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Cells, Volume 2, Issue 2 (June 2013), Pages 188-459

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Research

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Open AccessArticle A Drosophila Model to Image Phagosome Maturation
Cells 2013, 2(2), 188-201; doi:10.3390/cells2020188
Received: 19 October 2012 / Revised: 21 February 2013 / Accepted: 14 March 2013 / Published: 26 March 2013
Cited by 1 | PDF Full-text (620 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Phagocytosis involves the internalization of extracellular material by invagination of the plasma membrane to form intracellular vesicles called phagosomes, which have functions that include pathogen degradation. The degradative properties of phagosomes are thought to be conferred by sequential fusion with endosomes and lysosomes;
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Phagocytosis involves the internalization of extracellular material by invagination of the plasma membrane to form intracellular vesicles called phagosomes, which have functions that include pathogen degradation. The degradative properties of phagosomes are thought to be conferred by sequential fusion with endosomes and lysosomes; however, this maturation process has not been studied in vivo. We employed Drosophila hemocytes, which are similar to mammalian professional macrophages, to establish a model of phagosome maturation. Adult Drosophila females, carrying transgenic Rab7-GFP endosome and Lamp1-GFP lysosome markers, were injected with E. coli DH5α and the hemocytes were collected at 15, 30, 45 and 60 minutes after infection. In wild-type females, E. coli were detected within enlarged Rab7-GFP positive phagosomes at 15 to 45 minutes after infection; and were also observed in enlarged Lamp1-GFP positive phagolysosomes at 45 minutes. Two-photon imaging of hemocytes in vivo confirmed this vesicle morphology, including enlargement of Rab7-GFP and Lamp1-GFP structures that often appeared to protrude from hemocytes. The interaction of endosomes and lysosomes with E. coli phagosomes observed in Drosophila hemocytes was consistent with that previously described for phagosome maturation in human ex vivo macrophages. We also tested our model as a tool for genetic analysis using 14-3-3e mutants, and demonstrated altered phagosome maturation with delayed E. coli internalization, trafficking and/or degradation. These findings demonstrate that Drosophila hemocytes provide an appropriate, genetically amenable, model for analyzing phagosome maturation ex vivo and in vivo. Full article
(This article belongs to the Special Issue Imaging in Cell Biology and Development)
Open AccessArticle Temporal Gene Expression Kinetics for Human Keratinocytes Exposed to Hyperthermic Stress
Cells 2013, 2(2), 224-243; doi:10.3390/cells2020224
Received: 28 February 2013 / Revised: 29 March 2013 / Accepted: 2 April 2013 / Published: 10 April 2013
Cited by 1 | PDF Full-text (1460 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The gene expression kinetics for human cells exposed to hyperthermic stress are not well characterized. In this study, we identified and characterized the genes that are differentially expressed in human epidermal keratinocyte (HEK) cells exposed to hyperthermic stress. In order to obtain temporal
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The gene expression kinetics for human cells exposed to hyperthermic stress are not well characterized. In this study, we identified and characterized the genes that are differentially expressed in human epidermal keratinocyte (HEK) cells exposed to hyperthermic stress. In order to obtain temporal gene expression kinetics, we exposed HEK cells to a heat stress protocol (44 °C for 40 min) and used messenger RNA (mRNA) microarrays at 0 h, 4 h and 24 h post-exposure. Bioinformatics software was employed to characterize the chief biological processes and canonical pathways associated with these heat stress genes. The data shows that the genes encoding for heat shock proteins (HSPs) that function to prevent further protein denaturation and aggregation, such as HSP40, HSP70 and HSP105, exhibit maximal expression immediately after exposure to hyperthermic stress. In contrast, the smaller HSPs, such as HSP10 and HSP27, which function in mitochondrial protein biogenesis and cellular adaptation, exhibit maximal expression during the “recovery phase”, roughly 24 h post-exposure. These data suggest that the temporal expression kinetics for each particular HSP appears to correlate with the cellular function that is required at each time point. In summary, these data provide additional insight regarding the expression kinetics of genes that are triggered in HEK cells exposed to hyperthermic stress. Full article
(This article belongs to the Special Issue Cellular Stress Response)
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Open AccessArticle A Preliminary Evaluation of Lyophilized Gelatin Sponges, Enhanced with Platelet-Rich Plasma, Hydroxyapatite and Chitin Whiskers for Bone Regeneration
Cells 2013, 2(2), 244-265; doi:10.3390/cells2020244
Received: 24 January 2013 / Revised: 13 March 2013 / Accepted: 15 April 2013 / Published: 26 April 2013
Cited by 11 | PDF Full-text (2486 KB) | HTML Full-text | XML Full-text
Abstract
The purpose of this study was to perform a number of preliminary in vitro evaluations on an array of modified gelatin gel sponge scaffolds for use in a bone graft application. The gelatin gels were modified through the addition of a number of
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The purpose of this study was to perform a number of preliminary in vitro evaluations on an array of modified gelatin gel sponge scaffolds for use in a bone graft application. The gelatin gels were modified through the addition of a number of components which each possess unique properties conducive to the creation and regeneration of bone: a preparation rich in growth factors (PRGF, a bioactive, lyophilized form of platelet-rich plasma), hydroxyapatite, and chitin whiskers. Platelet-rich plasma therapy is an emerging practice that has proven effective in a number of clinical applications, including enhancing bone repair through improved deposition of new bony matrix and angiogenesis. As such, the inclusion of PRGF in our gelatin scaffolds was intended to significantly enhance scaffold bioactivity, while the addition of hydroxyapatite and chitin whiskers were anticipated to increase scaffold strength. Additionally, the gelatin sponges, which readily dissolve in aqueous solutions, were subjected to 1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC) cross-linking, either during or post-gelation, to control their rate of degradation. Scaffolds were evaluated in vitro with respect to compressive strength, mass loss/degradation, protein release, and cellular interaction, with results demonstrating the potential of the gelatin gel sponge scaffold for use in the regeneration of bone. Full article
(This article belongs to the Special Issue Tissue and Organ Regeneration)
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Open AccessArticle A New Integrated Lab-on-a-Chip System for Fast Dynamic Study of Mammalian Cells under Physiological Conditions in Bioreactor
Cells 2013, 2(2), 349-360; doi:10.3390/cells2020349
Received: 1 April 2013 / Revised: 29 April 2013 / Accepted: 16 May 2013 / Published: 27 May 2013
Cited by 6 | PDF Full-text (1004 KB) | HTML Full-text | XML Full-text
Abstract
For the quantitative analysis of cellular metabolism and its dynamics it is essential to achieve rapid sampling, fast quenching of metabolism and the removal of extracellular metabolites. Common manual sample preparation methods and protocols for cells are time-consuming and often lead to the
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For the quantitative analysis of cellular metabolism and its dynamics it is essential to achieve rapid sampling, fast quenching of metabolism and the removal of extracellular metabolites. Common manual sample preparation methods and protocols for cells are time-consuming and often lead to the loss of physiological conditions. In this work, we present a microchip-bioreactor setup which provides an integrated and rapid sample preparation of mammalian cells. The lab-on-a-chip system consists of five connected units that allow sample treatment, mixing and incubation of the cells, followed by cell separation and simultaneous exchange of media within seconds. This microsystem is directly integrated into a bioreactor for mammalian cell cultivation. By applying overpressure (2 bar) onto the bioreactor, this setup allows pulsation free, defined, fast, and continuous sampling. Experiments evince that Chinese Hamster Ovary cells (CHO-K1) can be separated from the culture broth and transferred into a new medium efficiently. Furthermore, this setup permits the treatment of cells for a defined time (9 s or 18 s) which can be utilized for pulse experiments, quenching of cell metabolism, and/or another defined chemical treatment. Proof of concept experiments were performed using glutamine containing medium for pulse experiments. Continuous sampling of cells showed a high reproducibility over a period of 18 h. Full article
(This article belongs to the Special Issue Feature Papers 2013)
Open AccessArticle Monte Carlo Study Elucidates the Type 1/Type 2 Choice in Apoptotic Death Signaling in Healthy and Cancer Cells
Cells 2013, 2(2), 361-392; doi:10.3390/cells2020361
Received: 13 March 2013 / Revised: 10 May 2013 / Accepted: 14 May 2013 / Published: 30 May 2013
Cited by 2 | PDF Full-text (1771 KB) | HTML Full-text | XML Full-text
Abstract
Apoptotic cell death is coordinated through two distinct (type 1 and type 2) intracellular signaling pathways. How the type 1/type 2 choice is made remains a central problem in the biology of apoptosis and has implications for apoptosis related diseases and therapy. We
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Apoptotic cell death is coordinated through two distinct (type 1 and type 2) intracellular signaling pathways. How the type 1/type 2 choice is made remains a central problem in the biology of apoptosis and has implications for apoptosis related diseases and therapy. We study the problem of type 1/type 2 choice in silico utilizing a kinetic Monte Carlo model of cell death signaling. Our results show that the type 1/type 2 choice is linked to deterministic versus stochastic cell death activation, elucidating a unique regulatory control of the apoptotic pathways. Consistent with previous findings, our results indicate that caspase 8 activation level is a key regulator of the choice between deterministic type 1 and stochastic type 2 pathways, irrespective of cell types. Expression levels of signaling molecules downstream also regulate the type 1/type 2 choice. A simplified model of DISC clustering elucidates the mechanism of increased active caspase 8 generation and type 1 activation in cancer cells having increased sensitivity to death receptor activation. We demonstrate that rapid deterministic activation of the type 1 pathway can selectively target such cancer cells, especially if XIAP is also inhibited; while inherent cell-to-cell variability would allow normal cells stay protected. Full article
(This article belongs to the Special Issue Apoptosis)
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Review

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Open AccessReview Tissue-Specific Actions of Glucocorticoids on Apoptosis: A Double-Edged Sword
Cells 2013, 2(2), 202-223; doi:10.3390/cells2020202
Received: 4 February 2013 / Revised: 5 March 2013 / Accepted: 12 March 2013 / Published: 26 March 2013
Cited by 9 | PDF Full-text (523 KB) | HTML Full-text | XML Full-text
Abstract
First described for their metabolic and immunosuppressive effects, glucocorticoids are widely prescribed in clinical settings of inflammation. However, glucocorticoids are also potent inducers of apoptosis in many cell types and tissues. This review will focus on the established mechanisms of glucocorticoid-induced apoptosis and
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First described for their metabolic and immunosuppressive effects, glucocorticoids are widely prescribed in clinical settings of inflammation. However, glucocorticoids are also potent inducers of apoptosis in many cell types and tissues. This review will focus on the established mechanisms of glucocorticoid-induced apoptosis and outline what is known about the apoptotic response in cells and tissues of the body after exposure to glucocorticoids. Glucocorticoid-induced apoptosis affects the skeletal system, muscular system, circulatory system, nervous system, endocrine system, reproductive system, and the immune system. Interestingly, several cell types have an anti-apoptotic response to glucocorticoids that is cytoprotective. Lastly, we will discuss the pro- and anti-apoptotic effects of glucocorticoids in cancers and their clinical implications. Full article
(This article belongs to the Special Issue Apoptosis)
Open AccessReview Linking Metabolic Abnormalities to Apoptotic Pathways in Beta Cells in Type 2 Diabetes
Cells 2013, 2(2), 266-283; doi:10.3390/cells2020266
Received: 14 February 2013 / Revised: 3 April 2013 / Accepted: 5 April 2013 / Published: 26 April 2013
Cited by 4 | PDF Full-text (322 KB) | HTML Full-text | XML Full-text
Abstract
Pancreatic beta-cell apoptosis is an important feature of islets in type 2 diabetes. Apoptosis can occur through two major pathways, the extrinsic or death receptor mediated pathway, and the intrinsic or Bcl-2-regulated pathway. Hyperglycaemia, hyperlipidaemia and islet amyloid poly-peptide (IAPP) represent important possible
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Pancreatic beta-cell apoptosis is an important feature of islets in type 2 diabetes. Apoptosis can occur through two major pathways, the extrinsic or death receptor mediated pathway, and the intrinsic or Bcl-2-regulated pathway. Hyperglycaemia, hyperlipidaemia and islet amyloid poly-peptide (IAPP) represent important possible causes of increased beta-cell apoptosis. Hyperglycaemia induces islet-cell apoptosis by the intrinsic pathway involving molecules of the Bcl-2 family. High concentrations of palmitate also activate intrinsic apoptosis in islets cells. IAPP oligomers can induce apoptosis by both intrinsic and extrinsic pathways. IL-1b produced through NLRP3 inflammasome activation can also induce islet cell death. Activation of the NLRP3 inflammasome may not be important for glucose or palmitate induced apoptosis in islets but may be important for IAPP mediated cell death. Endoplasmic reticulum (ER) and oxidative stress have been observed in beta cells in type 2 diabetes, and these could be the link between upstream metabolic abnormalities and downstream apoptotic machinery. Full article
(This article belongs to the Special Issue Apoptosis)
Open AccessReview Morphological Features of Organelles during Apoptosis: An Overview
Cells 2013, 2(2), 294-305; doi:10.3390/cells2020294
Received: 31 January 2013 / Revised: 24 March 2013 / Accepted: 19 April 2013 / Published: 8 May 2013
Cited by 7 | PDF Full-text (637 KB) | HTML Full-text | XML Full-text
Abstract
An apoptotic program leading to controlled cell dismantling implies perturbations of nuclear dynamics, as well as changes affecting the organelle structure and distribution. In human cancer cells driven to apoptosis by different stimuli, we have recently investigated the morphological properties of several organelles,
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An apoptotic program leading to controlled cell dismantling implies perturbations of nuclear dynamics, as well as changes affecting the organelle structure and distribution. In human cancer cells driven to apoptosis by different stimuli, we have recently investigated the morphological properties of several organelles, including mitochondria, lysosomes, endoplasmic reticulum and Golgi apparatus. In this review, we will discuss the body of evidence in the literature suggesting that organelles are generally relocated and/or degraded during apoptosis, irrespectively of the apoptogenic stimulus and cell type. Full article
(This article belongs to the Special Issue Apoptosis)
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Open AccessReview Reverse Engineering Cellular Networks with Information Theoretic Methods
Cells 2013, 2(2), 306-329; doi:10.3390/cells2020306
Received: 26 February 2013 / Revised: 22 April 2013 / Accepted: 27 April 2013 / Published: 10 May 2013
Cited by 9 | PDF Full-text (245 KB) | HTML Full-text | XML Full-text
Abstract
Building mathematical models of cellular networks lies at the core of systems biology. It involves, among other tasks, the reconstruction of the structure of interactions between molecular components, which is known as network inference or reverse engineering. Information theory can help in the
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Building mathematical models of cellular networks lies at the core of systems biology. It involves, among other tasks, the reconstruction of the structure of interactions between molecular components, which is known as network inference or reverse engineering. Information theory can help in the goal of extracting as much information as possible from the available data. A large number of methods founded on these concepts have been proposed in the literature, not only in biology journals, but in a wide range of areas. Their critical comparison is difficult due to the different focuses and the adoption of different terminologies. Here we attempt to review some of the existing information theoretic methodologies for network inference, and clarify their differences. While some of these methods have achieved notable success, many challenges remain, among which we can mention dealing with incomplete measurements, noisy data, counterintuitive behaviour emerging from nonlinear relations or feedback loops, and computational burden of dealing with large data sets. Full article
(This article belongs to the Special Issue Successes of Systems Biology and Future Challenges)
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Open AccessReview Targeting Neutrophil Apoptosis for Enhancing the Resolution of Inflammation
Cells 2013, 2(2), 330-348; doi:10.3390/cells2020330
Received: 15 April 2013 / Revised: 25 April 2013 / Accepted: 14 May 2013 / Published: 22 May 2013
Cited by 12 | PDF Full-text (293 KB) | HTML Full-text | XML Full-text
Abstract
Resolution of acute inflammation is an active process that requires inhibition of further leukocyte recruitment and removal of leukocytes from inflamed sites. Emigrated neutrophils undergo apoptosis before being removed by scavenger macrophages. Recent studies using a variety of gene knockout, transgenic and pharmacological
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Resolution of acute inflammation is an active process that requires inhibition of further leukocyte recruitment and removal of leukocytes from inflamed sites. Emigrated neutrophils undergo apoptosis before being removed by scavenger macrophages. Recent studies using a variety of gene knockout, transgenic and pharmacological strategies in diverse models of inflammation established neutrophil apoptosis as a critical control point in resolving inflammation. Analysis of death mechanisms revealed distinct features in executing the death program in neutrophils, which can be exploited as targets for controlling the lifespan of neutrophils. Indeed, anti-inflammatory and pro-resolution lipid mediators derived from essential fatty acids, such as lipoxin A4 and resolvin E1, autacoids and proteins, such as annexin A1 and TRAIL, and cyclin-dependent kinase inhibitors, can enhance the resolution of inflammation through induction of neutrophil apoptosis and promoting their removal by efferocytosis. In this review, we discuss recent advances in understanding the molecular basis of these actions, highlighting the potential of therapeutic induction of neutrophil apoptosis for dampening neutrophil-mediated tissue injury and inflammation underlying a variety of diseases. Full article
(This article belongs to the Special Issue Apoptosis)
Open AccessReview Systems Biology: The Role of Engineering in the Reverse Engineering of Biological Signaling
Cells 2013, 2(2), 393-413; doi:10.3390/cells2020393
Received: 4 April 2013 / Revised: 6 May 2013 / Accepted: 15 May 2013 / Published: 31 May 2013
Cited by 6 | PDF Full-text (683 KB) | HTML Full-text | XML Full-text
Abstract
One of the principle tasks of systems biology has been the reverse engineering of signaling networks. Because of the striking similarities to engineering systems, a number of analysis and design tools from engineering disciplines have been used in this process. This review looks
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One of the principle tasks of systems biology has been the reverse engineering of signaling networks. Because of the striking similarities to engineering systems, a number of analysis and design tools from engineering disciplines have been used in this process. This review looks at several examples including the analysis of homeostasis using control theory, the attenuation of noise using signal processing, statistical inference and the use of information theory to understand both binary decision systems and the response of eukaryotic chemotactic cells. Full article
(This article belongs to the Special Issue Successes of Systems Biology and Future Challenges)
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Open AccessReview Apoptotic Cell Death in Neuroblastoma
Cells 2013, 2(2), 432-459; doi:10.3390/cells2020432
Received: 10 May 2013 / Revised: 30 May 2013 / Accepted: 8 June 2013 / Published: 20 June 2013
Cited by 3 | PDF Full-text (265 KB) | HTML Full-text | XML Full-text
Abstract
Neuroblastoma (NB) is one of the most common malignant solid tumors in childhood, which derives from the sympathoadrenal lineage of the neural crest and exhibits extremely heterogeneous biological and clinical behaviors. The infant patients frequently undergo spontaneous regression even with metastatic disease, whereas
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Neuroblastoma (NB) is one of the most common malignant solid tumors in childhood, which derives from the sympathoadrenal lineage of the neural crest and exhibits extremely heterogeneous biological and clinical behaviors. The infant patients frequently undergo spontaneous regression even with metastatic disease, whereas the patients of more than one year of age who suffer from disseminated disease have a poor outcome despite intensive multimodal treatment. Spontaneous regression in favorable NBs has been proposed to be triggered by nerve growth factor (NGF) deficiency in the tumor with NGF dependency for survival, while aggressive NBs have defective apoptotic machinery which enables the tumor cells to evade apoptosis and confers the resistance to treatment. This paper reviews the molecules and pathways that have been recently identified to be involved in apoptotic cell death in NB and discusses their potential prospects for developing more effective therapeutic strategies against aggressive NB. Full article
(This article belongs to the Special Issue Apoptosis)

Other

Jump to: Research, Review

Open AccessEssay A Checklist for Successful Quantitative Live Cell Imaging in Systems Biology
Cells 2013, 2(2), 284-293; doi:10.3390/cells2020284
Received: 20 February 2013 / Revised: 3 April 2013 / Accepted: 15 April 2013 / Published: 29 April 2013
Cited by 2 | PDF Full-text (368 KB) | HTML Full-text | XML Full-text
Abstract
Mathematical modeling of signaling and gene regulatory networks has provided unique insights about systems behaviors for many cell biological problems of medical importance. Quantitative single cell monitoring has a crucial role in advancing systems modeling of molecular networks. However, due to the multidisciplinary
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Mathematical modeling of signaling and gene regulatory networks has provided unique insights about systems behaviors for many cell biological problems of medical importance. Quantitative single cell monitoring has a crucial role in advancing systems modeling of molecular networks. However, due to the multidisciplinary techniques that are necessary for adaptation of such systems biology approaches, dissemination to a wide research community has been relatively slow. In this essay, I focus on some technical aspects that are often under-appreciated, yet critical in harnessing live cell imaging methods to achieve single-cell-level understanding and quantitative modeling of molecular networks. The importance of these technical considerations will be elaborated with examples of successes and shortcomings. Future efforts will benefit by avoiding some pitfalls and by utilizing the lessons collectively learned from recent applications of imaging in systems biology. Full article
(This article belongs to the Special Issue Successes of Systems Biology and Future Challenges)
Open AccessEssay Systems Biology — the Broader Perspective
Cells 2013, 2(2), 414-431; doi:10.3390/cells2020414
Received: 1 April 2013 / Revised: 17 May 2013 / Accepted: 5 June 2013 / Published: 19 June 2013
Cited by 1 | PDF Full-text (933 KB) | HTML Full-text | XML Full-text
Abstract
Systems biology has two general aims: a narrow one, which is to discover how complex networks of proteins work, and a broader one, which is to integrate the molecular and network data with the generation and function of organism phenotypes. Doing all this
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Systems biology has two general aims: a narrow one, which is to discover how complex networks of proteins work, and a broader one, which is to integrate the molecular and network data with the generation and function of organism phenotypes. Doing all this involves complex methodologies, but underpinning the subject are more general conceptual problems about upwards and downwards causality, complexity and information storage, and their solutions provide the constraints within which these methodologies can be used. This essay considers these general aspects and the particular role of protein networks; their functional outputs are often the processes driving phenotypic change and physiological function—networks are, in a sense, the units of systems biology much as proteins are for molecular biology. It goes on to argue that the natural language for systems-biological descriptions of biological phenomena is the mathematical graph (a set of connected facts of the general form <state 1> [process] <state 2> (e.g., <membrane-bound delta> [activates] <notch pathway>). Such graphs not only integrate events at different levels but emphasize the distributed nature of control as well as displaying a great deal of data. The implications and successes of these ideas for physiology, pharmacology, development and evolution are briefly considered. The paper concludes with some challenges for the future. Full article
(This article belongs to the Special Issue Successes of Systems Biology and Future Challenges)

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