-01-01

This contributed volume comprises research articles and reviews on topics connected to the mathematical modeling of cellular systems. These contributions cover signaling pathways, stochastic effects, cell motility and mechanics, pattern formation processes, as well as multi-scale approaches. All authors attended the workshop on "Modeling Cellular Systems" which took place in Heidelberg in October 2014. The target audience primarily comprises researchers and experts in the field, but the book may also be beneficial for graduate students.

A computational model predicting disruption of blood vessel development.

Directory of Open Access Journals (Sweden)

Nicole Kleinstreuer

2013-04-01

Full Text Available Vascular development is a complex process regulated by dynamic biological networks that vary in topology and state across different tissues and developmental stages. Signals regulating de novo blood vessel formation (vasculogenesis and remodeling (angiogenesis come from a variety of biological pathways linked to endothelial cell (EC behavior, extracellular matrix (ECM remodeling and the local generation of chemokines and growth factors. Simulating these interactions at a systems level requires sufficient biological detail about the relevant molecular pathways and associated cellular behaviors, and tractable computational models that offset mathematical and biological complexity. Here, we describe a novel multicellular agent-based model of vasculogenesis using the CompuCell3D (http://www.compucell3d.org/ modeling environment supplemented with semi-automatic knowledgebase creation. The model incorporates vascular endothelial growth factor signals, pro- and anti-angiogenic inflammatory chemokine signals, and the plasminogen activating system of enzymes and proteases linked to ECM interactions, to simulate nascent EC organization, growth and remodeling. The model was shown to recapitulate stereotypical capillary plexus formation and structural emergence of non-coded cellular behaviors, such as a heterologous bridging phenomenon linking endothelial tip cells together during formation of polygonal endothelial cords. Molecular targets in the computational model were mapped to signatures of vascular disruption derived from in vitro chemical profiling using the EPA's ToxCast high-throughput screening (HTS dataset. Simulating the HTS data with the cell-agent based model of vascular development predicted adverse effects of a reference anti-angiogenic thalidomide analog, 5HPP-33, on in vitro angiogenesis with respect to both concentration-response and morphological consequences. These findings support the utility of cell agent-based models for simulating a

Validation of Embedded System Verification Models

NARCIS (Netherlands)

Marincic, J.; Mader, Angelika H.; Wieringa, Roelf J.

The result of a model-based requirements verification shows that the model of a system satisfies (or not) formalised system requirements. The verification result is correct only if the model represents the system adequately. No matter what modelling technique we use, what precedes the model

Advancing coupled human-earth system models: The integrated Earth System Model Project

Science.gov (United States)

Thomson, A. M.; Edmonds, J. A.; Collins, W.; Thornton, P. E.; Hurtt, G. C.; Janetos, A. C.; Jones, A.; Mao, J.; Chini, L. P.; Calvin, K. V.; Bond-Lamberty, B. P.; Shi, X.

2012-12-01

As human and biogeophysical models develop, opportunities for connections between them evolve and can be used to advance our understanding of human-earth systems interaction in the context of a changing climate. One such integration is taking place with the Community Earth System Model (CESM) and the Global Change Assessment Model (GCAM). A multi-disciplinary, multi-institution team has succeeded in integrating the GCAM integrated assessment model of human activity into CESM to dynamically represent the feedbacks between changing climate and human decision making, in the context of greenhouse gas mitigation policies. The first applications of this capability have focused on the feedbacks between climate change impacts on terrestrial ecosystem productivity and human decisions affecting future land use change, which are in turn connected to human decisions about energy systems and bioenergy production. These experiments have been conducted in the context of the RCP4.5 scenario, one of four pathways of future radiative forcing being used in CMIP5, which constrains future human-induced greenhouse gas emissions from energy and land activities to stabilize radiative forcing at 4.5 W/m2 (~650 ppm CO2 -eq) by 2100. When this pathway is run in GCAM with the climate feedback on terrestrial productivity from CESM, there are implications for both the land use and energy system changes required for stabilization. Early findings indicate that traditional definitions of radiative forcing used in scenario development are missing a critical component of the biogeophysical consequences of land use change and their contribution to effective radiative forcing. Initial full coupling of the two global models has important implications for how climate impacts on terrestrial ecosystems changes the dynamics of future land use change for agriculture and forestry, particularly in the context of a climate mitigation policy designed to reduce emissions from land use as well as energy systems

Sordaria macrospora, a model organism to study fungal cellular development.

Science.gov (United States)

Engh, Ines; Nowrousian, Minou; Kück, Ulrich

2010-12-01

During the development of multicellular eukaryotes, the processes of cellular growth and organogenesis are tightly coordinated. Since the 1940s, filamentous fungi have served as genetic model organisms to decipher basic mechanisms underlying eukaryotic cell differentiation. Here, we focus on Sordaria macrospora, a homothallic ascomycete and important model organism for developmental biology. During its sexual life cycle, S. macrospora forms three-dimensional fruiting bodies, a complex process involving the formation of different cell types. S. macrospora can be used for genetic, biochemical and cellular experimental approaches since diverse tools, including fluorescence microscopy, a marker recycling system and gene libraries, are available. Moreover, the genome of S. macrospora has been sequenced and allows functional genomics analyses. Over the past years, our group has generated and analysed a number of developmental mutants which has greatly enhanced our fundamental understanding about fungal morphogenesis. In addition, our recent research activities have established a link between developmental proteins and conserved signalling cascades, ultimately leading to a regulatory network controlling differentiation processes in a eukaryotic model organism. This review summarizes the results of our recent findings, thus advancing current knowledge of the general principles and paradigms underpinning eukaryotic cell differentiation and development. Copyright © 2010 Elsevier GmbH. All rights reserved.

Pembangunan Model Restaurant Management System

OpenAIRE

Fredy Jingga; Natalia Limantara

2014-01-01

Model design for Restaurant Management System aims to help in restaurant business process, where Restaurant Management System (RMS) help the waitress and chef could interact each other without paper limitation.  This Restaurant Management System Model develop using Agile Methodology and developed based on PHP Programming Langguage. The database management system is using MySQL. This web-based application model will enable the waitress and the chef to interact in realtime, from the time they a...

In vitro and in vivo ion beam targeted micro-irradiation for radiobiology

International Nuclear Information System (INIS)

Vianna, Francois

2014-01-01

The main goal of radiobiology is to understand the effects of ionizing radiations on the living. These past decades, ion microbeams have shown to be important tools to study for example the effects of low dose exposure, or the bystander effect. Since 2003, the CENBG has been equipped with a system to perform targeted micro-irradiation of living samples. Recently, microbeams applications on this subject have diversified and the study of DNA repair mechanisms at the cellular and multicellular scales, in vitro and in vivo, has become possible thanks to important evolutions of fluorescence imaging techniques and cellular biology. To take into account these new approaches, the CENBG micro-irradiation beamline has been entirely redesigned and rebuilt to implement new features and to improve the existing ones. My PhD objectives were i) commissioning the facility, ii) characterizing the system on track etch detectors, and on living samples, iii) implementing protocols to perform targeted irradiations of living samples with a con-trolled delivered dose, at the cellular and multicellular scales, and to visualize the early consequences online, iv) modelling these irradiations to explain the biological results using the calculated physical data. The work of these past years has allowed us i) to measure the performances of our system: a beam spot size of about 2 μm and a targeting accuracy of ± 2 μm, and to develop ion detection systems for an absolute delivered dose control, ii) to create highly localized radiation-induced DNA damages and to see online the recruitment of DNA repair proteins, iii) to apply these protocols to generate radiation-induced DNA damages in vivo inside a multicellular organism at the embryonic stage: Caenorhabditis elegans. These results have opened up many perspectives on the study of the interaction between ionizing radiations and the living, at the cellular and multicellular scales, in vitro and in vivo. (author) [fr

Treatment Analysis in a Cancer Stem Cell Context Using a Tumor Growth Model Based on Cellular Automata.

Directory of Open Access Journals (Sweden)

Ángel Monteagudo

Full Text Available Cancer can be viewed as an emergent behavior in terms of complex system theory and artificial life, Cellular Automata (CA being the tool most used for studying and characterizing the emergent behavior. Different approaches with CA models were used to model cancer growth. The use of the abstract model of acquired cancer hallmarks permits the direct modeling at cellular level, where a cellular automaton defines the mitotic and apoptotic behavior of cells, and allows for an analysis of different dynamics of the cellular system depending on the presence of the different hallmarks. A CA model based on the presence of hallmarks in the cells, which includes a simulation of the behavior of Cancer Stem Cells (CSC and their implications for the resultant growth behavior of the multicellular system, was employed. This modeling of cancer growth, in the avascular phase, was employed to analyze the effect of cancer treatments in a cancer stem cell context. The model clearly explains why, after treatment against non-stem cancer cells, the regrowth capability of CSCs generates a faster regrowth of tumor behavior, and also shows that a continuous low-intensity treatment does not favor CSC proliferation and differentiation, thereby allowing an unproblematic control of future tumor regrowth. The analysis performed indicates that, contrary to the current attempts at CSC control, trying to make CSC proliferation more difficult is an important point to consider, especially in the immediate period after a standard treatment for controlling non-stem cancer cell proliferation.

On Modelling an Immune System

OpenAIRE

Monroy, Raúl; Saab, Rosa; Godínez, Fernando

2004-01-01

Immune systems of live forms have been an abundant source of inspiration to contemporary computer scientists. Problem solving strategies, stemming from known immune system phenomena, have been successfully applied to challenging problems of modern computing. However, research in artificial immune systems has overlooked establishing a coherent model of known immune system behaviour. This paper aims reports on an preliminary computer model of an immune system, where each immune system component...

Multiple system modelling of waste management

International Nuclear Information System (INIS)

Eriksson, Ola; Bisaillon, Mattias

2011-01-01

Highlights: → Linking of models will provide a more complete, correct and credible picture of the systems. → The linking procedure is easy to perform and also leads to activation of project partners. → The simulation procedure is a bit more complicated and calls for the ability to run both models. - Abstract: Due to increased environmental awareness, planning and performance of waste management has become more and more complex. Therefore waste management has early been subject to different types of modelling. Another field with long experience of modelling and systems perspective is energy systems. The two modelling traditions have developed side by side, but so far there are very few attempts to combine them. Waste management systems can be linked together with energy systems through incineration plants. The models for waste management can be modelled on a quite detailed level whereas surrounding systems are modelled in a more simplistic way. This is a problem, as previous studies have shown that assumptions on the surrounding system often tend to be important for the conclusions. In this paper it is shown how two models, one for the district heating system (MARTES) and another one for the waste management system (ORWARE), can be linked together. The strengths and weaknesses with model linking are discussed when compared to simplistic assumptions on effects in the energy and waste management systems. It is concluded that the linking of models will provide a more complete, correct and credible picture of the consequences of different simultaneous changes in the systems. The linking procedure is easy to perform and also leads to activation of project partners. However, the simulation procedure is a bit more complicated and calls for the ability to run both models.

Transforming Graphical System Models to Graphical Attack Models

DEFF Research Database (Denmark)

Ivanova, Marieta Georgieva; Probst, Christian W.; Hansen, Rene Rydhof

2016-01-01

Manually identifying possible attacks on an organisation is a complex undertaking; many different factors must be considered, and the resulting attack scenarios can be complex and hard to maintain as the organisation changes. System models provide a systematic representation of organisations...... approach to transforming graphical system models to graphical attack models in the form of attack trees. Based on an asset in the model, our transformations result in an attack tree that represents attacks by all possible actors in the model, after which the actor in question has obtained the asset....

A Model-Based Systems Engineering Methodology for Employing Architecture In System Analysis: Developing Simulation Models Using Systems Modeling Language Products to Link Architecture and Analysis

Science.gov (United States)

2016-06-01

18 Figure 5 Spiral Model ...............................................................................................20 Figure 6...Memorandum No. 1. Tallahassee, FL: Florida Department of Transportation. 19 The spiral model of system development, first introduced in Boehm...system capabilities into the waterfall model would prove quite difficult, the spiral model assumes that available technologies will change over the

Excitable signal relay in Dictyostelium discoideum

Science.gov (United States)

Mestler, Troy; Schwab, David; Mehta, Pankaj; Gregor, Thomas

2011-03-01

The social amoeba D. discoideum transitions when starved from a collection of individual cells into a multicellular spore-complex. During this process, amoebae display several interesting phenomena including intercellular signaling, pattern formation, and cell differentiation. At the heart of these phenomena is the exchange of the signaling molecule cyclic-AMP, which has previously been extensively studied using a variety of indirect methods. Here we employ a sensor that uses a compound fluorescent protein whose emission spectrum changes in the presence of bound cyclic AMP to directly monitor, in real time and in vivo, intracellular cAMP concentrations. We use cells expressing this sensor in microchemostats to study intracellular cAMP concentrations at the single-cell level in response to precise, dynamically-controlled external cAMP stimulation. Specifically, we show that these cells display excitability much like that found in neurons and agree experimentally quite well with a modified FitzHugh-Nagumo dynamical systems model. This single-cell model sets groundwork for a comprehensive multicellular model that promises to explain emergent behavior in D. discoideum.

Modeling Multi-Level Systems

CERN Document Server

Iordache, Octavian

2011-01-01

This book is devoted to modeling of multi-level complex systems, a challenging domain for engineers, researchers and entrepreneurs, confronted with the transition from learning and adaptability to evolvability and autonomy for technologies, devices and problem solving methods. Chapter 1 introduces the multi-scale and multi-level systems and highlights their presence in different domains of science and technology. Methodologies as, random systems, non-Archimedean analysis, category theory and specific techniques as model categorification and integrative closure, are presented in chapter 2. Chapters 3 and 4 describe polystochastic models, PSM, and their developments. Categorical formulation of integrative closure offers the general PSM framework which serves as a flexible guideline for a large variety of multi-level modeling problems. Focusing on chemical engineering, pharmaceutical and environmental case studies, the chapters 5 to 8 analyze mixing, turbulent dispersion and entropy production for multi-scale sy...

Brief history of agricultural systems modeling.

Science.gov (United States)

Jones, James W; Antle, John M; Basso, Bruno; Boote, Kenneth J; Conant, Richard T; Foster, Ian; Godfray, H Charles J; Herrero, Mario; Howitt, Richard E; Janssen, Sander; Keating, Brian A; Munoz-Carpena, Rafael; Porter, Cheryl H; Rosenzweig, Cynthia; Wheeler, Tim R

2017-07-01

Agricultural systems science generates knowledge that allows researchers to consider complex problems or take informed agricultural decisions. The rich history of this science exemplifies the diversity of systems and scales over which they operate and have been studied. Modeling, an essential tool in agricultural systems science, has been accomplished by scientists from a wide range of disciplines, who have contributed concepts and tools over more than six decades. As agricultural scientists now consider the "next generation" models, data, and knowledge products needed to meet the increasingly complex systems problems faced by society, it is important to take stock of this history and its lessons to ensure that we avoid re-invention and strive to consider all dimensions of associated challenges. To this end, we summarize here the history of agricultural systems modeling and identify lessons learned that can help guide the design and development of next generation of agricultural system tools and methods. A number of past events combined with overall technological progress in other fields have strongly contributed to the evolution of agricultural system modeling, including development of process-based bio-physical models of crops and livestock, statistical models based on historical observations, and economic optimization and simulation models at household and regional to global scales. Characteristics of agricultural systems models have varied widely depending on the systems involved, their scales, and the wide range of purposes that motivated their development and use by researchers in different disciplines. Recent trends in broader collaboration across institutions, across disciplines, and between the public and private sectors suggest that the stage is set for the major advances in agricultural systems science that are needed for the next generation of models, databases, knowledge products and decision support systems. The lessons from history should be

The systems integration modeling system

International Nuclear Information System (INIS)

Danker, W.J.; Williams, J.R.

1990-01-01

This paper discusses the systems integration modeling system (SIMS), an analysis tool for the detailed evaluation of the structure and related performance of the Federal Waste Management System (FWMS) and its interface with waste generators. It's use for evaluations in support of system-level decisions as to FWMS configurations, the allocation, sizing, balancing and integration of functions among elements, and the establishment of system-preferred waste selection and sequencing methods and other operating strategies is presented. SIMS includes major analysis submodels which quantify the detailed characteristics of individual waste items, loaded casks and waste packages, simulate the detailed logistics of handling and processing discrete waste items and packages, and perform detailed cost evaluations

Inhibition of hexokinase-2 with targeted liposomal 3-bromopyruvate in an ovarian tumor spheroid model of aerobic glycolysis.

Science.gov (United States)

Gandham, Srujan Kumar; Talekar, Meghna; Singh, Amit; Amiji, Mansoor M

2015-01-01

The objective of this study was to evaluate the expression levels of glycolytic markers, especially hexokinase-2 (HK2), using a three-dimensional multicellular spheroid model of human ovarian adenocarcinoma (SKOV-3) cells and to develop an epidermal growth factor receptor-targeted liposomal formulation for improving inhibition of HK2 and the cytotoxicity of 3-bromopyruvate (3-BPA). Multicellular SKOV-3 tumor spheroids were developed using the hanging drop method and expression levels of glycolytic markers were examined. Non-targeted and epidermal growth factor receptor-targeted liposomal formulations of 3-BPA were formulated and characterized. Permeability and cellular uptake of the liposomal formulations in three-dimensional SKOV-3 spheroids was evaluated using confocal microscopy. The cytotoxicity and HK2 inhibition potential of solution form of 3-BPA was compared to the corresponding liposomal formulation by using cell proliferation and HK2 enzymatic assays. SKOV-3 spheroids were reproducibly developed using the 96-well hanging drop method, with an average size of 900 µm by day 5. HK2 enzyme activity levels under hypoxic conditions were found to be higher than under normoxic conditions (P<0.0001, Student's t-test, unpaired and two-tailed). Liposomal formulations (both non-targeted and targeted) of 3-BPA showed a more potent inhibitory effect (P<0.001, Student's t-test, unpaired and two-tailed) at a dose of 50 µM than the aqueous solution form at 3, 6, and 24 hours post administration. Similarly, the cytotoxic activity 3-BPA at various concentrations (10 µM-100 µM) showed that the liposomal formulations had an enhanced cytotoxic effect of 2-5-fold (P<0.0001, Student's t-test, unpaired and two-tailed) when compared to the aqueous solution form for both 10 µM and 25 µM concentrations. SKOV-3 spheroids developed by the hanging drop method can be used as a tumor aerobic glycolysis model for evaluation of therapies targeting the glycolytic pathway in cancer

Insight into the Microbial Multicellular Lifestyle via Flow-Cell Technology and Confocal Microscopy

DEFF Research Database (Denmark)

Pamp, Sünje Johanna; Sternberg, Claus; Tolker-Nielsen, Tim

2009-01-01

, industry, and human health. Accordingly a number of biofilm model systems, molecular tools, microscopic techniques, and image analysis programs have been employed for the study of biofilms under controlled and reproducible conditions. Studies using confocal laser scanning microscopy (CLSM) of biofilms...

Long-term culture of organotypic multicellular glioma spheroids: a good culture model for studying gliomas

NARCIS (Netherlands)

Kaaijk, P.; Troost, D.; Das, P. K.; Leenstra, S.; Bosch, D. A.

1995-01-01

Gliomas, as well as other solid tumours, contain tumour stroma composed of connective tissue, macrophages, capillaries and other non-cellular constituents. Therefore, a homogeneous culture of tumour cells alone, as is often used as a culture model for gliomas, is not ideal to study all aspects of

Service systems concepts, modeling, and programming

CERN Document Server

Cardoso, Jorge; Poels, Geert

2014-01-01

This SpringerBrief explores the internal workings of service systems. The authors propose a lightweight semantic model for an effective representation to capture the essence of service systems. Key topics include modeling frameworks, service descriptions and linked data, creating service instances, tool support, and applications in enterprises.Previous books on service system modeling and various streams of scientific developments used an external perspective to describe how systems can be integrated. This brief introduces the concept of white-box service system modeling as an approach to mo

Modeling bistable cell-fate choices in the Drosophila eye: qualitative and quantitative perspectives

Science.gov (United States)

Graham, Thomas G. W.; Tabei, S. M. Ali; Dinner, Aaron R.; Rebay, Ilaria

2010-01-01

A major goal of developmental biology is to understand the molecular mechanisms whereby genetic signaling networks establish and maintain distinct cell types within multicellular organisms. Here, we review cell-fate decisions in the developing eye of Drosophila melanogaster and the experimental results that have revealed the topology of the underlying signaling circuitries. We then propose that switch-like network motifs based on positive feedback play a central role in cell-fate choice, and discuss how mathematical modeling can be used to understand and predict the bistable or multistable behavior of such networks. PMID:20570936

The filamentous fungus Sordaria macrospora as a genetic model to study fruiting body development.

Science.gov (United States)

Teichert, Ines; Nowrousian, Minou; Pöggeler, Stefanie; Kück, Ulrich

2014-01-01

Filamentous fungi are excellent experimental systems due to their short life cycles as well as easy and safe manipulation in the laboratory. They form three-dimensional structures with numerous different cell types and have a long tradition as genetic model organisms used to unravel basic mechanisms underlying eukaryotic cell differentiation. The filamentous ascomycete Sordaria macrospora is a model system for sexual fruiting body (perithecia) formation. S. macrospora is homothallic, i.e., self-fertile, easily genetically tractable, and well suited for large-scale genomics, transcriptomics, and proteomics studies. Specific features of its life cycle and the availability of a developmental mutant library make it an excellent system for studying cellular differentiation at the molecular level. In this review, we focus on recent developments in identifying gene and protein regulatory networks governing perithecia formation. A number of tools have been developed to genetically analyze developmental mutants and dissect transcriptional profiles at different developmental stages. Protein interaction studies allowed us to identify a highly conserved eukaryotic multisubunit protein complex, the striatin-interacting phosphatase and kinase complex and its role in sexual development. We have further identified a number of proteins involved in chromatin remodeling and transcriptional regulation of fruiting body development. Furthermore, we review the involvement of metabolic processes from both primary and secondary metabolism, and the role of nutrient recycling by autophagy in perithecia formation. Our research has uncovered numerous players regulating multicellular development in S. macrospora. Future research will focus on mechanistically understanding how these players are orchestrated in this fungal model system. Copyright © 2014 Elsevier Inc. All rights reserved.

Agent-based model of fecal microbial transplant effect on bile acid metabolism on suppressing Clostridium difficile infection: an example of agent-based modeling of intestinal bacterial infection.

Science.gov (United States)

Peer, Xavier; An, Gary

2014-10-01

Agent-based modeling is a computational modeling method that represents system-level behavior as arising from multiple interactions between the multiple components that make up a system. Biological systems are thus readily described using agent-based models (ABMs), as multi-cellular organisms can be viewed as populations of interacting cells, and microbial systems manifest as colonies of individual microbes. Intersections between these two domains underlie an increasing number of pathophysiological processes, and the intestinal tract represents one of the most significant locations for these inter-domain interactions, so much so that it can be considered an internal ecology of varying robustness and function. Intestinal infections represent significant disturbances of this internal ecology, and one of the most clinically relevant intestinal infections is Clostridium difficile infection (CDI). CDI is precipitated by the use of broad-spectrum antibiotics, involves the depletion of commensal microbiota, and alterations in bile acid composition in the intestinal lumen. We present an example ABM of CDI (the C. difficile Infection ABM, or CDIABM) to examine fundamental dynamics of the pathogenesis of CDI and its response to treatment with anti-CDI antibiotics and a newer treatment therapy, fecal microbial transplant. The CDIABM focuses on one specific mechanism of potential CDI suppression: commensal modulation of bile acid composition. Even given its abstraction, the CDIABM reproduces essential dynamics of CDI and its response to therapy, and identifies a paradoxical zone of behavior that provides insight into the role of intestinal nutritional status and the efficacy of anti-CDI therapies. It is hoped that this use case example of the CDIABM can demonstrate the usefulness of both agent-based modeling and the application of abstract functional representation as the biomedical community seeks to address the challenges of increasingly complex diseases with the goal of

Stochastic Modelling of Energy Systems

DEFF Research Database (Denmark)

Andersen, Klaus Kaae

2001-01-01

is that the model structure has to be adequate for practical applications, such as system simulation, fault detection and diagnosis, and design of control strategies. This also reflects on the methods used for identification of the component models. The main result from this research is the identification......In this thesis dynamic models of typical components in Danish heating systems are considered. Emphasis is made on describing and evaluating mathematical methods for identification of such models, and on presentation of component models for practical applications. The thesis consists of seven...... research papers (case studies) together with a summary report. Each case study takes it's starting point in typical heating system components and both, the applied mathematical modelling methods and the application aspects, are considered. The summary report gives an introduction to the scope...

Test-driven modeling of embedded systems

DEFF Research Database (Denmark)

Munck, Allan; Madsen, Jan

2015-01-01

To benefit maximally from model-based systems engineering (MBSE) trustworthy high quality models are required. From the software disciplines it is known that test-driven development (TDD) can significantly increase the quality of the products. Using a test-driven approach with MBSE may have...... a similar positive effect on the quality of the system models and the resulting products and may therefore be desirable. To define a test-driven model-based systems engineering (TD-MBSE) approach, we must define this approach for numerous sub disciplines such as modeling of requirements, use cases...... suggest that our method provides a sound foundation for rapid development of high quality system models....

Modeling on a PWR power conversion system with system program

International Nuclear Information System (INIS)

Gao Rui; Yang Yanhua; Lin Meng

2007-01-01

Based on the power conversion system of nuclear and conventional islands of Daya Bay Power Station, this paper models the thermal-hydraulic systems of primary and secondary loops for PWR by using the PWR best-estimate program-RELAP5. To simulate the full-scope power conversion system, not only the traditional basic system models of nuclear island, but also the major system models of conventional island are all considered and modeled. A comparison between the calculated results and the actual data of reactor demonstrates a fine match for Daya Bay Nuclear Power Station, and manifests the feasibility in simulating full-scope power conversion system of PWR by RELAP5 at the same time. (authors)

Formal heterogeneous system modeling with SystemC

DEFF Research Database (Denmark)

Niaki, Seyed Hosein Attarzadeh; Jakobsen, Mikkel Koefoed; Sulonen, Tero

2012-01-01

Electronic System Level (ESL) design of embedded systems proposes raising the abstraction level of the design entry to cope with the increasing complexity of such systems. To exploit the benefits of ESL, design languages should allow specification of models which are a) heterogeneous, to describe...

Model Driven Development of Data Sensitive Systems

DEFF Research Database (Denmark)

Olsen, Petur

2014-01-01

storage systems, where the actual values of the data is not relevant for the behavior of the system. For many systems the values are important. For instance the control flow of the system can be dependent on the input values. We call this type of system data sensitive, as the execution is sensitive...... to the values of variables. This theses strives to improve model-driven development of such data-sensitive systems. This is done by addressing three research questions. In the first we combine state-based modeling and abstract interpretation, in order to ease modeling of data-sensitive systems, while allowing...... efficient model-checking and model-based testing. In the second we develop automatic abstraction learning used together with model learning, in order to allow fully automatic learning of data-sensitive systems to allow learning of larger systems. In the third we develop an approach for modeling and model-based...

Mathematical Modeling Of Life-Support Systems

Science.gov (United States)

Seshan, Panchalam K.; Ganapathi, Balasubramanian; Jan, Darrell L.; Ferrall, Joseph F.; Rohatgi, Naresh K.

1994-01-01

Generic hierarchical model of life-support system developed to facilitate comparisons of options in design of system. Model represents combinations of interdependent subsystems supporting microbes, plants, fish, and land animals (including humans). Generic model enables rapid configuration of variety of specific life support component models for tradeoff studies culminating in single system design. Enables rapid evaluation of effects of substituting alternate technologies and even entire groups of technologies and subsystems. Used to synthesize and analyze life-support systems ranging from relatively simple, nonregenerative units like aquariums to complex closed-loop systems aboard submarines or spacecraft. Model, called Generic Modular Flow Schematic (GMFS), coded in such chemical-process-simulation languages as Aspen Plus and expressed as three-dimensional spreadsheet.

Interaction of Defensins with Model Cell Membranes

Science.gov (United States)

Sanders, Lori K.; Schmidt, Nathan W.; Yang, Lihua; Mishra, Abhijit; Gordon, Vernita D.; Selsted, Michael E.; Wong, Gerard C. L.

2009-03-01

Antimicrobial peptides (AMPs) comprise a key component of innate immunity for a wide range of multicellular organisms. For many AMPs, activity comes from their ability to selectively disrupt and lyse bacterial cell membranes. There are a number of proposed models for this action, but the detailed molecular mechanism of selective membrane permeation remains unclear. Theta defensins are circularized peptides with a high degree of selectivity. We investigate the interaction of model bacterial and eukaryotic cell membranes with theta defensins RTD-1, BTD-7, and compare them to protegrin PG-1, a prototypical AMP, using synchrotron small angle x-ray scattering (SAXS). The relationship between membrane composition and peptide induced changes in membrane curvature and topology is examined. By comparing the membrane phase behavior induced by these different peptides we will discuss the importance of amino acid composition and placement on membrane rearrangement.

Mobility Models for Systems Evaluation

Science.gov (United States)

Musolesi, Mirco; Mascolo, Cecilia

Mobility models are used to simulate and evaluate the performance of mobile wireless systems and the algorithms and protocols at the basis of them. The definition of realistic mobility models is one of the most critical and, at the same time, difficult aspects of the simulation of applications and systems designed for mobile environments. There are essentially two possible types of mobility patterns that can be used to evaluate mobile network protocols and algorithms by means of simulations: traces and synthetic models [130]. Traces are obtained by means of measurements of deployed systems and usually consist of logs of connectivity or location information, whereas synthetic models are mathematical models, such as sets of equations, which try to capture the movement of the devices.

Modeling and estimating system availability

International Nuclear Information System (INIS)

Gaver, D.P.; Chu, B.B.

1976-11-01

Mathematical models to infer the availability of various types of more or less complicated systems are described. The analyses presented are probabilistic in nature and consist of three parts: a presentation of various analytic models for availability; a means of deriving approximate probability limits on system availability; and a means of statistical inference of system availability from sparse data, using a jackknife procedure. Various low-order redundant systems are used as examples, but extension to more complex systems is not difficult

Grey Box Modelling of Hydrological Systems

DEFF Research Database (Denmark)

Thordarson, Fannar Ørn

of two papers where the stochastic differential equation based model is used for sewer runoff from a drainage system. A simple model is used to describe a complex rainfall-runoff process in a catchment, but the stochastic part of the system is formulated to include the increasing uncertainty when...... rainwater flows through the system, as well as describe the lower limit of the uncertainty when the flow approaches zero. The first paper demonstrates in detail the grey box model and all related transformations required to obtain a feasible model for the sewer runoff. In the last paper this model is used......The main topic of the thesis is grey box modelling of hydrologic systems, as well as formulation and assessment of their embedded uncertainties. Grey box model is a combination of a white box model, a physically-based model that is traditionally formulated using deterministic ordinary differential...

Model systems in photosynthesis research

International Nuclear Information System (INIS)

Katz, J.J.; Hindman, J.C.

1981-01-01

After a general discussion of model studies in photosynthesis research, three recently developed model systems are described. The current status of covalently linked chlorophyll pairs as models for P700 and P865 is first briefly reviewed. Mg-tris(pyrochlorophyllide)1,1,1-tris(hydroxymethyl) ethane triester in its folded configuration is then discussed as a rudimentary antenna-photoreaction center model. Finally, self-assembled chlorophyll systems that contain a mixture of monomeric, oligomeric and special pair chlorophyll are shown to have fluorescence emission characteristics that resemble thoe of intact Tribonema aequale at room temperature in that both show fluorescence emission at 675 and 695 nm. In the self-assembled systems the wavelength of the emitted fluorescence depends on the wavelength of excitation, arguing that energy transfer between different chlorophyll species in these systems may be more complex than previously suspected

[Model-based biofuels system analysis: a review].

Science.gov (United States)

Chang, Shiyan; Zhang, Xiliang; Zhao, Lili; Ou, Xunmin

2011-03-01

Model-based system analysis is an important tool for evaluating the potential and impacts of biofuels, and for drafting biofuels technology roadmaps and targets. The broad reach of the biofuels supply chain requires that biofuels system analyses span a range of disciplines, including agriculture/forestry, energy, economics, and the environment. Here we reviewed various models developed for or applied to modeling biofuels, and presented a critical analysis of Agriculture/Forestry System Models, Energy System Models, Integrated Assessment Models, Micro-level Cost, Energy and Emission Calculation Models, and Specific Macro-level Biofuel Models. We focused on the models' strengths, weaknesses, and applicability, facilitating the selection of a suitable type of model for specific issues. Such an analysis was a prerequisite for future biofuels system modeling, and represented a valuable resource for researchers and policy makers.

Pathogen-triggered ethylene signaling mediates systemic-induced susceptibility to herbivory in Arabidopsis.

Science.gov (United States)

Groen, Simon C; Whiteman, Noah K; Bahrami, Adam K; Wilczek, Amity M; Cui, Jianping; Russell, Jacob A; Cibrian-Jaramillo, Angelica; Butler, Ian A; Rana, Jignasha D; Huang, Guo-Hua; Bush, Jenifer; Ausubel, Frederick M; Pierce, Naomi E

2013-11-01

Multicellular eukaryotic organisms are attacked by numerous parasites from diverse phyla, often simultaneously or sequentially. An outstanding question in these interactions is how hosts integrate signals induced by the attack of different parasites. We used a model system comprised of the plant host Arabidopsis thaliana, the hemibiotrophic bacterial phytopathogen Pseudomonas syringae, and herbivorous larvae of the moth Trichoplusia ni (cabbage looper) to characterize mechanisms involved in systemic-induced susceptibility (SIS) to T. ni herbivory caused by prior infection by virulent P. syringae. We uncovered a complex multilayered induction mechanism for SIS to herbivory. In this mechanism, antiherbivore defenses that depend on signaling via (1) the jasmonic acid-isoleucine conjugate (JA-Ile) and (2) other octadecanoids are suppressed by microbe-associated molecular pattern-triggered salicylic acid (SA) signaling and infection-triggered ethylene signaling, respectively. SIS to herbivory is, in turn, counteracted by a combination of the bacterial JA-Ile mimic coronatine and type III virulence-associated effectors. Our results show that SIS to herbivory involves more than antagonistic signaling between SA and JA-Ile and provide insight into the unexpectedly complex mechanisms behind a seemingly simple trade-off in plant defense against multiple enemies.

Selfish genetic elements favor the evolution of a distinction between soma and germline.

Science.gov (United States)

Johnson, Louise J

2008-08-01

Many multicellular organisms have evolved a dedicated germline. This can benefit the whole organism, but its advantages to genetic parasites have not been explored. Here I model the evolutionary success of a selfish element, such as a transposable element or endosymbiont, which is capable of creating or strengthening a germline-soma distinction in a primitively multicellular host, and find that it will always benefit the element to do so. Genes causing germline sequestration can therefore spread in a population even if germline sequestration is maladaptive for the host organism. Costly selfish elements are expected to survive only in sexual populations, so sexual species may experience an additional push toward germline-soma distinction, and hence toward cell differentiation and multicellularity.

Pembangunan Model Restaurant Management System

Directory of Open Access Journals (Sweden)

Fredy Jingga

2014-12-01

Full Text Available Model design for Restaurant Management System aims to help in restaurant business process, where Restaurant Management System (RMS help the waitress and chef could interact each other without paper limitation.  This Restaurant Management System Model develop using Agile Methodology and developed based on PHP Programming Langguage. The database management system is using MySQL. This web-based application model will enable the waitress and the chef to interact in realtime, from the time they accept the customer order until the chef could know what to cook and checklist for the waitress wheter the order is fullfill or not, until the cahsier that will calculate the bill and the payment that they accep from the customer.

Semantic models for adaptive interactive systems

CERN Document Server

Hussein, Tim; Lukosch, Stephan; Ziegler, Jürgen; Calvary, Gaëlle

2013-01-01

Providing insights into methodologies for designing adaptive systems based on semantic data, and introducing semantic models that can be used for building interactive systems, this book showcases many of the applications made possible by the use of semantic models.Ontologies may enhance the functional coverage of an interactive system as well as its visualization and interaction capabilities in various ways. Semantic models can also contribute to bridging gaps; for example, between user models, context-aware interfaces, and model-driven UI generation. There is considerable potential for using

Pressurized water reactor system model for control system design and analysis

International Nuclear Information System (INIS)

Cooper, K.F.; Cain, J.T.

1975-01-01

Satisfactory operation of present generation Pressurized Water Reactor (PWR) Nuclear Power systems requires that several independent and interactive control systems be designed. Since it is not practical to use an actual PWR system as a design tool, a mathematical model of the system must be developed as a design and analysis tool. The model presented has been developed to be used as an aid in applying optimal control theory to design and implement new control systems for PWR plants. To be applicable, the model developed must represent the PWR system in its normal operating range. For safety analysis the operating conditions of the system are usually abnormal and, therefore, the system modeling requirements are different from those for control system design and analysis

System Dynamics Modeling of Multipurpose Reservoir Operation

Directory of Open Access Journals (Sweden)

Ebrahim Momeni

2006-03-01

Full Text Available System dynamics, a feedback – based object – oriented simulation approach, not only represents complex dynamic systemic systems in a realistic way but also allows the involvement of end users in model development to increase their confidence in modeling process. The increased speed of model development, the possibility of group model development, the effective communication of model results, and the trust developed in the model due to user participation are the main strengths of this approach. The ease of model modification in response to changes in the system and the ability to perform sensitivity analysis make this approach more attractive compared with systems analysis techniques for modeling water management systems. In this study, a system dynamics model was developed for the Zayandehrud basin in central Iran. This model contains river basin, dam reservoir, plains, irrigation systems, and groundwater. Current operation rule is conjunctive use of ground and surface water. Allocation factor for each irrigation system is computed based on the feedback from groundwater storage in its zone. Deficit water is extracted from groundwater.The results show that applying better rules can not only satisfy all demands such as Gawkhuni swamp environmental demand, but it can also  prevent groundwater level drawdown in future.

Modeling Sustainable Food Systems.

Science.gov (United States)

Allen, Thomas; Prosperi, Paolo

2016-05-01

The processes underlying environmental, economic, and social unsustainability derive in part from the food system. Building sustainable food systems has become a predominating endeavor aiming to redirect our food systems and policies towards better-adjusted goals and improved societal welfare. Food systems are complex social-ecological systems involving multiple interactions between human and natural components. Policy needs to encourage public perception of humanity and nature as interdependent and interacting. The systemic nature of these interdependencies and interactions calls for systems approaches and integrated assessment tools. Identifying and modeling the intrinsic properties of the food system that will ensure its essential outcomes are maintained or enhanced over time and across generations, will help organizations and governmental institutions to track progress towards sustainability, and set policies that encourage positive transformations. This paper proposes a conceptual model that articulates crucial vulnerability and resilience factors to global environmental and socio-economic changes, postulating specific food and nutrition security issues as priority outcomes of food systems. By acknowledging the systemic nature of sustainability, this approach allows consideration of causal factor dynamics. In a stepwise approach, a logical application is schematized for three Mediterranean countries, namely Spain, France, and Italy.

System Advisor Model: Flat Plate Photovoltaic Performance Modeling Validation Report

Energy Technology Data Exchange (ETDEWEB)

Freeman, Janine [National Renewable Energy Lab. (NREL), Golden, CO (United States); Whitmore, Jonathan [National Renewable Energy Lab. (NREL), Golden, CO (United States); Kaffine, Leah [National Renewable Energy Lab. (NREL), Golden, CO (United States); Blair, Nate [National Renewable Energy Lab. (NREL), Golden, CO (United States); Dobos, Aron P. [National Renewable Energy Lab. (NREL), Golden, CO (United States)

2013-12-01

The System Advisor Model (SAM) is a free software tool that performs detailed analysis of both system performance and system financing for a variety of renewable energy technologies. This report provides detailed validation of the SAM flat plate photovoltaic performance model by comparing SAM-modeled PV system generation data to actual measured production data for nine PV systems ranging from 75 kW to greater than 25 MW in size. The results show strong agreement between SAM predictions and field data, with annualized prediction error below 3% for all fixed tilt cases and below 8% for all one axis tracked cases. The analysis concludes that snow cover and system outages are the primary sources of disagreement, and other deviations resulting from seasonal biases in the irradiation models and one axis tracking issues are discussed in detail.

The UK Earth System Model project

Science.gov (United States)

Tang, Yongming

2016-04-01

In this talk we will describe the development and current status of the UK Earth System Model (UKESM). This project is a NERC/Met Office collaboration and has two objectives; to develop and apply a world-leading Earth System Model, and to grow a community of UK Earth System Model scientists. We are building numerical models that include all the key components of the global climate system, and contain the important process interactions between global biogeochemistry, atmospheric chemistry and the physical climate system. UKESM will be used to make key CMIP6 simulations as well as long-time (e.g. millennium) simulations, large ensemble experiments and investigating a range of future carbon emission scenarios.

Model-based version management system framework

International Nuclear Information System (INIS)

Mehmood, W.

2016-01-01

In this paper we present a model-based version management system. Version Management System (VMS) a branch of software configuration management (SCM) aims to provide a controlling mechanism for evolution of software artifacts created during software development process. Controlling the evolution requires many activities to perform, such as, construction and creation of versions, identification of differences between versions, conflict detection and merging. Traditional VMS systems are file-based and consider software systems as a set of text files. File based VMS systems are not adequate for performing software configuration management activities such as, version control on software artifacts produced in earlier phases of the software life cycle. New challenges of model differencing, merge, and evolution control arise while using models as central artifact. The goal of this work is to present a generic framework model-based VMS which can be used to overcome the problem of tradition file-based VMS systems and provide model versioning services. (author)

Modeling and simulation of systems using Matlab and Simulink

CERN Document Server

Chaturvedi, Devendra K

2009-01-01

Introduction to SystemsSystemClassification of SystemsLinear SystemsTime-Varying vs. Time-Invariant Systems Lumped vs. Distributed Parameter SystemsContinuous- and Discrete-Time Systems Deterministic vs. Stochastic Systems Hard and Soft Systems Analysis of Systems Synthesis of Systems Introduction to System Philosophy System Thinking Large and Complex Applied System Engineering: A Generic ModelingSystems ModelingIntroduction Need of System Modeling Modeling Methods for Complex Systems Classification of ModelsCharacteristics of Models ModelingMathematical Modeling of Physical SystemsFormulation of State Space Model of SystemsPhysical Systems Theory System Components and Interconnections Computation of Parameters of a Component Single Port and Multiport Systems Techniques of System Analysis Basics of Linear Graph Theoretic ApproachFormulation of System Model for Conceptual SystemFormulation System Model for Physical SystemsTopological RestrictionsDevelopment of State Model of Degenerative SystemSolution of Stat...

Fuzzy model-based servo and model following control for nonlinear systems.

Science.gov (United States)

Ohtake, Hiroshi; Tanaka, Kazuo; Wang, Hua O

2009-12-01

This correspondence presents servo and nonlinear model following controls for a class of nonlinear systems using the Takagi-Sugeno fuzzy model-based control approach. First, the construction method of the augmented fuzzy system for continuous-time nonlinear systems is proposed by differentiating the original nonlinear system. Second, the dynamic fuzzy servo controller and the dynamic fuzzy model following controller, which can make outputs of the nonlinear system converge to target points and to outputs of the reference system, respectively, are introduced. Finally, the servo and model following controller design conditions are given in terms of linear matrix inequalities. Design examples illustrate the utility of this approach.

Distribution system modeling and analysis

CERN Document Server

Kersting, William H

2001-01-01

For decades, distribution engineers did not have the sophisticated tools developed for analyzing transmission systems-often they had only their instincts. Things have changed, and we now have computer programs that allow engineers to simulate, analyze, and optimize distribution systems. Powerful as these programs are, however, without a real understanding of the operating characteristics of a distribution system, engineers using the programs can easily make serious errors in their designs and operating procedures. Distribution System Modeling and Analysis helps prevent those errors. It gives readers a basic understanding of the modeling and operating characteristics of the major components of a distribution system. One by one, the author develops and analyzes each component as a stand-alone element, then puts them all together to analyze a distribution system comprising the various shunt and series devices for power-flow and short-circuit studies. He includes the derivation of all models and includes many num...

Analysis hierarchical model for discrete event systems

Science.gov (United States)

Ciortea, E. M.

2015-11-01

The This paper presents the hierarchical model based on discrete event network for robotic systems. Based on the hierarchical approach, Petri network is analysed as a network of the highest conceptual level and the lowest level of local control. For modelling and control of complex robotic systems using extended Petri nets. Such a system is structured, controlled and analysed in this paper by using Visual Object Net ++ package that is relatively simple and easy to use, and the results are shown as representations easy to interpret. The hierarchical structure of the robotic system is implemented on computers analysed using specialized programs. Implementation of hierarchical model discrete event systems, as a real-time operating system on a computer network connected via a serial bus is possible, where each computer is dedicated to local and Petri model of a subsystem global robotic system. Since Petri models are simplified to apply general computers, analysis, modelling, complex manufacturing systems control can be achieved using Petri nets. Discrete event systems is a pragmatic tool for modelling industrial systems. For system modelling using Petri nets because we have our system where discrete event. To highlight the auxiliary time Petri model using transport stream divided into hierarchical levels and sections are analysed successively. Proposed robotic system simulation using timed Petri, offers the opportunity to view the robotic time. Application of goods or robotic and transmission times obtained by measuring spot is obtained graphics showing the average time for transport activity, using the parameters sets of finished products. individually.

Human performance modeling for system of systems analytics :soldier fatigue.

Energy Technology Data Exchange (ETDEWEB)

Lawton, Craig R.; Campbell, James E.; Miller, Dwight Peter

2005-10-01

The military has identified Human Performance Modeling (HPM) as a significant requirement and challenge of future systems modeling and analysis initiatives as can be seen in the Department of Defense's (DoD) Defense Modeling and Simulation Office's (DMSO) Master Plan (DoD 5000.59-P 1995). To this goal, the military is currently spending millions of dollars on programs devoted to HPM in various military contexts. Examples include the Human Performance Modeling Integration (HPMI) program within the Air Force Research Laboratory, which focuses on integrating HPMs with constructive models of systems (e.g. cockpit simulations) and the Navy's Human Performance Center (HPC) established in September 2003. Nearly all of these initiatives focus on the interface between humans and a single system. This is insufficient in the era of highly complex network centric SoS. This report presents research and development in the area of HPM in a system-of-systems (SoS). Specifically, this report addresses modeling soldier fatigue and the potential impacts soldier fatigue can have on SoS performance.

Comparative genomics of phylogenetically diverse unicellular eukaryotes provide new insights into the genetic basis for the evolution of the programmed cell death machinery.

Science.gov (United States)

Nedelcu, Aurora M

2009-03-01

Programmed cell death (PCD) represents a significant component of normal growth and development in multicellular organisms. Recently, PCD-like processes have been reported in single-celled eukaryotes, implying that some components of the PCD machinery existed early in eukaryotic evolution. This study provides a comparative analysis of PCD-related sequences across more than 50 unicellular genera from four eukaryotic supergroups: Unikonts, Excavata, Chromalveolata, and Plantae. A complex set of PCD-related sequences that correspond to domains or proteins associated with all main functional classes--from ligands and receptors to executors of PCD--was found in many unicellular lineages. Several PCD domains and proteins previously thought to be restricted to animals or land plants are also present in unicellular species. Noteworthy, the yeast, Saccharomyces cerevisiae--used as an experimental model system for PCD research, has a rather reduced set of PCD-related sequences relative to other unicellular species. The phylogenetic distribution of the PCD-related sequences identified in unicellular lineages suggests that the genetic basis for the evolution of the complex PCD machinery present in extant multicellular lineages has been established early in the evolution of eukaryotes. The shaping of the PCD machinery in multicellular lineages involved the duplication, co-option, recruitment, and shuffling of domains already present in their unicellular ancestors.

Dynamic Model of Kaplan Turbine Regulating System Suitable for Power System Analysis

OpenAIRE

Zhao, Jie; Wang, Li; Liu, Dichen; Wang, Jun; Zhao, Yu; Liu, Tian; Wang, Haoyu

2015-01-01

Accurate modeling of Kaplan turbine regulating system is of great significance for grid security and stability analysis. In this paper, Kaplan turbine regulating system model is divided into the governor system model, the blade control system model, and the turbine and water diversion system model. The Kaplan turbine has its particularity, and the on-cam relationship between the wicket gate opening and the runner blade angle under a certain water head on the whole range was obtained by high-o...

System Dynamics Modeling for Emergency Operating System Resilience

Energy Technology Data Exchange (ETDEWEB)

Eng, Ang Wei; Kim, Jong Hyun [KEPCO International Nuclear Graduate School, Ulsan (Korea, Republic of)

2014-10-15

The purpose of this paper is to present a causal model which explain human error cause-effect relationships of emergency operating system (EOS) by using system dynamics (SD) approach. The causal model will further quantified by analyzes nuclear power plant incidents/accidents data in Korea for simulation modeling. Emergency Operating System (EOS) is generally defined as a system which consists personnel, human-machine interface and procedures; and how these components interact and coordinate to respond to an incident or accident. Understanding the behavior of EOS especially personnel behavior and the factors influencing it during accident will contribute in human reliability evaluation. Human Reliability Analysis (HRA) is a method which assesses how human decisions and actions affect to system risk and further used to reduce the human errors probability. There are many HRA method used performance influencing factors (PIFs) to identify the causes of human errors. However, these methods have several limitations. In HRA, PIFs are assumed independent each other and relationship between them are not been study. Through the SD simulation, users able to simulate various situation of nuclear power plant respond to emergency from human and organizational aspects. The simulation also provides users a comprehensive view on how to improve the safety in plants. This paper presents a causal model that explained cause-effect relationships of EOS human. Through SD simulation, users able to identify the main contribution of human error easily. Users can also use SD simulation to predict when and how a human error occurs over time. In future work, the SD model can be expanded more on low level factors. The relationship within low level factors can investigated by using correlation method and further included in the model. This can enables users to study more detailed human error cause-effect relationships and the behavior of EOS. Another improvement can be made is on EOS factors

System Dynamics Modeling for Emergency Operating System Resilience

International Nuclear Information System (INIS)

Eng, Ang Wei; Kim, Jong Hyun

2014-01-01

The purpose of this paper is to present a causal model which explain human error cause-effect relationships of emergency operating system (EOS) by using system dynamics (SD) approach. The causal model will further quantified by analyzes nuclear power plant incidents/accidents data in Korea for simulation modeling. Emergency Operating System (EOS) is generally defined as a system which consists personnel, human-machine interface and procedures; and how these components interact and coordinate to respond to an incident or accident. Understanding the behavior of EOS especially personnel behavior and the factors influencing it during accident will contribute in human reliability evaluation. Human Reliability Analysis (HRA) is a method which assesses how human decisions and actions affect to system risk and further used to reduce the human errors probability. There are many HRA method used performance influencing factors (PIFs) to identify the causes of human errors. However, these methods have several limitations. In HRA, PIFs are assumed independent each other and relationship between them are not been study. Through the SD simulation, users able to simulate various situation of nuclear power plant respond to emergency from human and organizational aspects. The simulation also provides users a comprehensive view on how to improve the safety in plants. This paper presents a causal model that explained cause-effect relationships of EOS human. Through SD simulation, users able to identify the main contribution of human error easily. Users can also use SD simulation to predict when and how a human error occurs over time. In future work, the SD model can be expanded more on low level factors. The relationship within low level factors can investigated by using correlation method and further included in the model. This can enables users to study more detailed human error cause-effect relationships and the behavior of EOS. Another improvement can be made is on EOS factors

Mathematical Modeling of Constrained Hamiltonian Systems

NARCIS (Netherlands)

Schaft, A.J. van der; Maschke, B.M.

1995-01-01

Network modelling of unconstrained energy conserving physical systems leads to an intrinsic generalized Hamiltonian formulation of the dynamics. Constrained energy conserving physical systems are directly modelled as implicit Hamiltonian systems with regard to a generalized Dirac structure on the

A model management system for combat simulation

OpenAIRE

Dolk, Daniel R.

1986-01-01

The design and implementation of a model management system to support combat modeling is discussed. Structured modeling is introduced as a formalism for representing mathematical models. A relational information resource dictionary system is developed which can accommodate structured models. An implementation is described. Structured modeling is then compared to Jackson System Development (JSD) as a methodology for facilitating discrete event simulation. JSD is currently better at representin...

Dynamic Model of Kaplan Turbine Regulating System Suitable for Power System Analysis

Directory of Open Access Journals (Sweden)

Jie Zhao

2015-01-01

Full Text Available Accurate modeling of Kaplan turbine regulating system is of great significance for grid security and stability analysis. In this paper, Kaplan turbine regulating system model is divided into the governor system model, the blade control system model, and the turbine and water diversion system model. The Kaplan turbine has its particularity, and the on-cam relationship between the wicket gate opening and the runner blade angle under a certain water head on the whole range was obtained by high-order curve fitting method. Progressively the linearized Kaplan turbine model, improved ideal Kaplan turbine model, and nonlinear Kaplan turbine model were developed. The nonlinear Kaplan turbine model considered the correction function of the blade angle on the turbine power, thereby improving the model simulation accuracy. The model parameters were calculated or obtained by the improved particle swarm optimization (IPSO algorithm. For the blade control system model, the default blade servomotor time constant given by value of one simplified the modeling and experimental work. Further studies combined with measured test data verified the established model accuracy and laid a foundation for further research into the influence of Kaplan turbine connecting to the grid.

How clonal is clonal? Genome plasticity across multicellular segments of a "Candidatus Marithrix sp." filament from sulfidic, briny seafloor sediments in the Gulf of Mexico

Directory of Open Access Journals (Sweden)

Verena Salman-Carvalho

2016-08-01

Full Text Available Candidatus Marithrix is a recently described lineage within the group of large sulfur bacteria (Beggiatoaceae, Gammaproteobacteria. This group of bacteria comprises vacuolated, attached-living filaments that inhabit the sediment surface around vent and seep sites in the marine environment. A single filament is ca. 100 µm in diameter, several millimeters long, and consists of hundreds of clonal cells, which are considered highly polyploid. Based on these characteristics, Candidatus Marithrix was used as a model organism for the assessment of genomic plasticity along segments of a single filament using next generation sequencing to possibly identify hotspots of microevolution. Using six consecutive segments of a single filament sampled from a mud volcano in the Gulf of Mexico, we recovered ca. 90% of the Candidatus Marithrix genome in each segment. There was a high level of genome conservation along the filament with average nucleotide identities between 99.98-100%. Different approaches to assemble all reads into a complete consensus genome could not fill the gaps. Each of the six segment datasets encoded merely a few hundred unique nucleotides and 5 or less unique genes - the residual content was redundant in all datasets. Besides the overall high genomic identity, we identified a similar number of single nucleotide polymorphisms (SNPs between the clonal segments, which are comparable to numbers reported for other clonal organisms. An increase of SNPs with greater distance of filament segments was not observed. The polyploidy of the cells was apparent when analyzing the heterogeneity of reads within a segment. Here, a strong increase in single nucleotide variants, or 'intrasegmental sequence heterogeneity' (ISH events, was observed. These sites may represent hotspots for genome plasticity, and possibly microevolution, since two thirds of these variants were not co-localized across the genome copies of the multicellular filament.

A Model-Driven Visualization Tool for Use with Model-Based Systems Engineering Projects

Science.gov (United States)

Trase, Kathryn; Fink, Eric

2014-01-01

Model-Based Systems Engineering (MBSE) promotes increased consistency between a system's design and its design documentation through the use of an object-oriented system model. The creation of this system model facilitates data presentation by providing a mechanism from which information can be extracted by automated manipulation of model content. Existing MBSE tools enable model creation, but are often too complex for the unfamiliar model viewer to easily use. These tools do not yet provide many opportunities for easing into the development and use of a system model when system design documentation already exists. This study creates a Systems Modeling Language (SysML) Document Traceability Framework (SDTF) for integrating design documentation with a system model, and develops an Interactive Visualization Engine for SysML Tools (InVEST), that exports consistent, clear, and concise views of SysML model data. These exported views are each meaningful to a variety of project stakeholders with differing subjects of concern and depth of technical involvement. InVEST allows a model user to generate multiple views and reports from a MBSE model, including wiki pages and interactive visualizations of data. System data can also be filtered to present only the information relevant to the particular stakeholder, resulting in a view that is both consistent with the larger system model and other model views. Viewing the relationships between system artifacts and documentation, and filtering through data to see specialized views improves the value of the system as a whole, as data becomes information

Cyber Physical System Modelling of Distribution Power Systems for Dynamic Demand Response

Science.gov (United States)

Chu, Xiaodong; Zhang, Rongxiang; Tang, Maosen; Huang, Haoyi; Zhang, Lei

2018-01-01

Dynamic demand response (DDR) is a package of control methods to enhance power system security. A CPS modelling and simulation platform for DDR in distribution power systems is presented in this paper. CPS modelling requirements of distribution power systems are analyzed. A coupled CPS modelling platform is built for assessing DDR in the distribution power system, which combines seamlessly modelling tools of physical power networks and cyber communication networks. Simulations results of IEEE 13-node test system demonstrate the effectiveness of the modelling and simulation platform.

ECONOMIC MODELING STOCKS CONTROL SYSTEM: SIMULATION MODEL

OpenAIRE

Климак, М.С.; Войтко, С.В.

2016-01-01

Considered theoretical and applied aspects of the development of simulation models to predictthe optimal development and production systems that create tangible products andservices. It isproved that theprocessof inventory control needs of economicandmathematical modeling in viewof thecomplexity of theoretical studies. A simulation model of stocks control that allows make managementdecisions with production logistics

Modeling Control Situations in Power System Operations

DEFF Research Database (Denmark)

Saleem, Arshad; Lind, Morten; Singh, Sri Niwas

2010-01-01

for intelligent operation and control must represent system features, so that information from measurements can be related to possible system states and to control actions. These general modeling requirements are well understood, but it is, in general, difficult to translate them into a model because of the lack...... of explicit principles for model construction. This paper presents a work on using explicit means-ends model based reasoning about complex control situations which results in maintaining consistent perspectives and selecting appropriate control action for goal driven agents. An example of power system......Increased interconnection and loading of the power system along with deregulation has brought new challenges for electric power system operation, control and automation. Traditional power system models used in intelligent operation and control are highly dependent on the task purpose. Thus, a model...

On Verification Modelling of Embedded Systems

NARCIS (Netherlands)

Brinksma, Hendrik; Mader, Angelika H.

Computer-aided verification of embedded systems hinges on the availability of good verification models of the systems at hand. Such models must be much simpler than full design models or specifications to be of practical value, because of the unavoidable combinatorial complexities in the

Some implications of Scale Relativity theory in avascular stages of growth of solid tumors in the presence of an immune system response.

Science.gov (United States)

Buzea, C Gh; Agop, M; Moraru, Evelina; Stana, Bogdan A; Gîrţu, Manuela; Iancu, D

2011-08-07

We present a traveling-wave analysis of a reduced mathematical model describing the growth of a solid tumor in the presence of an immune system response in the framework of Scale Relativity theory. Attention is focused upon the attack of tumor cells by tumor-infiltrating cytotoxic lymphocytes (TICLs), in a small multicellular tumor, without necrosis and at some stage prior to (tumor-induced) angiogenesis. For a particular choice of parameters, the underlying system of partial differential equations is able to simulate the well-documented phenomenon of cancer dormancy and propagation of a perturbation in the tumor cell concentration by cnoidal modes, by depicting spatially heterogeneous tumor cell distributions that are characterized by a relatively small total number of tumor cells. This behavior is consistent with several immunomorphological investigations. Moreover, the alteration of certain parameters of the model is enough to induce soliton like modes and soliton packets into the system, which in turn result in tumor invasion in the form of a standard traveling wave. In the same framework of Scale Relativity theory, a very important feature of malignant tumors also results, that even in avascular stages they might propagate and invade healthy tissues, by means of a diffusion on a Newtonian fluid. Copyright © 2011 Elsevier Ltd. All rights reserved.

Modeling and analysis of stochastic systems

CERN Document Server

Kulkarni, Vidyadhar G

2011-01-01

Based on the author's more than 25 years of teaching experience, Modeling and Analysis of Stochastic Systems, Second Edition covers the most important classes of stochastic processes used in the modeling of diverse systems, from supply chains and inventory systems to genetics and biological systems. For each class of stochastic process, the text includes its definition, characterization, applications, transient and limiting behavior, first passage times, and cost/reward models. Along with reorganizing the material, this edition revises and adds new exercises and examples. New to the second edi

Developmental plasticity of bacterial colonies and consortia in germ-free and gnotobiotic settings

Directory of Open Access Journals (Sweden)

Pátková Irena

2012-08-01

Full Text Available Abstract Background Bacteria grown on semi-solid media can build two types of multicellular structures, depending on the circumstances. Bodies (colonies arise when a single clone is grown axenically (germ-free, whereas multispecies chimeric consortia contain monoclonal microcolonies of participants. Growth of an axenic colony, mutual interactions of colonies, and negotiation of the morphospace in consortial ecosystems are results of intricate regulatory and metabolic networks. Multicellular structures developed by Serratia sp. are characteristically shaped and colored, forming patterns that reflect their growth conditions (in particular medium composition and the presence of other bacteria. Results Building on our previous work, we developed a model system for studying ontogeny of multicellular bacterial structures formed by five Serratia sp. morphotypes of two species grown in either "germ-free" or "gnotobiotic" settings (i.e. in the presence of bacteria of other conspecific morphotype, other Serratia species, or E. coli. Monoclonal bodies show regular and reproducible macroscopic appearance of the colony, as well as microscopic pattern of its growing margin. Standard development can be modified in a characteristic and reproducible manner in close vicinity of other bacterial structures (or in the presence of their products. Encounters of colonies with neighbors of a different morphotype or species reveal relationships of dominance, cooperation, or submission; multiple interactions can be summarized in "rock – paper – scissors" network of interrelationships. Chimerical (mixed plantings consisting of two morphotypes usually produced a “consortium” whose structure is consistent with the model derived from interaction patterns observed in colonies. Conclusions Our results suggest that development of a bacterial colony can be considered analogous to embryogenesis in animals, plants, or fungi: to proceed, early stages require thorough

Yeast replicative aging: a paradigm for defining conserved longevity interventions

OpenAIRE

Wasko, Brian M.; Kaeberlein, Matt

2013-01-01

The finite replicative life span of budding yeast mother cells was demonstrated as early as 1959, but the idea that budding yeast could be used to model aging of multicellular eukaryotes did not enter the scientific mainstream until relatively recently. Despite continued skepticism by some, there are now abundant data that several interventions capable of extending yeast replicative life span have a similar effect in multicellular eukaryotes including nematode worms, fruit flies, and rodents....

Biofilms

OpenAIRE

López, Daniel; Vlamakis, Hera; Kolter, Roberto

2010-01-01

The ability to form biofilms is a universal attribute of bacteria. Biofilms are multicellular communities held together by a self-produced extracellular matrix. The mechanisms that different bacteria employ to form biofilms vary, frequently depending on environmental conditions and specific strain attributes. In this review, we emphasize four well-studied model systems to give an overview of how several organisms form biofilms: Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, and ...

Modelling of Context: Designing Mobile Systems from Domain-Dependent Models

DEFF Research Database (Denmark)

Nielsen, Peter Axel; Stage, Jan

2009-01-01

Modelling of domain-dependent aspects is a key prerequisite for the design of software for mobile systems. Most mobile systems include a more or less advanced model of selected aspects of the domain in which they are used. This paper discusses the creation of such a model and its relevance for te...

Model Reduction of Fuzzy Logic Systems

Directory of Open Access Journals (Sweden)

Zhandong Yu

2014-01-01

Full Text Available This paper deals with the problem of ℒ2-ℒ∞ model reduction for continuous-time nonlinear uncertain systems. The approach of the construction of a reduced-order model is presented for high-order nonlinear uncertain systems described by the T-S fuzzy systems, which not only approximates the original high-order system well with an ℒ2-ℒ∞ error performance level γ but also translates it into a linear lower-dimensional system. Then, the model approximation is converted into a convex optimization problem by using a linearization procedure. Finally, a numerical example is presented to show the effectiveness of the proposed method.

Distinguishing Environment and System in Coloured Petri Net Models of Reactive Systems

DEFF Research Database (Denmark)

Tjell, Simon

2007-01-01

This paper introduces and formally defines the environment-and-system-partitioned property for behavioral models of reactive systems expressed in the formal modeling language Coloured Petri Net. The purpose of the formalization is to make it possible to automatically validate any CPN model...... with respect to this property based on structural analysis. A model has the environment-and-system-partitioned property if it is based on a clear division between environment and system. This division is important in many model-driven approaches to software development such as model-based testing and automated...

Modeling the Dynamic Digestive System Microbiome†

OpenAIRE

Estes, Anne M.

2015-01-01

“Modeling the Dynamic Digestive System Microbiome” is a hands-on activity designed to demonstrate the dynamics of microbiome ecology using dried pasta and beans to model disturbance events in the human digestive system microbiome. This exercise demonstrates how microbiome diversity is influenced by: 1) niche availability and habitat space and 2) a major disturbance event, such as antibiotic use. Students use a pictorial key to examine prepared models of digestive system microbiomes to determi...

Modeling of the DZero data acquisition system

Energy Technology Data Exchange (ETDEWEB)

Angstadt, R.; Johnson, M.; Manning, I.L. [Fermi National Accelerator Lab., Batavia, IL (United States); Wightman, J.A. [Texas A and M Univ., College Station, TX (United States). Dept. of Physics]|[Texas Accelerator Center, The Woodlands, TX (United States)

1991-12-01

A queuing theory model was used in the initial design of the D0 data acquisition system. It was mainly used for the front end electronic systems. Since then the model has been extended to include the entire data path for the tracking system. The tracking system generates the most data so we expect this system to determine the overall transfer rate. The model was developed using both analytical and simulation methods for solving a series of single server queues. We describe the model and the methods used to develop it. We also present results from the original models, updated calculations representing the system as built and comparisons with measurements made with the hardware in place for the cosmic ray test run. 3 refs.

Coupling population dynamics with earth system models: the POPEM model.

Science.gov (United States)

Navarro, Andrés; Moreno, Raúl; Jiménez-Alcázar, Alfonso; Tapiador, Francisco J

2017-09-16

Precise modeling of CO 2 emissions is important for environmental research. This paper presents a new model of human population dynamics that can be embedded into ESMs (Earth System Models) to improve climate modeling. Through a system dynamics approach, we develop a cohort-component model that successfully simulates historical population dynamics with fine spatial resolution (about 1°×1°). The population projections are used to improve the estimates of CO 2 emissions, thus transcending the bulk approach of existing models and allowing more realistic non-linear effects to feature in the simulations. The module, dubbed POPEM (from Population Parameterization for Earth Models), is compared with current emission inventories and validated against UN aggregated data. Finally, it is shown that the module can be used to advance toward fully coupling the social and natural components of the Earth system, an emerging research path for environmental science and pollution research.

Modeling, Control and Coordination of Helicopter Systems

CERN Document Server

Ren, Beibei; Chen, Chang; Fua, Cheng-Heng; Lee, Tong Heng

2012-01-01

Modeling, Control and Coordination of Helicopter Systems provides a comprehensive treatment of helicopter systems, ranging from related nonlinear flight dynamic modeling and stability analysis to advanced control design for single helicopter systems, and also covers issues related to the coordination and formation control of multiple helicopter systems to achieve high performance tasks. Ensuring stability in helicopter flight is a challenging problem for nonlinear control design and development. This book is a valuable reference on modeling, control and coordination of helicopter systems,providing readers with practical solutions for the problems that still plague helicopter system design and implementation. Readers will gain a complete picture of helicopters at the systems level, as well as a better understanding of the technical intricacies involved. This book also: Presents a complete picture of modeling, control and coordination for helicopter systems Provides a modeling platform for a general class of ro...

Identifying and Quantifying Emergent Behavior Through System of Systems Modeling and Simulation

Science.gov (United States)

2015-09-01

the similarities and differences between Agent Based Modeling ( ABM ) and Equation Based Modeling (EBM). Both modeling approaches “simulate a system by...entities. For the latter difference, EBM focuses on the system level observables, while ABM defines behaviors at the individual agent level and observes...EMERGENT BEHAVIOR THROUGH SYSTEM OF SYSTEMS MODELING AND SIMULATION by Mary Ann Cummings September 2015 Dissertation Supervisor: Man-Tak Shing

Modelling of intercellular synchronization in the Drosophila circadian clock

International Nuclear Information System (INIS)

Jun-Wei, Wang; Ai-Min, Chen; Jia-Jun, Zhang; Zhan-Jiang, Yuan; Tian-Shou, Zhou

2009-01-01

In circadian rhythm generation, intercellular signaling factors are shown to play a crucial role in both sustaining intrinsic cellular rhythmicity and acquiring collective behaviours across a population of circadian neurons. However, the physical mechanism behind their role remains to be fully understood. In this paper, we propose an indirectly coupled multicellular model for the synchronization of Drosophila circadian oscillators combining both intracellular and intercellular dynamics. By simulating different experimental conditions, we find that such an indirect coupling way can synchronize both heterogeneous self-sustained circadian neurons and heterogeneous mutational damped circadian neurons. Moreover, they can also be entrained to ambient light-dark (LD) cycles depending on intercellular signaling. (cross-disciplinary physics and related areas of science and technology)

Bond graph modeling of centrifugal compression systems

OpenAIRE

Uddin, Nur; Gravdahl, Jan Tommy

2015-01-01

A novel approach to model unsteady fluid dynamics in a compressor network by using a bond graph is presented. The model is intended in particular for compressor control system development. First, we develop a bond graph model of a single compression system. Bond graph modeling offers a different perspective to previous work by modeling the compression system based on energy flow instead of fluid dynamics. Analyzing the bond graph model explains the energy flow during compressor surge. Two pri...

A system-level multiprocessor system-on-chip modeling framework

DEFF Research Database (Denmark)

Virk, Kashif Munir; Madsen, Jan

2004-01-01

We present a system-level modeling framework to model system-on-chips (SoC) consisting of heterogeneous multiprocessors and network-on-chip communication structures in order to enable the developers of today's SoC designs to take advantage of the flexibility and scalability of network-on-chip and...... SoC design. We show how a hand-held multimedia terminal, consisting of JPEG, MP3 and GSM applications, can be modeled as a multiprocessor SoC in our framework....

Investigating immune system aging: system dynamics and agent-based modeling

OpenAIRE

Figueredo, Grazziela; Aickelin, Uwe

2010-01-01

System dynamics and agent based simulation models can\\ud both be used to model and understand interactions of entities within a population. Our modeling work presented here is concerned with understanding the suitability of the different types of simulation for the immune system aging problems and comparing their results. We are trying to answer questions such as: How fit is the immune system given a certain age? Would an immune boost be of therapeutic value, e.g. to improve the effectiveness...

Elasticity-based development of functionally enhanced multicellular 3D liver encapsulated in hybrid hydrogel.

Science.gov (United States)

Lee, Ho-Joon; Son, Myung Jin; Ahn, Jiwon; Oh, Soo Jin; Lee, Mihee; Kim, Ansoon; Jeung, Yun-Ji; Kim, Han-Gyeul; Won, Misun; Lim, Jung Hwa; Kim, Nam-Soon; Jung, Cho-Rock; Chung, Kyung-Sook

2017-12-01

Current in vitro liver models provide three-dimensional (3-D) microenvironments in combination with tissue engineering technology and can perform more accurate in vivo mimicry than two-dimensional models. However, a human cell-based, functionally mature liver model is still desired, which would provide an alternative to animal experiments and resolve low-prediction issues on species differences. Here, we prepared hybrid hydrogels of varying elasticity and compared them with a normal liver, to develop a more mature liver model that preserves liver properties in vitro. We encapsulated HepaRG cells, either alone or with supporting cells, in a biodegradable hybrid hydrogel. The elastic modulus of the 3D liver dynamically changed during culture due to the combined effects of prolonged degradation of hydrogel and extracellular matrix formation provided by the supporting cells. As a result, when the elastic modulus of the 3D liver model converges close to that of the in vivo liver (≅ 2.3 to 5.9 kPa), both phenotypic and functional maturation of the 3D liver were realized, while hepatic gene expression, albumin secretion, cytochrome p450-3A4 activity, and drug metabolism were enhanced. Finally, the 3D liver model was expanded to applications with embryonic stem cell-derived hepatocytes and primary human hepatocytes, and it supported prolonged hepatocyte survival and functionality in long-term culture. Our model represents critical progress in developing a biomimetic liver system to simulate liver tissue remodeling, and provides a versatile platform in drug development and disease modeling, ranging from physiology to pathology. We provide a functionally improved 3D liver model that recapitulates in vivo liver stiffness. We have experimentally addressed the issues of orchestrated effects of mechanical compliance, controlled matrix formation by stromal cells in conjunction with hepatic differentiation, and functional maturation of hepatocytes in a dynamic 3D

Compositional Modelling of Stochastic Hybrid Systems

NARCIS (Netherlands)

Strubbe, S.N.

2005-01-01

In this thesis we present a modelling framework for compositional modelling of stochastic hybrid systems. Hybrid systems consist of a combination of continuous and discrete dynamics. The state space of a hybrid system is hybrid in the sense that it consists of a continuous component and a discrete

System Identification, Environmental Modelling, and Control System Design

CERN Document Server

Garnier, Hugues

2012-01-01

System Identification, Environmetric Modelling, and Control Systems Design is dedicated to Professor Peter Young on the occasion of his seventieth birthday. Professor Young has been a pioneer in systems and control, and over the past 45 years he has influenced many developments in this field. This volume is comprised of a collection of contributions by leading experts in system identification, time-series analysis, environmetric modelling and control system design – modern research in topics that reflect important areas of interest in Professor Young’s research career. Recent theoretical developments in and relevant applications of these areas are explored treating the various subjects broadly and in depth. The authoritative and up-to-date research presented here will be of interest to academic researcher in control and disciplines related to environmental research, particularly those to with water systems. The tutorial style in which many of the contributions are composed also makes the book suitable as ...

CTBT Integrated Verification System Evaluation Model

Energy Technology Data Exchange (ETDEWEB)

Edenburn, M.W.; Bunting, M.L.; Payne, A.C. Jr.

1997-10-01

Sandia National Laboratories has developed a computer based model called IVSEM (Integrated Verification System Evaluation Model) to estimate the performance of a nuclear detonation monitoring system. The IVSEM project was initiated in June 1994, by Sandia`s Monitoring Systems and Technology Center and has been funded by the US Department of Energy`s Office of Nonproliferation and National Security (DOE/NN). IVSEM is a simple, top-level, modeling tool which estimates the performance of a Comprehensive Nuclear Test Ban Treaty (CTBT) monitoring system and can help explore the impact of various sensor system concepts and technology advancements on CTBT monitoring. One of IVSEM`s unique features is that it integrates results from the various CTBT sensor technologies (seismic, infrasound, radionuclide, and hydroacoustic) and allows the user to investigate synergy among the technologies. Specifically, IVSEM estimates the detection effectiveness (probability of detection) and location accuracy of the integrated system and of each technology subsystem individually. The model attempts to accurately estimate the monitoring system`s performance at medium interfaces (air-land, air-water) and for some evasive testing methods such as seismic decoupling. This report describes version 1.2 of IVSEM.

Integrating systems biology models and biomedical ontologies.

Science.gov (United States)

Hoehndorf, Robert; Dumontier, Michel; Gennari, John H; Wimalaratne, Sarala; de Bono, Bernard; Cook, Daniel L; Gkoutos, Georgios V

2011-08-11

Systems biology is an approach to biology that emphasizes the structure and dynamic behavior of biological systems and the interactions that occur within them. To succeed, systems biology crucially depends on the accessibility and integration of data across domains and levels of granularity. Biomedical ontologies were developed to facilitate such an integration of data and are often used to annotate biosimulation models in systems biology. We provide a framework to integrate representations of in silico systems biology with those of in vivo biology as described by biomedical ontologies and demonstrate this framework using the Systems Biology Markup Language. We developed the SBML Harvester software that automatically converts annotated SBML models into OWL and we apply our software to those biosimulation models that are contained in the BioModels Database. We utilize the resulting knowledge base for complex biological queries that can bridge levels of granularity, verify models based on the biological phenomenon they represent and provide a means to establish a basic qualitative layer on which to express the semantics of biosimulation models. We establish an information flow between biomedical ontologies and biosimulation models and we demonstrate that the integration of annotated biosimulation models and biomedical ontologies enables the verification of models as well as expressive queries. Establishing a bi-directional information flow between systems biology and biomedical ontologies has the potential to enable large-scale analyses of biological systems that span levels of granularity from molecules to organisms.

Mechatronic Systems Design Methods, Models, Concepts

CERN Document Server

Janschek, Klaus

2012-01-01

In this textbook, fundamental methods for model-based design of mechatronic systems are presented in a systematic, comprehensive form. The method framework presented here comprises domain-neutral methods for modeling and performance analysis: multi-domain modeling (energy/port/signal-based), simulation (ODE/DAE/hybrid systems), robust control methods, stochastic dynamic analysis, and quantitative evaluation of designs using system budgets. The model framework is composed of analytical dynamic models for important physical and technical domains of realization of mechatronic functions, such as multibody dynamics, digital information processing and electromechanical transducers. Building on the modeling concept of a technology-independent generic mechatronic transducer, concrete formulations for electrostatic, piezoelectric, electromagnetic, and electrodynamic transducers are presented. More than 50 fully worked out design examples clearly illustrate these methods and concepts and enable independent study of th...

Inhibition of hexokinase-2 with targeted liposomal 3-bromopyruvate in an ovarian tumor spheroid model of aerobic glycolysis

Directory of Open Access Journals (Sweden)

Gandham SK

2015-07-01

Full Text Available Srujan Kumar Gandham, Meghna Talekar, Amit Singh, Mansoor M Amiji Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA, USA Background: The objective of this study was to evaluate the expression levels of glycolytic markers, especially hexokinase-2 (HK2, using a three-dimensional multicellular spheroid model of human ovarian adenocarcinoma (SKOV-3 cells and to develop an epidermal growth factor receptor-targeted liposomal formulation for improving inhibition of HK2 and the cytotoxicity of 3-bromopyruvate (3-BPA. Methods: Multicellular SKOV-3 tumor spheroids were developed using the hanging drop method and expression levels of glycolytic markers were examined. Non-targeted and epidermal growth factor receptor-targeted liposomal formulations of 3-BPA were formulated and characterized. Permeability and cellular uptake of the liposomal formulations in three-dimensional SKOV-3 spheroids was evaluated using confocal microscopy. The cytotoxicity and HK2 inhibition potential of solution form of 3-BPA was compared to the corresponding liposomal formulation by using cell proliferation and HK2 enzymatic assays. Results: SKOV-3 spheroids were reproducibly developed using the 96-well hanging drop method, with an average size of 900 µm by day 5. HK2 enzyme activity levels under hypoxic conditions were found to be higher than under normoxic conditions (P<0.0001, Student’s t-test, unpaired and two-tailed. Liposomal formulations (both non-targeted and targeted of 3-BPA showed a more potent inhibitory effect (P<0.001, Student’s t-test, unpaired and two-tailed at a dose of 50 µM than the aqueous solution form at 3, 6, and 24 hours post administration. Similarly, the cytotoxic activity 3-BPA at various concentrations (10 µM–100 µM showed that the liposomal formulations had an enhanced cytotoxic effect of 2–5-fold (P<0.0001, Student’s t-test, unpaired and two-tailed when compared to the aqueous solution form

A strategic review of electricity systems models

International Nuclear Information System (INIS)

Foley, A.M.; O Gallachoir, B.P.; McKeogh, E.J.; Hur, J.; Baldick, R.

2010-01-01

Electricity systems models are software tools used to manage electricity demand and the electricity systems, to trade electricity and for generation expansion planning purposes. Various portfolios and scenarios are modelled in order to compare the effects of decision making in policy and on business development plans in electricity systems so as to best advise governments and industry on the least cost economic and environmental approach to electricity supply, while maintaining a secure supply of sufficient quality electricity. The modelling techniques developed to study vertically integrated state monopolies are now applied in liberalised markets where the issues and constraints are more complex. This paper reviews the changing role of electricity systems modelling in a strategic manner, focussing on the modelling response to key developments, the move away from monopoly towards liberalised market regimes and the increasing complexity brought about by policy targets for renewable energy and emissions. The paper provides an overview of electricity systems modelling techniques, discusses a number of key proprietary electricity systems models used in the USA and Europe and provides an information resource to the electricity analyst not currently readily available in the literature on the choice of model to investigate different aspects of the electricity system. (author)

In vitro microfluidic models of tumor microenvironment to screen transport of drugs and nanoparticles.

Science.gov (United States)

Ozcelikkale, Altug; Moon, Hye-Ran; Linnes, Michael; Han, Bumsoo

2017-09-01

Advances in nanotechnology have enabled numerous types of nanoparticles (NPs) to improve drug delivery to tumors. While many NP systems have been proposed, their clinical translation has been less than anticipated primarily due to failure of current preclinical evaluation techniques to adequately model the complex interactions between the NP and physiological barriers of tumor microenvironment. This review focuses on microfluidic tumor models for characterization of delivery efficacy and toxicity of cancer nanomedicine. Microfluidics offer significant advantages over traditional macroscale cell cultures by enabling recapitulation of tumor microenvironment through precise control of physiological cues such as hydrostatic pressure, shear stress, oxygen, and nutrient gradients. Microfluidic systems have recently started to be adapted for screening of drugs and NPs under physiologically relevant settings. So far the two primary application areas of microfluidics in this area have been high-throughput screening using traditional culture settings such as single cells or multicellular tumor spheroids, and mimicry of tumor microenvironment for study of cancer-related cell-cell and cell-matrix interactions. These microfluidic technologies are also useful in modeling specific steps in NP delivery to tumor and characterize NP transport properties and outcomes by systematic variation of physiological conditions. Ultimately, it will be possible to design drug-screening platforms uniquely tailored for individual patient physiology using microfluidics. These in vitro models can contribute to development of precision medicine by enabling rapid and patient-specific evaluation of cancer nanomedicine. WIREs Nanomed Nanobiotechnol 2017, 9:e1460. doi: 10.1002/wnan.1460 For further resources related to this article, please visit the WIREs website. © 2017 Wiley Periodicals, Inc.

A systems modelling framework for the design of integrated process control systems

International Nuclear Information System (INIS)

Lind, M.

1983-12-01

The paper describes a systems modelling methodology, called multilevel flow modelling, or MFM, which aims at describing complex production plants as designs, i.e. as systems having goals, functions and equipment realizing these functions. The modelling concepts are based on thermodynamics and lead to a system description in terms of multiple levels of interrelated mass or energy flow structures. The paper discusses as a basis for the modelling framework the general properties of artifacts or designs, characterizes the complexity of production systems and defines the MFM concepts which allow a consistent specification of goals and functions of these systems as generated in the process design. A modelling example is given and the application of the models for the design of plant control strategies is outlined. (author)

Use of an operational model evaluation system for model intercomparison

Energy Technology Data Exchange (ETDEWEB)

Foster, K. T., LLNL

1998-03-01

The Atmospheric Release Advisory Capability (ARAC) is a centralized emergency response system used to assess the impact from atmospheric releases of hazardous materials. As part of an on- going development program, new three-dimensional diagnostic windfield and Lagrangian particle dispersion models will soon replace ARAC`s current operational windfield and dispersion codes. A prototype model performance evaluation system has been implemented to facilitate the study of the capabilities and performance of early development versions of these new models relative to ARAC`s current operational codes. This system provides tools for both objective statistical analysis using common performance measures and for more subjective visualization of the temporal and spatial relationships of model results relative to field measurements. Supporting this system is a database of processed field experiment data (source terms and meteorological and tracer measurements) from over 100 individual tracer releases.

A multifunctional 3D co-culture system for studies of mammary tissue morphogenesis and stem cell biology.

Directory of Open Access Journals (Sweden)

Jonathan J Campbell

Full Text Available Studies on the stem cell niche and the efficacy of cancer therapeutics require complex multicellular structures and interactions between different cell types and extracellular matrix (ECM in three dimensional (3D space. We have engineered a 3D in vitro model of mammary gland that encompasses a defined, porous collagen/hyaluronic acid (HA scaffold forming a physiologically relevant foundation for epithelial and adipocyte co-culture. Polarized ductal and acinar structures form within this scaffold recapitulating normal tissue morphology in the absence of reconstituted basement membrane (rBM hydrogel. Furthermore, organoid developmental outcome can be controlled by the ratio of collagen to HA, with a higher HA concentration favouring acinar morphological development. Importantly, this culture system recapitulates the stem cell niche as primary mammary stem cells form complex organoids, emphasising the utility of this approach for developmental and tumorigenic studies using genetically altered animals or human biopsy material, and for screening cancer therapeutics for personalised medicine.

Modeling soft interface dominated systems

NARCIS (Netherlands)

Lamorgese, A.; Mauri, R.; Sagis, L.M.C.

2017-01-01

The two main continuum frameworks used for modeling the dynamics of soft multiphase systems are the Gibbs dividing surface model, and the diffuse interface model. In the former the interface is modeled as a two dimensional surface, and excess properties such as a surface density, or surface energy

Data management system performance modeling

Science.gov (United States)

Kiser, Larry M.

1993-01-01

This paper discusses analytical techniques that have been used to gain a better understanding of the Space Station Freedom's (SSF's) Data Management System (DMS). The DMS is a complex, distributed, real-time computer system that has been redesigned numerous times. The implications of these redesigns have not been fully analyzed. This paper discusses the advantages and disadvantages for static analytical techniques such as Rate Monotonic Analysis (RMA) and also provides a rationale for dynamic modeling. Factors such as system architecture, processor utilization, bus architecture, queuing, etc. are well suited for analysis with a dynamic model. The significance of performance measures for a real-time system are discussed.

The charophycean green algae as model systems to study plant cell walls and other evolutionary adaptations that gave rise to land plants

DEFF Research Database (Denmark)

Sørensen, Iben; Rose, Jocelyn K.C.; Doyle, Jeff J.

2012-01-01

for terrestrial colonization. The nature and molecular bases of such traits are still being determined, but one critical adaptation is thought to have been the evolution of a complex cell wall. Very little is known about the identity, origins and diversity of the biosynthetic machinery producing the major suites......, during times of radical habitat changes. Orders of the CGA span early diverging taxa retaining more ancestral characters, through complex multicellular organisms with morphological characteristics resembling those of land plants. Examination of gene diversity and evolution within the CGA could help...

Integrative systems and synthetic biology of cell-matrix adhesion sites.

Science.gov (United States)

Zamir, Eli

2016-09-02

The complexity of cell-matrix adhesion convolves its roles in the development and functioning of multicellular organisms and their evolutionary tinkering. Cell-matrix adhesion is mediated by sites along the plasma membrane that anchor the actin cytoskeleton to the matrix via a large number of proteins, collectively called the integrin adhesome. Fundamental challenges for understanding how cell-matrix adhesion sites assemble and function arise from their multi-functionality, rapid dynamics, large number of components and molecular diversity. Systems biology faces these challenges in its strive to understand how the integrin adhesome gives rise to functional adhesion sites. Synthetic biology enables engineering intracellular modules and circuits with properties of interest. In this review I discuss some of the fundamental questions in systems biology of cell-matrix adhesion and how synthetic biology can help addressing them.

Compiling models into real-time systems

International Nuclear Information System (INIS)

Dormoy, J.L.; Cherriaux, F.; Ancelin, J.

1992-08-01

This paper presents an architecture for building real-time systems from models, and model-compiling techniques. This has been applied for building a real-time model-based monitoring system for nuclear plants, called KSE, which is currently being used in two plants in France. We describe how we used various artificial intelligence techniques for building it: a model-based approach, a logical model of its operation, a declarative implementation of these models, and original knowledge-compiling techniques for automatically generating the real-time expert system from those models. Some of those techniques have just been borrowed from the literature, but we had to modify or invent other techniques which simply did not exist. We also discuss two important problems, which are often underestimated in the artificial intelligence literature: size, and errors. Our architecture, which could be used in other applications, combines the advantages of the model-based approach with the efficiency requirements of real-time applications, while in general model-based approaches present serious drawbacks on this point

Compiling models into real-time systems

International Nuclear Information System (INIS)

Dormoy, J.L.; Cherriaux, F.; Ancelin, J.

1992-08-01

This paper presents an architecture for building real-time systems from models, and model-compiling techniques. This has been applied for building a real-time model-base monitoring system for nuclear plants, called KSE, which is currently being used in two plants in France. We describe how we used various artificial intelligence techniques for building it: a model-based approach, a logical model of its operation, a declarative implementation of these models, and original knowledge-compiling techniques for automatically generating the real-time expert system from those models. Some of those techniques have just been borrowed from the literature, but we had to modify or invent other techniques which simply did not exist. We also discuss two important problems, which are often underestimated in the artificial intelligence literature: size, and errors. Our architecture, which could be used in other applications, combines the advantages of the model-based approach with the efficiency requirements of real-time applications, while in general model-based approaches present serious drawbacks on this point

Modeling Adaptive Behavior for Systems Design

DEFF Research Database (Denmark)

Rasmussen, Jens

1994-01-01

Field studies in modern work systems and analysis of recent major accidents have pointed to a need for better models of the adaptive behavior of individuals and organizations operating in a dynamic and highly competitive environment. The paper presents a discussion of some key characteristics.......) The basic difference between the models of system functions used in engineering and design and those evolving from basic research within the various academic disciplines and finally 3.) The models and methods required for closed-loop, feedback system design....

REQUIREMENTS FOR SYSTEMS DEVELOPMENT LIFE CYCLE MODELS FOR LARGE-SCALE DEFENSE SYSTEMS

Directory of Open Access Journals (Sweden)

Kadir Alpaslan DEMIR

2015-10-01

Full Text Available TLarge-scale defense system projects are strategic for maintaining and increasing the national defense capability. Therefore, governments spend billions of dollars in the acquisition and development of large-scale defense systems. The scale of defense systems is always increasing and the costs to build them are skyrocketing. Today, defense systems are software intensive and they are either a system of systems or a part of it. Historically, the project performances observed in the development of these systems have been signifi cantly poor when compared to other types of projects. It is obvious that the currently used systems development life cycle models are insuffi cient to address today’s challenges of building these systems. Using a systems development life cycle model that is specifi cally designed for largescale defense system developments and is effective in dealing with today’s and near-future challenges will help to improve project performances. The fi rst step in the development a large-scale defense systems development life cycle model is the identifi cation of requirements for such a model. This paper contributes to the body of literature in the fi eld by providing a set of requirements for system development life cycle models for large-scale defense systems. Furthermore, a research agenda is proposed.

Down-regulation of DNA mismatch repair proteins in human and murine tumor spheroids: implications for multicellular resistance to alkylating agents.

Science.gov (United States)

Francia, Giulio; Green, Shane K; Bocci, Guido; Man, Shan; Emmenegger, Urban; Ebos, John M L; Weinerman, Adina; Shaked, Yuval; Kerbel, Robert S

2005-10-01

Similar to other anticancer agents, intrinsic or acquired resistance to DNA-damaging chemotherapeutics is a major obstacle for cancer therapy. Current strategies aimed at overcoming this problem are mostly based on the premise that tumor cells acquire heritable genetic mutations that contribute to drug resistance. Here, we present evidence for an epigenetic, tumor cell adhesion-mediated, and reversible form of drug resistance that is associated with a reduction of DNA mismatch repair proteins PMS2 and/or MLH1 as well as other members of this DNA repair process. Growth of human breast cancer, human melanoma, and murine EMT-6 breast cancer cell lines as multicellular spheroids in vitro, which is associated with increased resistance to many chemotherapeutic drugs, including alkylating agents, is shown to lead to a reproducible down-regulation of PMS2, MLH1, or, in some cases, both as well as MHS6, MSH3, and MSH2. The observed down-regulation is in part reversible by treatment of tumor spheroids with the DNA-demethylating agent, 5-azacytidine. Thus, treatment of EMT-6 mouse mammary carcinoma spheroids with 5-azacytidine resulted in reduced and/or disrupted cell-cell adhesion, which in turn sensitized tumor spheroids to cisplatin-mediated killing in vitro. Our results suggest that antiadhesive agents might sensitize tumor spheroids to alkylating agents in part by reversing or preventing reduced DNA mismatch repair activity and that the chemosensitization properties of 5-azacytidine may conceivably reflect its role as a potential antiadhesive agent as well as reversal agent for MLH1 gene silencing in human tumors.

Identifying optimal models to represent biochemical systems.

Directory of Open Access Journals (Sweden)

Mochamad Apri

Full Text Available Biochemical systems involving a high number of components with intricate interactions often lead to complex models containing a large number of parameters. Although a large model could describe in detail the mechanisms that underlie the system, its very large size may hinder us in understanding the key elements of the system. Also in terms of parameter identification, large models are often problematic. Therefore, a reduced model may be preferred to represent the system. Yet, in order to efficaciously replace the large model, the reduced model should have the same ability as the large model to produce reliable predictions for a broad set of testable experimental conditions. We present a novel method to extract an "optimal" reduced model from a large model to represent biochemical systems by combining a reduction method and a model discrimination method. The former assures that the reduced model contains only those components that are important to produce the dynamics observed in given experiments, whereas the latter ensures that the reduced model gives a good prediction for any feasible experimental conditions that are relevant to answer questions at hand. These two techniques are applied iteratively. The method reveals the biological core of a model mathematically, indicating the processes that are likely to be responsible for certain behavior. We demonstrate the algorithm on two realistic model examples. We show that in both cases the core is substantially smaller than the full model.

Construction and analysis of a modular model of caspase activation in apoptosis

Directory of Open Access Journals (Sweden)

Ho Kenneth L

2008-12-01

Full Text Available Abstract Background A key physiological mechanism employed by multicellular organisms is apoptosis, or programmed cell death. Apoptosis is triggered by the activation of caspases in response to both extracellular (extrinsic and intracellular (intrinsic signals. The extrinsic and intrinsic pathways are characterized by the formation of the death-inducing signaling complex (DISC and the apoptosome, respectively; both the DISC and the apoptosome are oligomers with complex formation dynamics. Additionally, the extrinsic and intrinsic pathways are coupled through the mitochondrial apoptosis-induced channel via the Bcl-2 family of proteins. Results A model of caspase activation is constructed and analyzed. The apoptosis signaling network is simplified through modularization methodologies and equilibrium abstractions for three functional modules. The mathematical model is composed of a system of ordinary differential equations which is numerically solved. Multiple linear regression analysis investigates the role of each module and reduced models are constructed to identify key contributions of the extrinsic and intrinsic pathways in triggering apoptosis for different cell lines. Conclusion Through linear regression techniques, we identified the feedbacks, dissociation of complexes, and negative regulators as the key components in apoptosis. The analysis and reduced models for our model formulation reveal that the chosen cell lines predominately exhibit strong extrinsic caspase, typical of type I cell, behavior. Furthermore, under the simplified model framework, the selected cells lines exhibit different modes by which caspase activation may occur. Finally the proposed modularized model of apoptosis may generalize behavior for additional cells and tissues, specifically identifying and predicting components responsible for the transition from type I to type II cell behavior.

Revised sequence components power system models for unbalanced power system studies

Energy Technology Data Exchange (ETDEWEB)

Abdel-Akher, M. [Tunku Abdul Rahman Univ., Kuala Lumpur (Malaysia); Nor, K.-M. [Univ. of Technology Malaysia, Johor (Malaysia); Rashid, A.H.A. [Univ. of Malaya, Kuala Lumpur (Malaysia)

2007-07-01

The principle method of analysis using positive, negative, and zero-sequence networks has been used to examine the balanced power system under both balanced and unbalanced loading conditions. The significant advantage of the sequence networks is that the sequence networks become entirely uncoupled in the case of balanced three-phase power systems. The uncoupled sequence networks then can be solved in independent way such as in fault calculation programs. However, the hypothesis of balanced power systems cannot be considered in many cases due to untransposed transmission lines; multiphase line segments in a distribution power system; or transformer phase shifts which cannot be incorporated in the existing models. A revised sequence decoupled power system models for analyzing unbalanced power systems based on symmetrical networks was presented in this paper. These models included synchronous machines, transformers, transmission lines, and voltage regulators. The models were derived from their counterpart's models in phase coordinates frame of reference. In these models, the three sequence networks were fully decoupled with a three-phase coordinates features such as transformer phase shifts and transmission line coupling. The proposed models were used to develop an unbalanced power-flow program for analyzing both balanced and unbalanced networks. The power flow solution was identical to results obtained from a full phase coordinate three-phase power-flow program. 11 refs., 3 tabs.

Model Reduction of Hybrid Systems

DEFF Research Database (Denmark)

Shaker, Hamid Reza

gramians. Generalized gramians are the solutions to the observability and controllability Lyapunov inequalities. In the first framework the projection matrices are found based on the common generalized gramians. This framework preserves the stability of the original switched system for all switching...... is guaranteed to be preserved for arbitrary switching signal. To compute the common generalized gramians linear matrix inequalities (LMI’s) need to be solved. These LMI’s are not always feasible. In order to solve the problem of conservatism, the second framework is presented. In this method the projection......High-Technological solutions of today are characterized by complex dynamical models. A lot of these models have inherent hybrid/switching structure. Hybrid/switched systems are powerful models for distributed embedded systems design where discrete controls are applied to continuous processes...

Discrete modelling of drapery systems

Science.gov (United States)

Thoeni, Klaus; Giacomini, Anna

2016-04-01

Drapery systems are an efficient and cost-effective measure in preventing and controlling rockfall hazards on rock slopes. The simplest form consists of a row of ground anchors along the top of the slope connected to a horizontal support cable from which a wire mesh is suspended down the face of the slope. Such systems are generally referred to as simple or unsecured draperies (Badger and Duffy 2012). Variations such as secured draperies, where a pattern of ground anchors is incorporated within the field of the mesh, and hybrid systems, where the upper part of an unsecured drapery is elevated to intercept rockfalls originating upslope of the installation, are becoming more and more popular. This work presents a discrete element framework for simulation of unsecured drapery systems and its variations. The numerical model is based on the classical discrete element method (DEM) and implemented into the open-source framework YADE (Šmilauer et al., 2010). The model takes all relevant interactions between block, drapery and slope into account (Thoeni et al., 2014) and was calibrated and validated based on full-scale experiments (Giacomini et al., 2012).The block is modelled as a rigid clump made of spherical particles which allows any shape to be approximated. The drapery is represented by a set of spherical particle with remote interactions. The behaviour of the remote interactions is governed by the constitutive behaviour of the wire and generally corresponds to a piecewise linear stress-strain relation (Thoeni et al., 2013). The same concept is used to model wire ropes. The rock slope is represented by rigid triangular elements where material properties (e.g., normal coefficient of restitution, friction angle) are assigned to each triangle. The capabilities of the developed model to simulate drapery systems and estimate the residual hazard involved with such systems is shown. References Badger, T.C., Duffy, J.D. (2012) Drapery systems. In: Turner, A.K., Schuster R

An Empirical Model for Energy Storage Systems

Energy Technology Data Exchange (ETDEWEB)

Rosewater, David Martin [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Scott, Paul [TransPower, Poway, CA (United States)

2016-03-17

Improved models of energy storage systems are needed to enable the electric grid’s adaptation to increasing penetration of renewables. This paper develops a generic empirical model of energy storage system performance agnostic of type, chemistry, design or scale. Parameters for this model are calculated using test procedures adapted from the US DOE Protocol for Uniformly Measuring and Expressing the Performance of Energy Storage. We then assess the accuracy of this model for predicting the performance of the TransPower GridSaver – a 1 MW rated lithium-ion battery system that underwent laboratory experimentation and analysis. The developed model predicts a range of energy storage system performance based on the uncertainty of estimated model parameters. Finally, this model can be used to better understand the integration and coordination of energy storage on the electric grid.

A coordination model for ultra-large scale systems of systems

Directory of Open Access Journals (Sweden)

Manuela L. Bujorianu

2013-11-01

Full Text Available The ultra large multi-agent systems are becoming increasingly popular due to quick decay of the individual production costs and the potential of speeding up the solving of complex problems. Examples include nano-robots, or systems of nano-satellites for dangerous meteorite detection, or cultures of stem cells for organ regeneration or nerve repair. The topics associated with these systems are usually dealt within the theories of intelligent swarms or biologically inspired computation systems. Stochastic models play an important role and they are based on various formulations of the mechanical statistics. In these cases, the main assumption is that the swarm elements have a simple behaviour and that some average properties can be deduced for the entire swarm. In contrast, complex systems in areas like aeronautics are formed by elements with sophisticated behaviour, which are even autonomous. In situations like this, a new approach to swarm coordination is necessary. We present a stochastic model where the swarm elements are communicating autonomous systems, the coordination is separated from the component autonomous activity and the entire swarm can be abstracted away as a piecewise deterministic Markov process, which constitutes one of the most popular model in stochastic control. Keywords: ultra large multi-agent systems, system of systems, autonomous systems, stochastic hybrid systems.

In Silico Dynamics: computer simulation in a Virtual Embryo ...

Science.gov (United States)

Abstract: Utilizing cell biological information to predict higher order biological processes is a significant challenge in predictive toxicology. This is especially true for highly dynamical systems such as the embryo where morphogenesis, growth and differentiation require precisely orchestrated interactions between diverse cell populations. In patterning the embryo, genetic signals setup spatial information that cells then translate into a coordinated biological response. This can be modeled as ‘biowiring diagrams’ representing genetic signals and responses. Because the hallmark of multicellular organization resides in the ability of cells to interact with one another via well-conserved signaling pathways, multiscale computational (in silico) models that enable these interactions provide a platform to translate cellular-molecular lesions perturbations into higher order predictions. Just as ‘the Cell’ is the fundamental unit of biology so too should it be the computational unit (‘Agent’) for modeling embryogenesis. As such, we constructed multicellular agent-based models (ABM) with ‘CompuCell3D’ (www.compucell3d.org) to simulate kinematics of complex cell signaling networks and enable critical tissue events for use in predictive toxicology. Seeding the ABMs with HTS/HCS data from ToxCast demonstrated the potential to predict, quantitatively, the higher order impacts of chemical disruption at the cellular or biochemical level. This is demonstrate

Data retrieval systems and models of information situations

International Nuclear Information System (INIS)

Jankowski, L.

1984-01-01

Demands placed on data retrieval systems and their basic parameters are given. According to the stage of development of data collection and processing, data retrieval systems may be divided into systems for the simple recording and provision of data, systems for recording and providing data with integrated statistical functions, and logical information systems. The structure is characterized of the said information systems as are methods of processing and representation of facts. The notion is defined of ''artificial intelligence'' in the development of logical information systems. The structure of representing knowledge in diverse forms of the model is decisive in logical information systems related to nuclear research. The main model elements are the characteristics of data, forms of representation and program. In dependence on the structure of data, the structure of the preparatory and transformation algorithms and on the aim of the system it is possible to classify data retrieval systems related to nuclear research and technology into five logical information models: linear, identification, advisory, theory-experiment models and problem solving models. The characteristics are given of the said models and examples of data retrieval systems for the individual models. (E.S.)

Review of the systems biology of the immune system using agent-based models.

Science.gov (United States)

Shinde, Snehal B; Kurhekar, Manish P

2018-06-01

The immune system is an inherent protection system in vertebrate animals including human beings that exhibit properties such as self-organisation, self-adaptation, learning, and recognition. It interacts with the other allied systems such as the gut and lymph nodes. There is a need for immune system modelling to know about its complex internal mechanism, to understand how it maintains the homoeostasis, and how it interacts with the other systems. There are two types of modelling techniques used for the simulation of features of the immune system: equation-based modelling (EBM) and agent-based modelling. Owing to certain shortcomings of the EBM, agent-based modelling techniques are being widely used. This technique provides various predictions for disease causes and treatments; it also helps in hypothesis verification. This study presents a review of agent-based modelling of the immune system and its interactions with the gut and lymph nodes. The authors also review the modelling of immune system interactions during tuberculosis and cancer. In addition, they also outline the future research directions for the immune system simulation through agent-based techniques such as the effects of stress on the immune system, evolution of the immune system, and identification of the parameters for a healthy immune system.

Stochastic Models of Polymer Systems

Science.gov (United States)

2016-01-01

Distribution Unlimited Final Report: Stochastic Models of Polymer Systems The views, opinions and/or findings contained in this report are those of the...ADDRESS. Princeton University PO Box 0036 87 Prospect Avenue - 2nd floor Princeton, NJ 08544 -2020 14-Mar-2014 ABSTRACT Number of Papers published in...peer-reviewed journals: Number of Papers published in non peer-reviewed journals: Final Report: Stochastic Models of Polymer Systems Report Title

Regulation of Development and Nitrogen Fixation in Anabaena

Energy Technology Data Exchange (ETDEWEB)

James W. Golden

2008-10-17

The regulation of development and cellular differentiation is important for all multicellular organisms. The nitrogen-fixing filamentous cyanobacterium Anabaena (also Nostoc) sp. PCC 7120 (hereafter Anabaena) provides a model of multicellular microbial development and pattern formation. Anabaena reduces N2 to ammonia in specialized terminally differentiated cells called heterocysts. A one-dimensional developmental pattern of single heterocysts regularly spaced along filaments of photosynthetic vegetative cells is established to form a multicellular organism composed of these two interdependent cell types. This multicellular growth pattern, the distinct phylogeny of cyanobacteria, and the suspected antiquity of heterocyst development make this an important model system. Our long-term goal is to understand the regulatory network required for heterocyst development and nitrogen fixation. This project is focused on two key aspects of heterocyst regulation: one, the mechanism by which HetR controls the initiation of differentiation, and two, the cis and trans acting factors required for expression of the nitrogen-fixation (nif) genes. HetR is thought to be a central regulator of heterocyst development but the partners and mechanisms involved in this regulation are unknown. Our recent results indicate that PatS and other signals that regulate heterocyst pattern cannot interact, directly or indirectly, with a R223W mutant of HetR. We plan to use biochemical and genetic approaches to identify proteins that interact with the HetR protein, which will help reveal the mechanisms underlying its regulation of development. Our second goal is to determine how the nif genes are expressed. It is important to understand the mechanisms controlling nif genes since they represent the culmination of the differentiation process and the essence of heterocyst function. The Anabaena genome lacks the genes required for expression of nif genes present in other organisms such as rpoN (sigma 54

Modelling and Control of Thermal System

Directory of Open Access Journals (Sweden)

Vratislav Hladky

2014-01-01

Full Text Available Work presented here deals with the modelling of thermal processes in a thermal system consisting of direct and indirect heat exchangers. The overal thermal properties of the medium and the system itself such as liquid mixing or heat capacity are shortly analysed and their features required for modelling are reasoned and therefore simplified or neglected. Special attention is given to modelling heat losses radiated into the surroundings through the walls as they are the main issue of the effective work with the heat systems. Final part of the paper proposes several ways of controlling the individual parts’ temperatures as well as the temperature of the system considering heating elements or flowage rate as actuators.

The radionuclide migration model in river system

International Nuclear Information System (INIS)

Zhukova, O.M.; Shiryaeva, N.M.; Myshkina, M.K.; Shagalova, Eh.D.; Denisova, V.V.; Skurat, V.V.

2001-01-01

It was propose the model of radionuclide migration in river system based on principle of the compartmental model at hydraulically stationary and chemically equilibrium conditions of interaction of radionuclides in system water-dredge, water-sediments. Different conditions of radioactive contamination entry in river system were considered. The model was verified on the data of radiation monitoring of Iput' river

Model predictive control based on reduced order models applied to belt conveyor system.

Science.gov (United States)

Chen, Wei; Li, Xin

2016-11-01

In the paper, a model predictive controller based on reduced order model is proposed to control belt conveyor system, which is an electro-mechanics complex system with long visco-elastic body. Firstly, in order to design low-degree controller, the balanced truncation method is used for belt conveyor model reduction. Secondly, MPC algorithm based on reduced order model for belt conveyor system is presented. Because of the error bound between the full-order model and reduced order model, two Kalman state estimators are applied in the control scheme to achieve better system performance. Finally, the simulation experiments are shown that balanced truncation method can significantly reduce the model order with high-accuracy and model predictive control based on reduced-model performs well in controlling the belt conveyor system. Copyright © 2016 ISA. Published by Elsevier Ltd. All rights reserved.

Feature-based component model for design of embedded systems

Science.gov (United States)

Zha, Xuan Fang; Sriram, Ram D.

2004-11-01

An embedded system is a hybrid of hardware and software, which combines software's flexibility and hardware real-time performance. Embedded systems can be considered as assemblies of hardware and software components. An Open Embedded System Model (OESM) is currently being developed at NIST to provide a standard representation and exchange protocol for embedded systems and system-level design, simulation, and testing information. This paper proposes an approach to representing an embedded system feature-based model in OESM, i.e., Open Embedded System Feature Model (OESFM), addressing models of embedded system artifacts, embedded system components, embedded system features, and embedded system configuration/assembly. The approach provides an object-oriented UML (Unified Modeling Language) representation for the embedded system feature model and defines an extension to the NIST Core Product Model. The model provides a feature-based component framework allowing the designer to develop a virtual embedded system prototype through assembling virtual components. The framework not only provides a formal precise model of the embedded system prototype but also offers the possibility of designing variation of prototypes whose members are derived by changing certain virtual components with different features. A case study example is discussed to illustrate the embedded system model.

Imaging Herpes Simplex Virus Type 1 Amplicon Vector–Mediated Gene Expression in Human Glioma Spheroids

OpenAIRE

Christine Kaestle; Alexandra Winkeler; Raphaela Richter; Heinrich Sauer; Jürgen Hescheler; Cornel Fraefel; Maria Wartenberg; Andreas H. Jacobs

2011-01-01

Vectors derived from herpes simplex virus type 1 (HSV-1) have great potential for transducing therapeutic genes into the central nervous system; however, inefficient distribution of vector particles in vivo may limit their therapeutic potential in patients with gliomas. This study was performed to investigate the extent of HSV-1 amplicon vector–mediated gene expression in a three-dimensional glioma model of multicellular spheroids by imaging highly infectious HSV-1 virions expressing green fl...

An expert system for dispersion model interpretation

International Nuclear Information System (INIS)

Skyllingstad, E.D.; Ramsdell, J.V.

1988-10-01

A prototype expert system designed to diagnose dispersion model uncertainty is described in this paper with application to a puff transport model. The system obtains qualitative information from the model user and through an expert-derived knowledge base, performs a rating of the current simulation. These results can then be used in combination with dispersion model output for deciding appropriate evacuation measures. Ultimately, the goal of this work is to develop an expert system that may be operated accurately by an individual uneducated in meteorology or dispersion modeling. 5 refs., 3 figs

Modelling energy systems for developing countries

International Nuclear Information System (INIS)

Urban, F.; Benders, R.M.J.; Moll, H.C.

2007-01-01

Developing countries' energy use is rapidly increasing, which affects global climate change and global and regional energy settings. Energy models are helpful for exploring the future of developing and industrialised countries. However, energy systems of developing countries differ from those of industrialised countries, which has consequences for energy modelling. New requirements need to be met by present-day energy models to adequately explore the future of developing countries' energy systems. This paper aims to assess if the main characteristics of developing countries are adequately incorporated in present-day energy models. We first discuss these main characteristics, focusing particularly on developing Asia, and then present a model comparison of 12 selected energy models to test their suitability for developing countries. We conclude that many models are biased towards industrialised countries, neglecting main characteristics of developing countries, e.g. the informal economy, supply shortages, poor performance of the power sector, structural economic change, electrification, traditional bio-fuels, urban-rural divide. To more adequately address the energy systems of developing countries, energy models have to be adjusted and new models have to be built. We therefore indicate how to improve energy models for increasing their suitability for developing countries and give advice on modelling techniques and data requirements

Modelling the Replication Management in Information Systems

Directory of Open Access Journals (Sweden)

Cezar TOADER

2017-01-01

Full Text Available In the modern economy, the benefits of Web services are significant because they facilitates the activities automation in the framework of Internet distributed businesses as well as the cooperation between organizations through interconnection process running in the computer systems. This paper presents the development stages of a model for a reliable information system. This paper describes the communication between the processes within the distributed system, based on the message exchange, and also presents the problem of distributed agreement among processes. A list of objectives for the fault-tolerant systems is defined and a framework model for distributed systems is proposed. This framework makes distinction between management operations and execution operations. The proposed model promotes the use of a central process especially designed for the coordination and control of other application processes. The execution phases and the protocols for the management and the execution components are presented. This model of a reliable system could be a foundation for an entire class of distributed systems models based on the management of replication process.

Systems Engineering Model for ART Energy Conversion

Energy Technology Data Exchange (ETDEWEB)

Mendez Cruz, Carmen Margarita [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Rochau, Gary E. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Wilson, Mollye C. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

2017-02-01

The near-term objective of the EC team is to establish an operating, commercially scalable Recompression Closed Brayton Cycle (RCBC) to be constructed for the NE - STEP demonstration system (demo) with the lowest risk possible. A systems engineering approach is recommended to ensure adequate requirements gathering, documentation, and mode ling that supports technology development relevant to advanced reactors while supporting crosscut interests in potential applications. A holistic systems engineering model was designed for the ART Energy Conversion program by leveraging Concurrent Engineering, Balance Model, Simplified V Model, and Project Management principles. The resulting model supports the identification and validation of lifecycle Brayton systems requirements, and allows designers to detail system-specific components relevant to the current stage in the lifecycle, while maintaining a holistic view of all system elements.

System dynamics modelling of situation awareness

CSIR Research Space (South Africa)

Oosthuizen, R

2015-11-01

Full Text Available . The feedback loops and delays in the Command and Control system also contribute to the complex dynamic behavior. This paper will build on existing situation awareness models to develop a System Dynamics model to support a qualitative investigation through...

Modeling the Dynamic Digestive System Microbiome

Directory of Open Access Journals (Sweden)

Anne M. Estes

2015-08-01

Full Text Available “Modeling the Dynamic Digestive System Microbiome” is a hands-on activity designed to demonstrate the dynamics of microbiome ecology using dried pasta and beans to model disturbance events in the human digestive system microbiome. This exercise demonstrates how microbiome diversity is influenced by: 1 niche availability and habitat space and 2 a major disturbance event, such as antibiotic use. Students use a pictorial key to examine prepared models of digestive system microbiomes to determine what the person with the microbiome “ate.” Students then model the effect of taking antibiotics by removing certain “antibiotic sensitive” pasta. Finally, they add in “environmental microbes” or “native microbes” to recolonize the digestive system, determine how resilient their model microbome community is to disturbance, and discuss the implications. Throughout the exercise, students discuss differences in the habitat space available and microbiome community diversity. This exercise can be modified to discuss changes in the microbiome due to diet shifts and the emergence of antibiotic resistance in more depth.

Stirling Engine Dynamic System Modeling

Science.gov (United States)

Nakis, Christopher G.

2004-01-01

The Thermo-Mechanical systems branch at the Glenn Research Center focuses a large amount time on Stirling engines. These engines will be used on missions where solar power is inefficient, especially in deep space. I work with Tim Regan and Ed Lewandowski who are currently developing and validating a mathematical model for the Stirling engines. This model incorporates all aspects of the system including, mechanical, electrical and thermodynamic components. Modeling is done through Simplorer, a program capable of running simulations of the model. Once created and then proven to be accurate, a model is used for developing new ideas for engine design. My largest specific project involves varying key parameters in the model and quantifying the results. This can all be done relatively trouble-free with the help of Simplorer. Once the model is complete, Simplorer will do all the necessary calculations. The more complicated part of this project is determining which parameters to vary. Finding key parameters depends on the potential for a value to be independently altered in the design. For example, a change in one dimension may lead to a proportional change to the rest of the model, and no real progress is made. Also, the ability for a changed value to have a substantial impact on the outputs of the system is important. Results will be condensed into graphs and tables with the purpose of better communication and understanding of the data. With the changing of these parameters, a more optimal design can be created without having to purchase or build any models. Also, hours and hours of results can be simulated in minutes. In the long run, using mathematical models can save time and money. Along with this project, I have many other smaller assignments throughout the summer. My main goal is to assist in the processes of model development, validation and testing.

Executive Information Systems' Multidimensional Models

Directory of Open Access Journals (Sweden)

2007-01-01

Full Text Available Executive Information Systems are design to improve the quality of strategic level of management in organization through a new type of technology and several techniques for extracting, transforming, processing, integrating and presenting data in such a way that the organizational knowledge filters can easily associate with this data and turn it into information for the organization. These technologies are known as Business Intelligence Tools. But in order to build analytic reports for Executive Information Systems (EIS in an organization we need to design a multidimensional model based on the business model from the organization. This paper presents some multidimensional models that can be used in EIS development and propose a new model that is suitable for strategic business requests.

Balmorel open source energy system model

DEFF Research Database (Denmark)

Wiese, Frauke; Bramstoft, Rasmus; Koduvere, Hardi

2018-01-01

As the world progresses towards a cleaner energy future with more variable renewable energy sources, energy system models are required to deal with new challenges. This article describes design, development and applications of the open source energy system model Balmorel, which is a result...... of a long and fruitful cooperation between public and private institutions within energy system research and analysis. The purpose of the article is to explain the modelling approach, to highlight strengths and challenges of the chosen approach, to create awareness about the possible applications...... of Balmorel as well as to inspire to new model developments and encourage new users to join the community. Some of the key strengths of the model are the flexible handling of the time and space dimensions and the combination of operation and investment optimisation. Its open source character enables diverse...

Numerical Modeling of Microelectrochemical Systems

DEFF Research Database (Denmark)

Adesokan, Bolaji James

incorporates the finite size of ionic species in the transport equation. The model presents a more appropriate boundary conditions which describe the modified Butler-Volmer reaction kinetics and account for the surface capacitance of the thin electric double layer. We also have found analytical solution...... at the electrode in a microelectrochemical system. In our analysis, we account for the finite size properties of ions in the mass and the charge transport of ionic species in an electrochemical system. This term characterizes the saturation of the ionic species close to the electrode surface. We then analyse......The PhD dissertation is concerned with mathematical modeling and simulation of electrochemical systems. The first three chapters of the thesis consist of the introductory part, the model development chapter and the chapter on the summary of the main results. The remaining three chapters report...

Agent-based Modeling Methodology for Analyzing Weapons Systems

Science.gov (United States)

2015-03-26

technique involve model structure, system representation and the degree of validity, coupled with the simplicity, of the overall model. ABM is best suited... system representation of the air combat system . We feel that a simulation model that combines ABM with equation-based representation of weapons and...AGENT-BASED MODELING METHODOLOGY FOR ANALYZING WEAPONS SYSTEMS THESIS Casey D. Connors, Major, USA

A control strategy for electro-magneto-mechanical system based on virtual system model

Energy Technology Data Exchange (ETDEWEB)

Kim, Hong Youn; Heo, Hoon [Dept. of Control and Instrumentation Engineering, Korea University, Seoul (Korea, Republic of); Yun, Young Min [TPC Mechatronics Co., Ltd., Incheon (Korea, Republic of)

2016-09-15

A new approach to the control of electro-magneto-mechanical system is proposed in this paper. Conventionally, these systems are controlled based on the Maxwell system model via an on-off or PID control technique, which displays acceptable performance in the low frequency region, but not in the high frequency region where position control performance is greatly degraded. In order to improve the performance, a newly developed virtual 2nd order system modeling technique, SSID, is adopted for a complex electro-magnetomechanical system in the study. This technique states that any unknown system exposed to a random disturbance with unknown intensity can be identified in terms of a virtual 2nd order system model via the inverse process of a certain stochastic analysis. As a typical hybrid system, a solenoid valve is used as the target electro-magneto-mechanical system to study the modeling of the virtual 2nd order system. In order to confirm the performance of the proposed control strategy, autotuning PID controller in PWM mode is utilized. Simulations based on the conventional Maxwell system model with control via the bang-bang, autotuning PID, and the proposed virtual 2nd order system model approaches are conducted using MATLAB Simulink. Performance of these three systems in the low and high frequency bands is also compared. The simulation results reveal that the control performance of the virtual 2nd order system model is much improved compared with that of the Maxwell system model under autotuning PID and bang-bang controls in both low and high frequency regions, where the error is drastically reduced to approximately 1/5 of the original value.

Modeling of Generic Slung Load System

DEFF Research Database (Denmark)

Bisgaard, Morten; Bendtsen, Jan Dimon; la Cour-Harbo, Anders

2009-01-01

This paper presents the result of the modelling and verification of a generic slung load system using a small-scale helicopter. The model is intended for use in simulation, pilot training, estimation, and control. The model is derived using a redundant coordinate formulation based on Gauss...... slackening and tightening as well as aerodynamic coupling between the helicopter and the load. Furthermore, it is shown how the model can be easily used for multi-lift systems either with multiple helicopters or multiple loads. A numerical stabilisation algorithm is introduced and finally the use...... of the model is illustrated through simulations and flight verifications.  ...

Qualitative models for space system engineering

Science.gov (United States)

Forbus, Kenneth D.

1990-01-01

The objectives of this project were: (1) to investigate the implications of qualitative modeling techniques for problems arising in the monitoring, diagnosis, and design of Space Station subsystems and procedures; (2) to identify the issues involved in using qualitative models to enhance and automate engineering functions. These issues include representing operational criteria, fault models, alternate ontologies, and modeling continuous signals at a functional level of description; and (3) to develop a prototype collection of qualitative models for fluid and thermal systems commonly found in Space Station subsystems. Potential applications of qualitative modeling to space-systems engineering, including the notion of intelligent computer-aided engineering are summarized. Emphasis is given to determining which systems of the proposed Space Station provide the most leverage for study, given the current state of the art. Progress on using qualitative models, including development of the molecular collection ontology for reasoning about fluids, the interaction of qualitative and quantitative knowledge in analyzing thermodynamic cycles, and an experiment on building a natural language interface to qualitative reasoning is reported. Finally, some recommendations are made for future research.

Model Checking Real-Time Systems

DEFF Research Database (Denmark)

Bouyer, Patricia; Fahrenberg, Uli; Larsen, Kim Guldstrand

2018-01-01

This chapter surveys timed automata as a formalism for model checking real-time systems. We begin with introducing the model, as an extension of finite-state automata with real-valued variables for measuring time. We then present the main model-checking results in this framework, and give a hint...

Using A Model-Based Systems Engineering Approach For Exploration Medical System Development

Science.gov (United States)

Hanson, A.; Mindock, J.; McGuire, K.; Reilly, J.; Cerro, J.; Othon, W.; Rubin, D.; Urbina, M.; Canga, M.

2017-01-01

NASA's Human Research Program's Exploration Medical Capabilities (ExMC) element is defining the medical system needs for exploration class missions. ExMC's Systems Engineering (SE) team will play a critical role in successful design and implementation of the medical system into exploration vehicles. The team's mission is to "Define, develop, validate, and manage the technical system design needed to implement exploration medical capabilities for Mars and test the design in a progression of proving grounds." Development of the medical system is being conducted in parallel with exploration mission architecture and vehicle design development. Successful implementation of the medical system in this environment will require a robust systems engineering approach to enable technical communication across communities to create a common mental model of the emergent engineering and medical systems. Model-Based Systems Engineering (MBSE) improves shared understanding of system needs and constraints between stakeholders and offers a common language for analysis. The ExMC SE team is using MBSE techniques to define operational needs, decompose requirements and architecture, and identify medical capabilities needed to support human exploration. Systems Modeling Language (SysML) is the specific language the SE team is utilizing, within an MBSE approach, to model the medical system functional needs, requirements, and architecture. Modeling methods are being developed through the practice of MBSE within the team, and tools are being selected to support meta-data exchange as integration points to other system models are identified. Use of MBSE is supporting the development of relationships across disciplines and NASA Centers to build trust and enable teamwork, enhance visibility of team goals, foster a culture of unbiased learning and serving, and be responsive to customer needs. The MBSE approach to medical system design offers a paradigm shift toward greater integration between

Towards systems biology of the gravity response of higher plants -multiscale analysis of Arabidopsis thaliana root growth

Science.gov (United States)

Palme, Klaus; Aubry, D.; Bensch, M.; Schmidt, T.; Ronneberger, O.; Neu, C.; Li, X.; Wang, H.; Santos, F.; Wang, B.; Paponov, I.; Ditengou, F. A.; Teale, W. T.; Volkmann, D.; Baluska, F.; Nonis, A.; Trevisan, S.; Ruperti, B.; Dovzhenko, A.

Gravity plays a fundamental role in plant growth and development. Up to now, little is known about the molecular organisation of the signal transduction cascades and networks which co-ordinate gravity perception and response. By using an integrated systems biological approach, a systems analysis of gravity perception and the subsequent tightly-regulated growth response is planned in the model plant Arabidopsis thaliana. This approach will address questions such as: (i) what are the components of gravity signal transduction pathways? (ii) what are the dynamics of these components? (iii) what is their spatio-temporal regulation in different tis-sues? Using Arabidopsis thaliana as a model-we use root growth to obtain insights in the gravity response. New techniques enable identification of the individual genes affected by grav-ity and further integration of transcriptomics and proteomics data into interaction networks and cell communication events that operate during gravitropic curvature. Using systematic multiscale analysis we have identified regulatory networks consisting of transcription factors, the protein degradation machinery, vesicle trafficking and cellular signalling during the gravire-sponse. We developed approach allowing to incorporate key features of the root system across all relevant spatial and temporal scales to describe gene-expression patterns and correlate them with individual gene and protein functions. Combination of high-resolution microscopy and novel computational tools resulted in development of the root 3D model in which quantitative descriptions of cellular network properties and of multicellular interactions important in root growth and gravitropism can be integrated for the first time.

Graphical Model Debugger Framework for Embedded Systems

DEFF Research Database (Denmark)

Zeng, Kebin

2010-01-01

Model Driven Software Development has offered a faster way to design and implement embedded real-time software by moving the design to a model level, and by transforming models to code. However, the testing of embedded systems has remained at the code level. This paper presents a Graphical Model...... Debugger Framework, providing an auxiliary avenue of analysis of system models at runtime by executing generated code and updating models synchronously, which allows embedded developers to focus on the model level. With the model debugger, embedded developers can graphically test their design model...

Combining multimedia models with integrated urban water system models for micropollutants

DEFF Research Database (Denmark)

De Keyser, W.; Gevaert, V.; Verdonck, F.

2010-01-01

Integrated urban water system (IUWS) modeling aims at assessing the quality of the surface water receiving the urban emissions through sewage treatment plants, combined sewer overflows (CSOS) and stormwater drainage systems However, some micropollutants tend to appear in more than one environmental...... medium (air, water, sediment, soil, groundwater, etc) In this work, a multimedia fate and transport model (MFTM) is "wrapped around" a dynamic IUWS model for organic micropollutants to enable integrated environmental assessment The combined model was tested on a hypothetical catchment using two scenarios...... on the one hand a reference scenario with a combined sewerage system and on the other hand a stormwater infiltration pond scenario, as an example of a sustainable urban drainage system (SUDS) A case for Bis(2-ethylhexyl) phthalate (DEHP) was simulated and resulted in reduced surface water concentrations...

Natural gas transmission and distribution model of the National Energy Modeling System

International Nuclear Information System (INIS)

1997-02-01

The Natural Gas Transmission and Distribution Model (NGTDM) is the component of the National Energy Modeling System (NEMS) that is used to represent the domestic natural gas transmission and distribution system. NEMS was developed in the Office of Integrated Analysis and Forecasting of the Energy Information Administration (EIA). NEMS is the third in a series of computer-based, midterm energy modeling systems used since 1974 by the EIA and its predecessor, the Federal Energy Administration, to analyze domestic energy-economy markets and develop projections. From 1982 through 1993, the Intermediate Future Forecasting System (IFFS) was used by the EIA for its analyses, and the Gas Analysis Modeling System (GAMS) was used within IFFS to represent natural gas markets. Prior to 1982, the Midterm Energy Forecasting System (MEFS), also referred to as the Project Independence Evaluation System (PIES), was employed. NEMS was developed to enhance and update EIA's modeling capability by internally incorporating models of energy markets that had previously been analyzed off-line. In addition, greater structural detail in NEMS permits the analysis of a broader range of energy issues. The time horizon of NEMS is the midterm period (i.e., through 2015). In order to represent the regional differences in energy markets, the component models of NEMS function at regional levels appropriate for the markets represented, with subsequent aggregation/disaggregation to the Census Division level for reporting purposes

Natural gas transmission and distribution model of the National Energy Modeling System

Energy Technology Data Exchange (ETDEWEB)

NONE

1997-02-01

The Natural Gas Transmission and Distribution Model (NGTDM) is the component of the National Energy Modeling System (NEMS) that is used to represent the domestic natural gas transmission and distribution system. NEMS was developed in the Office of Integrated Analysis and Forecasting of the Energy Information Administration (EIA). NEMS is the third in a series of computer-based, midterm energy modeling systems used since 1974 by the EIA and its predecessor, the Federal Energy Administration, to analyze domestic energy-economy markets and develop projections. From 1982 through 1993, the Intermediate Future Forecasting System (IFFS) was used by the EIA for its analyses, and the Gas Analysis Modeling System (GAMS) was used within IFFS to represent natural gas markets. Prior to 1982, the Midterm Energy Forecasting System (MEFS), also referred to as the Project Independence Evaluation System (PIES), was employed. NEMS was developed to enhance and update EIA`s modeling capability by internally incorporating models of energy markets that had previously been analyzed off-line. In addition, greater structural detail in NEMS permits the analysis of a broader range of energy issues. The time horizon of NEMS is the midterm period (i.e., through 2015). In order to represent the regional differences in energy markets, the component models of NEMS function at regional levels appropriate for the markets represented, with subsequent aggregation/disaggregation to the Census Division level for reporting purposes.

A hierarchy for modeling high speed propulsion systems

Science.gov (United States)

Hartley, Tom T.; Deabreu, Alex

1991-01-01

General research efforts on reduced order propulsion models for control systems design are overviewed. Methods for modeling high speed propulsion systems are discussed including internal flow propulsion systems that do not contain rotating machinery such as inlets, ramjets, and scramjets. The discussion is separated into four sections: (1) computational fluid dynamics model for the entire nonlinear system or high order nonlinear models; (2) high order linearized model derived from fundamental physics; (3) low order linear models obtained from other high order models; and (4) low order nonlinear models. Included are special considerations on any relevant control system designs. The methods discussed are for the quasi-one dimensional Euler equations of gasdynamic flow. The essential nonlinear features represented are large amplitude nonlinear waves, moving normal shocks, hammershocks, subsonic combustion via heat addition, temperature dependent gases, detonation, and thermal choking.

Structural system identification: Structural dynamics model validation

Energy Technology Data Exchange (ETDEWEB)

Red-Horse, J.R.

1997-04-01

Structural system identification is concerned with the development of systematic procedures and tools for developing predictive analytical models based on a physical structure`s dynamic response characteristics. It is a multidisciplinary process that involves the ability (1) to define high fidelity physics-based analysis models, (2) to acquire accurate test-derived information for physical specimens using diagnostic experiments, (3) to validate the numerical simulation model by reconciling differences that inevitably exist between the analysis model and the experimental data, and (4) to quantify uncertainties in the final system models and subsequent numerical simulations. The goal of this project was to develop structural system identification techniques and software suitable for both research and production applications in code and model validation.

X-irradiation effects on growth and metamorphosis of gastropod larvae (Crepidula fornicata): A model for environmental radiation teratogenesis

International Nuclear Information System (INIS)

Gould, L.; Lord, A.; Pechenik, J.; Kase, K.; Fitzgerald, T.J.; Greenberger, J.S.

1985-01-01

Little information is available on the effects of x-irradiation on multicellular marine organisms. C. fornicata larvae were irradiated at 200 rad/min, 250 kVp x-rays to doses between 50 and 20,000 rad in a single fraction. Shell length, biomass, metamorphosis to the next stage of development, and mortality were measured. The results demonstrated a dose-dependent decrease in 20 day shell length at doses above 2000 rad (control 850 +- 110 μm length, 820 +- 100μm for 50 rad, 750 +- 30 μm for 2000 rad, 710 +- 30 μm for 5000 rad, 620 +- 30 μm for 10,000 rad, 580 +- 15 μm for 20,000 rad). There was a dose dependent decrease in shell length growth between days 1 and 20. Biomass was significantly decreased per 100μm shell length for doses above 10,000 rad. A significant increase in larvae mortality was detected with doses above 2000 rad. Most significantly, the cumulative percent of larval metamorphosis was significantly decreased by doses as low as 500 rad and was detectable as early as 18 days after irradiation. C. fornicata may provide a very sensitive system in which to study teratogenic effects of x-irradiation on multicellular organisms

Visual prosthesis wireless energy transfer system optimal modeling.

Science.gov (United States)

Li, Xueping; Yang, Yuan; Gao, Yong

2014-01-16

Wireless energy transfer system is an effective way to solve the visual prosthesis energy supply problems, theoretical modeling of the system is the prerequisite to do optimal energy transfer system design. On the basis of the ideal model of the wireless energy transfer system, according to visual prosthesis application condition, the system modeling is optimized. During the optimal modeling, taking planar spiral coils as the coupling devices between energy transmitter and receiver, the effect of the parasitic capacitance of the transfer coil is considered, and especially the concept of biological capacitance is proposed to consider the influence of biological tissue on the energy transfer efficiency, resulting in the optimal modeling's more accuracy for the actual application. The simulation data of the optimal model in this paper is compared with that of the previous ideal model, the results show that under high frequency condition, the parasitic capacitance of inductance and biological capacitance considered in the optimal model could have great impact on the wireless energy transfer system. The further comparison with the experimental data verifies the validity and accuracy of the optimal model proposed in this paper. The optimal model proposed in this paper has a higher theoretical guiding significance for the wireless energy transfer system's further research, and provide a more precise model reference for solving the power supply problem in visual prosthesis clinical application.

Hybrid Energy System Modeling in Modelica

Energy Technology Data Exchange (ETDEWEB)

William R. Binder; Christiaan J. J. Paredis; Humberto E. Garcia

2014-03-01

In this paper, a Hybrid Energy System (HES) configuration is modeled in Modelica. Hybrid Energy Systems (HES) have as their defining characteristic the use of one or more energy inputs, combined with the potential for multiple energy outputs. Compared to traditional energy systems, HES provide additional operational flexibility so that high variability in both energy production and consumption levels can be absorbed more effectively. This is particularly important when including renewable energy sources, whose output levels are inherently variable, determined by nature. The specific HES configuration modeled in this paper include two energy inputs: a nuclear plant, and a series of wind turbines. In addition, the system produces two energy outputs: electricity and synthetic fuel. The models are verified through simulations of the individual components, and the system as a whole. The simulations are performed for a range of component sizes, operating conditions, and control schemes.

Agent-Based Modeling in Systems Pharmacology.

Science.gov (United States)

Cosgrove, J; Butler, J; Alden, K; Read, M; Kumar, V; Cucurull-Sanchez, L; Timmis, J; Coles, M

2015-11-01

Modeling and simulation (M&S) techniques provide a platform for knowledge integration and hypothesis testing to gain insights into biological systems that would not be possible a priori. Agent-based modeling (ABM) is an M&S technique that focuses on describing individual components rather than homogenous populations. This tutorial introduces ABM to systems pharmacologists, using relevant case studies to highlight how ABM-specific strengths have yielded success in the area of preclinical mechanistic modeling.

Risk Modeling of Interdependent Complex Systems of Systems: Theory and Practice.

Science.gov (United States)

Haimes, Yacov Y

2018-01-01

The emergence of the complexity characterizing our systems of systems (SoS) requires a reevaluation of the way we model, assess, manage, communicate, and analyze the risk thereto. Current models for risk analysis of emergent complex SoS are insufficient because too often they rely on the same risk functions and models used for single systems. These models commonly fail to incorporate the complexity derived from the networks of interdependencies and interconnectedness (I-I) characterizing SoS. There is a need to reevaluate currently practiced risk analysis to respond to this reality by examining, and thus comprehending, what makes emergent SoS complex. The key to evaluating the risk to SoS lies in understanding the genesis of characterizing I-I of systems manifested through shared states and other essential entities within and among the systems that constitute SoS. The term "essential entities" includes shared decisions, resources, functions, policies, decisionmakers, stakeholders, organizational setups, and others. This undertaking can be accomplished by building on state-space theory, which is fundamental to systems engineering and process control. This article presents a theoretical and analytical framework for modeling the risk to SoS with two case studies performed with the MITRE Corporation and demonstrates the pivotal contributions made by shared states and other essential entities to modeling and analysis of the risk to complex SoS. A third case study highlights the multifarious representations of SoS, which require harmonizing the risk analysis process currently applied to single systems when applied to complex SoS. © 2017 Society for Risk Analysis.

Synthetic multicellular oscillatory systems: controlling protein dynamics with genetic circuits

International Nuclear Information System (INIS)

Koseska, Aneta; Volkov, Evgenii; Kurths, Juergen

2011-01-01

Synthetic biology is a relatively new research discipline that combines standard biology approaches with the constructive nature of engineering. Thus, recent efforts in the field of synthetic biology have given a perspective to consider cells as 'programmable matter'. Here, we address the possibility of using synthetic circuits to control protein dynamics. In particular, we show how intercellular communication and stochasticity can be used to manipulate the dynamical behavior of a population of coupled synthetic units and, in this manner, finely tune the expression of specific proteins of interest, e.g. in large bioreactors.

Analytical performance modeling for computer systems

CERN Document Server

Tay, Y C

2013-01-01

This book is an introduction to analytical performance modeling for computer systems, i.e., writing equations to describe their performance behavior. It is accessible to readers who have taken college-level courses in calculus and probability, networking and operating systems. This is not a training manual for becoming an expert performance analyst. Rather, the objective is to help the reader construct simple models for analyzing and understanding the systems that they are interested in.Describing a complicated system abstractly with mathematical equations requires a careful choice of assumpti

Modeling Of Proton Exchange Membrane Fuel Cell Systems

DEFF Research Database (Denmark)

Nielsen, Mads Pagh

The objective of this doctoral thesis was to develop reliable steady-state and transient component models suitable to asses-, develop- and optimize proton exchange membrane (PEM) fuel cell systems. Several components in PEM fuel cell systems were characterized and modeled. The developed component...... cell systems. Consequences of indirectly fueling PEM stacks with hydrocarbons using reforming technology were investigated using a PEM stack model including CO poisoning kinetics and a transient Simulink steam reforming system model. Aspects regarding the optimization of PEM fuel cell systems...