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Current Opinion in Systems Biology

Maelle Bellec, Ovidiu Radulescu, Mounia Lagha
During development, transcriptional properties of progenitor cells are stably propagated across multiple cellular divisions. Yet, at each division, chromatin faces structural constraints imposed by the important nuclear re-organization operating during mitosis. It is now clear that not all transcriptional regulators are ejected during mitosis, but rather that a subset of transcription factors, chromatin regulators and epigenetic histone marks are able to 'bookmark' specific loci, thereby providing a mitotic memory...
October 2018: Current Opinion in Systems Biology
Anna Reid, Baris Tursun
The direct conversion of one differentiated cell fate into another identity is a process known as Transdifferentiation. During Transdifferentiation, cells pass through intermediate states that are not well understood. Given the potential application of transdifferentiation in regenerative medicine and disease modeling, a better understanding of intermediate states is crucial to avoid uncontrolled conversion or proliferation, which pose a risk for patients. Researchers have begun to analyze the transcriptomes of donor, converting and target cells of Transdifferentiation with single cell resolution to compare transitional states to those found along the path of development...
October 2018: Current Opinion in Systems Biology
Karl Kochanowski, Leanna Morinishi, Steven Altschuler, Lani Wu
Drug-insensitive tumor subpopulations remain a significant barrier to effective cancer treatment. Recent works suggest that within isogenic drug-sensitive cancer populations, subsets of cells can enter a 'persister' state allowing them to survive prolonged drug treatment. Such persisters are well-described in antibiotic-treated bacterial populations. In this review, we compare mechanisms of drug persistence in bacteria and cancer. Both bacterial and cancer persisters are associated with slow-growing phenotypes, are metabolically distinct from non-persisters, and depend on the activation of specific regulatory programs...
August 2018: Current Opinion in Systems Biology
Christian Scheeder, Florian Heigwer, Michael Boutros
The increase in imaging throughput, new analytical frameworks and high-performance computational resources open new avenues for data-rich phenotypic profiling of small molecules in drug discovery. Image-based profiling assays assessing single-cell phenotypes have been used to explore mechanisms of action, target efficacy and toxicity of small molecules. Technological advances to generate large data sets together with new machine learning approaches for the analysis of high-dimensional profiling data create opportunities to improve many steps in drug discovery...
August 2018: Current Opinion in Systems Biology
Adam L MacLean, Tian Hong, Qing Nie
As our catalog of cell states expands, appropriate characterization of these states and the transitions between them is crucial. Here we discuss the roles of intermediate cell states (ICSs) in this growing collection. We begin with definitions and discuss evidence for the existence of ICSs and their relevance in various tissues. We then provide a list of possible functions for ICSs with examples. Finally, we describe means by which ICSs and their functional roles can be identified from single-cell data or predicted from models...
June 2018: Current Opinion in Systems Biology
Béla Novák, Frank Stefan Heldt, John J Tyson
Well-nourished cells in a favorable environment (well supplied with growth factors, cytokines, and/or hormones and free from stresses, ionizing radiation, etc.) will grow, replicate their genome, and divide into two daughter cells, fully prepared to repeat the process. This cycle of DNA replication and division underlies all aspects of biological growth, reproduction, repair and development. As such, it is essential that the cell's genome be guarded against damage during the replication/division process, lest the error(s) be irrevocably passed down to all future generations of progeny...
June 2018: Current Opinion in Systems Biology
Jimin Park, Harris H Wang
Microbial gene regulatory networks are composed of cis- and trans-components that in concert act to control essential and adaptive cellular functions. Regulatory components and interactions evolve to adopt new configurations through mutations and network rewiring events, resulting in novel phenotypes that may benefit the cell. Advances in high-throughput DNA synthesis and sequencing have enabled the development of new tools and approaches to better characterize and perturb various elements of regulatory networks...
April 2018: Current Opinion in Systems Biology
Cesar A Vargas-Garcia, Khem Raj Ghusinga, Abhyudai Singh
Growth of a cell and its subsequent division into daughters is a fundamental aspect of all cellular living systems. During these processes, how do individual cells correct size aberrations so that they do not grow abnormally large or small? How do cells ensure that the concentration of essential gene products are maintained at desired levels, in spite of dynamic/stochastic changes in cell size during growth and division? Both these questions have fascinated researchers for over a century. We review how advances in singe-cell technologies and measurements are providing unique insights into these questions across organisms from prokaryotes to human cells...
April 2018: Current Opinion in Systems Biology
Christopher M Jakobson, Daniel F Jarosz
Prion-like proteins have the capacity to adopt multiple stable conformations, at least one of which can recruit proteins from the native conformation into the alternative fold. Although classically associated with disease, prion-like assembly has recently been proposed to organize a range of normal biochemical processes in space and time. Organisms from bacteria to mammals use prion-like mechanisms to (re)organize their proteome in response to intracellular and extracellular stimuli. Prion-like behavior is an economical means to control biochemistry and gene regulation at the systems level, and prions can act as protein-based genes to facilitate quasi-Lamarckian inheritance of induced traits...
April 2018: Current Opinion in Systems Biology
Simon Mitchell, Alexander Hoffmann
Phenotypic differences often occur even in clonal cell populations. Many potential sources of such variation have been identified, from biophysical rate variance intrinsic to all chemical processes to asymmetric division of molecular components extrinsic to any particular signaling pathway. Identifying the sources of phenotypic variation and quantifying their contributions to cell fate variation is not possible without accurate single cell data. By combining such data with mathematical models of potential noise sources it is possible to characterize the impact of varying levels of each noise source and identify which sources of variation best explain the experimental observations...
April 2018: Current Opinion in Systems Biology
Matthew M Crane, Matt Kaeberlein
Aging is a fundamental aspect of life, yet also one of the most confounding. In individual cells, aging results in a progressive decline which affects all organelles and reduces a cell's ability to maintain homeostasis. Because of the interconnected nature of cellular systems, the failure of even a single organelle can have cascading effects. We are just beginning to understand the dramatic physiological changes that occur during aging. Because most aging research has focused on population dynamics, or differences between wild-type and mutant populations, single-cell behavior has been largely overlooked...
April 2018: Current Opinion in Systems Biology
Simona Patange, Michelle Girvan, Daniel R Larson
Gene expression varies across cells in a population or a tissue. This heterogeneity has come into sharp focus in recent years through developments in new imaging and sequencing technologies. However, our ability to measure variation has outpaced our ability to interpret it. Much of the variability may arise from random effects occurring in the processes of gene expression (transcription, RNA processing and decay, translation). The molecular basis of these effects is largely unknown. Likewise, a functional role of this variability in growth, differentiation and disease has only been elucidated in a few cases...
April 2018: Current Opinion in Systems Biology
Roy Wollman
The robustness of biological systems is often depicted as a key system-level emergent property that allows uniform phenotypes in fluctuating environments. Yet, analysis of single-cell signaling responses identified multiple examples of cellular responses with high degrees of heterogeneity. Here we discuss the implications of the observed lack of response accuracy in the context of new observations coming from single-cell approaches. Single-cell approaches provide a new way to measure the abundance of thousands of molecular species in a single-cell...
April 2018: Current Opinion in Systems Biology
Balázs Szigeti, Yosef D Roth, John A P Sekar, Arthur P Goldberg, Saahith C Pochiraju, Jonathan R Karr
Whole-cell dynamical models of human cells are a central goal of systems biology. Such models could help researchers understand cell biology and help physicians treat disease. Despite significant challenges, we believe that human whole-cell models are rapidly becoming feasible. To develop a plan for achieving human whole-cell models, we analyzed the existing models of individual cellular pathways, surveyed the biomodeling community, and reflected on our experience developing whole-cell models of bacteria. Based on these analyses, we propose a plan for a project, termed the Human Whole-Cell Modeling Project , to achieve human whole-cell models...
February 2018: Current Opinion in Systems Biology
Jolanda van Leeuwen, Charles Boone, Brenda J Andrews
Genetic interactions occur when the combination of multiple mutations yields an unexpected phenotype, and they may confound our ability to fully understand the genetic mechanisms underlying complex diseases. Genetic interactions are challenging to study because there are millions of possible different variant combinations within a given genome. Consequently, they have primarily been systematically explored in unicellular model organisms, such as yeast, with a focus on pairwise genetic interactions between loss-of-function alleles...
December 2017: Current Opinion in Systems Biology
Anne Richelle, Nathan E Lewis
Bioprocess optimization has yielded powerful clones for biotherapeutic production. However, new genomic technologies allow more targeted approaches to cell line development. Here we review efforts to enhance protein production in mammalian cells through metabolic engineering. Most efforts aimed to reduce toxic byproducts accumulation to enhance protein productivity. However, recent work highlights the possibility of regulating other desirable traits (e.g., apoptosis and glycosylation) by targeting central metabolism since these processes are interconnected...
December 2017: Current Opinion in Systems Biology
Tiffany Chien, Anjali Doshi, Tal Danino
Synthetic biology aims to apply engineering principles to biology by modulating the behavior of living organisms. An emerging application of this field is the engineering of bacteria as a cancer therapy by the programming of therapeutic, safety, and specificity features through genetic modification. Here, we review progress in this engineering including the targeting of bacteria to tumors, specific sensing and response to tumor microenvironments, remote induction methods, and controllable release of therapeutics...
October 2017: Current Opinion in Systems Biology
Denise Kirschner, Elsje Pienaar, Simeone Marino, Jennifer J Linderman
Tuberculosis (TB) is an ancient and deadly disease characterized by complex host-pathogen dynamics playing out over multiple time and length scales and physiological compartments. Computational modeling can be used to integrate various types of experimental data and suggest new hypotheses, mechanisms, and therapeutic approaches to TB. Here, we offer a first-time comprehensive review of work on within-host TB models that describe the immune response of the host to infection, including the formation of lung granulomas...
June 2017: Current Opinion in Systems Biology
Eric Batchelor, Alexander Loewer
In mammalian cells, the tumor suppressor p53 is activated upon a variety of cellular stresses and ensures an appropriate response ranging from arrest and repair to the induction of senescence and apoptosis. Quantitative measurements in individual living cells showed stimulus-dependent dynamics of p53 accumulation upon stress induction. Due to the complexity of the underlying biochemical interactions, mathematical models were indispensable for understanding the topology of the network regulating p53 dynamics...
June 2017: Current Opinion in Systems Biology
Joseph D Dougherty, Chengran Yang, Allison M Lake
As recent advances in human genetics have begun to more rapidly identify the individual genes contributing to risk of psychiatric disease, the spotlight now turns to understanding how disruption of these genes alters the brain, and thus behavior. Compared to other tissues, cellular complexity in the brain provides both a substantial challenge and a significant opportunity for systems biology approaches. Current methods are maturing that will allow for finally defining the 'parts list' for the functioning mouse and human brains, enabling new approaches to defining how the system goes awry in disorders of the CNS...
June 2017: Current Opinion in Systems Biology
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