Wiley Interdisciplinary Reviews Systems Biology and Medicine

Publications in this journal

• Article: Modeling actin dynamics.

  Mike Bindschadler
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  ABSTRACT: Actin monomers assemble into filaments that structurally support cells as well as drive membrane protrusion for cell movement. Within cells, some actin structures are very dynamic and turn over rapidly, while others are very stable. Even purified actin filament dynamics are complex, and researchers have often turned to mathematical models in order to interpret data, test hypotheses, make predictions, and deepen understanding. Models of actin dynamics can be broadly divided into time-dependent models and time-independent models. Most commonly, time-independent models use numerical solutions of sets of differential equations to explore the effects of key parameters on the actin cycle at steady state. Recent examples have been used to predict the nucleotide profile of steady-state filaments and to illuminate the mechanisms behind profilin's effects on actin dynamics. Time-dependent models of actin dynamics have been either Monte Carlo simulations, which track individual filaments at various levels of detail or less commonly stochastic models, which have been explored and solved analytically. These Monte Carlo and stochastic models have recently been used to investigate filament length diffusion, filament length distributions, annealing and fragmentation, and pyrene fluorescence overshoots. We do not review force production/protrusion models as they tend to reduce the complexity of actin dynamics to a single 'elongation rate' and because these models have been recently well reviewed.
  Wiley Interdisciplinary Reviews Systems Biology and Medicine 2(4):481-8.
• Article: Formaldehyde-assisted isolation of regulatory elements.

  Peter L Nagy, David H Price
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  ABSTRACT: Formaldehyde-Assisted Isolation of Regulatory Elements (FAIRE) is based on locus-specific variations in the ability of protein components of chromatin to trap genomic DNA following formaldehyde treatment. This variation is mostly due to uneven nucleosome distribution since histones are the most abundant and highly crosslinkable components of chromatin. The method can identify and enrich for physically accessible DNA segments of the eukaryotic genome corresponding to known regulatory regions and regions that might have thus far unidentified structural role in the nuclear organization of chromatin. The enrichment patterns are cell type specific and thus might provide information about how transcriptional systems are organized and regulated in various tissues and how they might be disrupted in disease states. Analysis of a 268 kb region of chromosome 19 in human fibroblasts shown here demonstrates that while most DNA fragments detected by FAIRE correspond to sites of DNaseI hypersensitivity in active regions of chromatin, some are found in otherwise repressed chromatin domains and at other sites that are not found with other methods used to probe chromatin structure. Further exploration of FAIRE is warrented due to the simplicity of the protocol and recent advancements in massively parallel sequencing.
  Wiley Interdisciplinary Reviews Systems Biology and Medicine 1(3):400-6.
• Article: Live cell imaging and systems biology.

  Myong-Hee Sung, James G McNally
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  ABSTRACT: Much of the experimental data used to construct mathematical models of molecular networks are derived from in vitro measurements. However, there is increasing evidence that in vitro measurements fail to capture both the complexity and the individuality found in single, living cells. These limitations can be overcome by live cell microscopy which is evolving to enable in vivo biochemistry. Here, we survey the current capabilities of live cell microscopy and illustrate how a number of different imaging approaches could be applied to analyze a specific molecular network. We argue that incorporation of such quantitative live-cell imaging methods is critical for the progress of systems biology.
  Wiley Interdisciplinary Reviews Systems Biology and Medicine 3(2):167-82.
• Article: Integrin activation in the immune system.

  Carlo Laudanna, Matteo Bolomini-Vittori
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  ABSTRACT: Modulation of leukocyte adhesiveness is critical to leukocyte function during the immune response. A central paradigm in this phenomenon is represented by integrin activation, which is controlled by inside-out signal transduction mechanisms triggered by selectins, chemoattractants and TcR-bound Ag and facilitated by mechanochemical forces. Integrins are heterodimeric adhesive receptors differently expressed on all leukocyte subtypes. At least two distinct modalities of integrin activation are known, namely conformational changes, leading to increased affinity, and lateral mobility leading to increased valency, both enhancing cell avidity (adhesiveness). Several signal transduction events have been correlated to integrin activation in leukocytes. The complexity of intracellular signaling networks leading to leukocyte integrin activation is likely functional to generate robustness and fine tuning of integrin activation allowing integration of qualitative and quantitative variations of extracellular signals leading to leukocyte-, agonist- and integrin-specific control of adhesion. In this context, the recent modular abstraction proposed for the functional architecture of biological networks may provide a powerful paradigm to understand regulation and specificity of signaling events. Accordingly, pro-adhesive intracellular signaling networks may be organized in regulatory signalosomes, or modules, corresponding to discrete clusters of interacting signaling proteins, with some devoted to context-dependent regulation of specificity and dynamics of integrin activation. The principles and technologies of systems biology, and more specifically of network theory, may help to address this complexity and unveil the inner logic governing leukocyte recruitment during the immune response.
  Wiley Interdisciplinary Reviews Systems Biology and Medicine 1(1):116-27.
• Article: Regulation of endothelial cell functions by basement membrane- and arachidonic acid-derived products.

  Ambra Pozzi, Roy Zent
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  ABSTRACT: Angiogenesis, the formation of new blood vessels from preexisting vasculature, is required for normal physiological as well as pathological events. The angiogenic process requires endothelial cells to proliferate, migrate, and undergo tubulogenesis. These multistep processes necessitate secretion of pro-angiogenic growth factors, activation of specific intracellular signaling, and interaction of endothelial cells with basement membrane (BM) extracellular matrix components. The generation and release of angiogenic molecules are highly regulated and are influenced by numerous factors, including BM-derived fragments, proteolytic enzymes, as well as metabolites of arachidonic acid (AA). The interactions between these key modulators of angiogenesis is extremely complex, as AA metabolites can regulate the synthesis of soluble angiogenic factors, BM components, as well as enzymes capable of cleaving BM components, which result in the generation of pro- and/or anti-angiogenic products. Furthermore, some BM-derived fragments can alter the expression of AA-converting enzymes and consequently the synthesis of angiogenic factors. In this review we describe the relationship between BM components and AA metabolites with respect to the regulation of endothelial cell functions in health and disease.
  Wiley Interdisciplinary Reviews Systems Biology and Medicine 1(2):254-72.
• Article: Whole animal imaging.

  Gurpreet Singh Sandhu, Luis Solorio, Ann-Marie Broome, Nicolas Salem, Jeff Kolthammer, Tejas Shah, Chris Flask, Jeffrey L Duerk
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  ABSTRACT: Translational research plays a vital role in understanding the underlying pathophysiology of human diseases, and hence development of new diagnostic and therapeutic options for their management. After creating an animal disease model, pathophysiologic changes and effects of a therapeutic intervention on them are often evaluated on the animals using immunohistologic or imaging techniques. In contrast to the immunohistologic techniques, the imaging techniques are noninvasive and hence can be used to investigate the whole animal, oftentimes in a single exam which provides opportunities to perform longitudinal studies and dynamic imaging of the same subject, and hence minimizes the experimental variability, requirement for the number of animals, and the time to perform a given experiment. Whole animal imaging can be performed by a number of techniques including x-ray computed tomography, magnetic resonance imaging, ultrasound imaging, positron emission tomography, single photon emission computed tomography, fluorescence imaging, and bioluminescence imaging, among others. Individual imaging techniques provide different kinds of information regarding the structure, metabolism, and physiology of the animal. Each technique has its own strengths and weaknesses, and none serves every purpose of image acquisition from all regions of an animal. In this review, a broad overview of basic principles, available contrast mechanisms, applications, challenges, and future prospects of many imaging techniques employed for whole animal imaging is provided. Our main goal is to briefly describe the current state of art to researchers and advanced students with a strong background in the field of animal research.
  Wiley Interdisciplinary Reviews Systems Biology and Medicine 2(4):398-421.
• Article: Systems analysis of bone.

  Karl J Jepsen
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  ABSTRACT: The genetic variants contributing to variability in skeletal traits has been well studied, and several hundred QTLs have been mapped and several genes contributing to trait variation have been identified. However, many questions remain unanswered. In particular, it is unclear whether variation in a single gene leads to alterations in function. Bone is a highly adaptive system and genetic variants affecting one trait are often accompanied by compensatory changes in other traits. The functional interactions among traits, which is known as phenotypic integration, has been observed in many biological systems, including bone. Phenotypic integration is a property of bone that is critically important for establishing a mechanically functional structure that is capable of supporting the forces imparted during daily activities. In this paper, bone is reviewed as a system and primarily in the context of functionality. A better understanding of the system properties of bone will lead to novel targets for future genetic analyses and the identification of genes that are directly responsible for regulating bone strength. This systems analysis has the added benefit of leaving a trail of valuable information about how the skeletal system works. This information will provide novel approaches to assessing skeletal health during growth and aging and for developing novel treatment strategies to reduce the morbidity and mortality associated with fragility fractures.
  Wiley Interdisciplinary Reviews Systems Biology and Medicine 1(1):73-88.
• Article: Mesenchymal stem cell differentiation and roles in regenerative medicine.

  Nathaniel S Hwang, Chao Zhang, Yong-Sung Hwang, Shyni Varghese
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  ABSTRACT: Adult stem cells with multi or unipotent differentiation potential are present in almost all tissues of adult organisms. The main function of these stem cells is to support normal repair and rejuvenation of diseased and aging tissues. Mesenchymal stem cells (MSCs) isolated from the bone marrow have the potential to differentiate into multiple connective tissues. Advancements in understanding tissue specific differentiation of MSCs in conjunction with global genomic and proteomic profiling of MSCs have not only provided insights into their biology but also made MSC based clinical trials a reality for treating various debilitating diseases and genetic disorders. The emerging evidence that MSCs are immunosuppressive makes them an even more attractive candidate for regenerative medicine as rejections of transplants by the recipient could be a limiting step for moving the stem cells based therapies from "bedside to bed side." To a large extent the therapeutic potential of MSCs is attributed to their differentiation ability. The fate and commitment of MSCs are regulated by various instructive signals from their immediate vicinity or microenvironment, which comprises many biological molecules (soluble and insoluble) and biomechanical forces. These biochemical and biophysical factors play a pivotal role in determining the efficacy of MSC differentiation and their contribution to the repair process. In this review, we discuss the characteristics of MSCs, their differentiation potential toward different skeletal tissues (cartilage and bone), and their emerging role in regenerative medicine.
  Wiley Interdisciplinary Reviews Systems Biology and Medicine 1(1):97-106.
• Article: APOBEC-1-mediated RNA editing.

  Valerie Blanc, Nicholas O Davidson
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  ABSTRACT: RNA editing defines a molecular process by which a nucleotide sequence is modified in the RNA transcript and results in an amino acid change in the recoded message from that specified in the gene. We will restrict our attention to the type of RNA editing peculiar to mammals, i.e., nuclear C to U RNA editing. This category of RNA editing contrasts with RNA modifications described in plants, i.e., organellar RNA editing (reviewed in Ref 1). Mammalian RNA editing is genetically and biochemically classified into two groups, namely insertion-deletional and substitutional. Substitutional RNA editing is exclusive to mammals, again with two types reported, namely adenosine to inosine and cytosine to uracil (C to U). This review will examine mammalian C to U RNA editing of apolipoproteinB (apoB) RNA and the role of the catalytic deaminase Apobec-1. We will speculate on the functions of Apobec-1 beyond C to U RNA editing as implied from its ability to bind AU-rich RNAs and discuss evidence that dysregulation of Apobec-1 expression might be associated with carcinogenesis through aberrant RNA editing or altered RNA stability.
  Wiley Interdisciplinary Reviews Systems Biology and Medicine 2(5):594-602.
• Article: Models at the single cell level.

  Raymond Cheong, Saurabh Paliwal, Andre Levchenko
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  ABSTRACT: Many cellular behaviors cannot be completely captured or appropriately described at the cell population level. Noise induced by stochastic chemical reactions, spatially polarized signaling networks, and heterogeneous cell-cell communication are among the many phenomena that require fine-grained analysis. Accordingly, the mathematical models used to describe such systems must be capable of single cell or subcellular resolution. Here, we review techniques for modeling single cells, including models of stochastic chemical kinetics, spatially heterogeneous intracellular signaling, and spatial stochastic systems. We also briefly discuss applications of each type of model.
  Wiley Interdisciplinary Reviews Systems Biology and Medicine 2(1):34-48.
• Source

  Available from: harvard.edu

  Article: Protein microarrays for genome-wide posttranslational modification analysis.

  Yifat Merbl, Marc W Kirschner
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  ABSTRACT: Protein microarray technology has emerged as a powerful tool for comparing binding interactions, expression level, substrate specificities, and posttranslational modifications (PTMs) of different proteins in a parallel and high-throughput manner. The ability to immobilize proteins to a solid surface and register the specific address of each protein has bridged major limitations for investigating the proteome in biological samples, namely, the wide dynamic range of protein concentrations and the perturbation of the physical and chemical properties of proteins by their modification. Recent advances introduced the use of functional mammalian cell extracts to assay PTMs under different cellular conditions. This assay offers a new approach for performing large-scale complex biochemical analysis of protein modifications. Here, we review studies of PTM profiling using protein microarrays and discuss the limitations and potential applications of the system. We believe that the information generated from such proteomic studies may be of significant value in our elucidation of the molecular mechanisms that govern human physiology.
  Wiley Interdisciplinary Reviews Systems Biology and Medicine 3(3):347-56.
• Article: Spatial regulation of PI3K signaling during chemotaxis.

  Pablo A Iglesias
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  ABSTRACT: Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that phosphorylate the 3' OH position of the inositol ring of phosphoinositides on the inner leaf of the plasma membrane. Receptor-mediated activation of the PI3K pathway plays a crucial role in numerous signaling pathways and regulates a number of critical cellular processes, including growth, differentiation, survival and directed migration. In this focus article, we review the temporal and spatial regulation of PI3K in chemotaxing cells with particular emphasis on the amoeba Dictyostelium as well as neutrophils. We also briefly discuss one model used to elucidate the PI3K pathway.
  Wiley Interdisciplinary Reviews Systems Biology and Medicine 1(2):247-53.
• Article: A systems biology approach to defining metastatic biomarkers and signaling pathways.

  Natalie E Goldberger, Kent W Hunter
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  ABSTRACT: Metastasis is the final stage of cancer and the primary cause of mortality for most solid malignancies. This terminal phase of cancer progression has been investigated using a variety of high-throughput technologies (i.e., gene expression arrays, array comparative genomic hybridization (aCGH), and proteomics) to identify prognostic expression profiles and better characterize the metastatic process. For decades, the predominant model for the metastatic process has been the 'progression model', yet recent microarray results tend to support an inherent metastatic capability within primary tumors. Moreover, studies using a highly metastatic transgenic mammary tumor model suggest that germline polymorphisms are significant determinants of metastatic efficiency. Likewise, a strong concordance of survival has been observed between family members with cancer, further supporting the link between genetic inheritance and survival. In addition, chromosomal aberrations and signaling pathways related to metastatic capacity have been identified by array comparative genomic hybridization (aCGH) and proteomic studies, respectively. Lastly, carcinoma enzyme activity profiles using activity-based proteomics (ABPP), may be more clinically useful than expression-based proteomics for certain cancers. Most importantly, the application of these high-throughput techniques should expedite the search for additional biomarkers, germline polymorphisms, and expression signatures with greater prognostic value.
  Wiley Interdisciplinary Reviews Systems Biology and Medicine 1(1):89-96.
• Source

  Available from: princeton.edu

  Article: Branch formation during organ development.

  Nikolce Gjorevski, Celeste M Nelson
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  ABSTRACT: Invertebrates and vertebrates use branching morphogenesis to build epithelial trees to maximize the surface area of organs within a given volume. Several molecular regulators of branching have recently been discovered, a number of which are conserved across different organs and species. Signals that control branching at the cellular and tissue levels are also starting to emerge, and are rapidly unveiling the physical nature of branch development. Here we discuss the molecular, cellular, and physical processes that govern branch formation, and highlight the major outstanding questions in the field.
  Wiley Interdisciplinary Reviews Systems Biology and Medicine 2(6):734-41.
• Article: Multiplex parallel pair-end-ditag sequencing approaches in system biology.

  Yijun Ruan, Chia-Lin Wei
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  ABSTRACT: Characterization of all the functional components constituted in human genome relies in our ability to completely elucidate the genetic/epigenetic regulatory networks, chromatin states, nuclear architectures, and genome variations. Such endeavors demand for the development of robust and effective genomic technologies. In the past few years, the availability of disruptive next generation DNA sequencing technologies has offered new promise for whole genome interrogation. However, despite the massive parallel and ultra-high throughput capacity, the common nature of short read lengths found within these platforms limits their applications for many types of whole genome-based analyses. To overcome such constrain, pair end ditag (PET) based sequencing concept was conceived as an immediate solution to expand the information content and extend the linear coverage. By sequencing paired end signatures from any desired DNA fragment and mapping them to the reference genome, PET strategy allows the accurate demarcation of target DNA boundaries and defines their locations on the genomic landscape. Furthermore, the ability to delineate relationship between two ends of a DNA molecule enables the full scale discovery of unconventional gene products, genome rearrangements, and chromatin interactions. Coupling with the massively parallel and ultra-high throughput sequencing platforms, such unique features of PET strategy have the potential to revolutionize the approaches used to decipher regulatory networks in system biology, define the genome organizations, and characterize genome variations; which ultimately leads to the development of strategies for personalized medicine.
  Wiley Interdisciplinary Reviews Systems Biology and Medicine 2(2):224-34.
• Article: Quantitative analysis of phosphorylation-based protein signaling networks in the immune system by mass spectrometry.

  Aleksandra Nita-Lazar
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  ABSTRACT: Dynamic modification of cell proteins with phosphate is one of the key regulators of the cellular response to external stimuli. Phosphorylation-based signaling networks mediate cell proliferation, differentiation, and migration, and their dysregulation is the basis of multiple diseases. However, the transient nature of the regulatory protein phosphorylation and low site occupancy mean that only a fraction of the protein is phosphorylated at a given time, and it is a challenge to measure the degree and dynamics of phosphorylation using traditional biochemical means. Technological advances in the field of mass spectrometry (MS) made it possible to generate large sets of phosphoproteomics data, probing the phosphoproteome with great depth, sensitivity, and accuracy. Therefore, quantitative phosphoproteomics emerged as one of the essential components of the systems biology approach for profiling of complex biological networks. Nowadays, the challenge lies in validation of the information and in its integration into the comprehensive models of cell decision processes. This article reviews the role of phosphoproteomics in systems biology, the MS-based approach, and technical details of the methods. Recent examples of quantitative measurements and methodologies as well as applications to the studies of the immune system and infectious diseases are presented and discussed.
  Wiley Interdisciplinary Reviews Systems Biology and Medicine 3(3):368-76.
• Article: Role of neutrophils in innate immunity: a systems biology-level approach.

  Scott D Kobayashi, Frank R DeLeo
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  ABSTRACT: The innate immune system is the first line of host defense against invading microorganisms. Polymorphonuclear leukocytes (PMNs or neutrophils) are the most abundant leukocyte in humans and essential to the innate immune response against invading pathogens. Compared with the acquired immune response, which requires time to develop and is dependent on previous interaction with specific microbes, the ability of neutrophils to kill microorganisms is immediate, non-specific, and not dependent on previous exposure to microorganisms. Historically, studies on PMN-pathogen interaction focused on the events leading to killing of microorganisms, such as recruitment/chemotaxis, transmigration, phagocytosis, and activation, whereas post-phagocytosis sequelae were infrequently considered. In addition, it was widely accepted that human neutrophils possessed limited capacity for new gene transcription and thus, relatively little biosynthetic capacity. This notion has changed dramatically within the past decade. Further, there is now more effort directed to understand the events occurring in PMNs after killing of microbes. Herein we review the systems biology-level approaches that have been used to gain an enhanced view of the role of neutrophils during host-pathogen interaction. We anticipate that these and future systems-level studies will ultimately provide information critical to our understanding, treatment, and control of diseases caused by pathogenic microorganisms.
  Wiley Interdisciplinary Reviews Systems Biology and Medicine 1(3):309-33.
• Article: Protein-membrane interactions: the virtue of minimal systems in systems biology.

  Senthil Arumugam, Grzegorz Chwastek, Petra Schwille
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  ABSTRACT: The plasma membrane of cells can be viewed as a highly dynamic, regulated, heterogeneous environment with multiple functions. It constitutes the boundary of the cell, encapsulating all its components. Proteins interact with the membrane in many ways to accommodate essential processes, such as membrane trafficking, membrane protrusions, cytokinesis, signaling, and cell-cell communication. A vast amount of literature has already fostered our current understanding of membrane-protein interactions. However, many phenomena still remain to be understood, e.g., the exact mechanisms of how certain proteins cause or assist membrane transformations. Systems biology aims to predict biological processes on the basis of the set of molecules involved. Many key processes arise from interactions with the lipid membrane. Protein interactome maps do not consider such specific interactions, and thus cannot predict precise outcomes of the interactions of the involved proteins. These can only be inferred from experimental approaches. We describe examples of how an emergent behavior of protein-membrane interactions has been demonstrated by the use of minimal systems. These studies contribute to a deeper understanding of protein interactomes involving membranes and complement other approaches of systems biology.
  Wiley Interdisciplinary Reviews Systems Biology and Medicine 3(3):269-80.
• Article: Systems analysis of salivary gland development and disease.

  Melinda Larsen, Kenneth M Yamada, Kurt Musselmann
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  ABSTRACT: Branching morphogenesis is a crucial developmental process in which vertebrate organs generate extensive epithelial surface area while retaining a compact size. In the vertebrate submandibular salivary gland, branching morphogenesis is crucial for the generation of the large surface area necessary to produce sufficient saliva. However, in many salivary gland diseases, saliva-producing acinar cells are destroyed, resulting in dry mouth and secondary health conditions. Systems-based approaches can provide insights into understanding salivary gland development, function, and disease. The traditional approach to understanding these processes is the identification of molecular signals using reductionist approaches; we review current progress with such methods in understanding salivary gland development. Taking a more global approach, multiple groups are currently profiling the transcriptome, the proteome, and other 'omes' in both developing mouse tissues and in human patient samples. Computational methods have been successful in deciphering large data sets, and mathematical models are starting to make predictions regarding the contribution of molecules to the physical processes of morphogenesis and cellular function. A challenge for the future will be to establish comprehensive, publicly accessible salivary gland databases spanning the full range of genes and proteins; plans are underway to provide these resources to researchers in centralized repositories. The greatest challenge for the future will be to develop realistic models that integrate multiple types of data to both describe and predict embryonic development and disease pathogenesis.
  Wiley Interdisciplinary Reviews Systems Biology and Medicine 2(6):670-82.