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https://www.readbyqxmd.com/read/28525642/dynamics-of-sequestration-based-gene-regulatory-cascades
#1
Tatenda Shopera, William R Henson, Tae Seok Moon
Gene regulatory cascades are ubiquitous in biology. Because regulatory cascades are integrated within complex networks, their quantitative analysis is challenging in native systems. Synthetic biologists have gained quantitative insights into the properties of regulatory cascades by building simple circuits, but sequestration-based regulatory cascades remain relatively unexplored. Particularly, it remains unclear how the cascade components collectively control the output dynamics. Here, we report the construction and quantitative analysis of the longest sequestration-based cascade in Escherichia coli...
May 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28494968/bistability-and-nonmonotonic-induction-of-the-lac-operon-in-the-natural-lactose-uptake-system
#2
Dominique Zander, Daniel Samaga, Ronny Straube, Katja Bettenbrock
The Escherichia coli lac operon is regulated by a positive feedback loop whose potential to generate an all-or-none response in single cells has been a paradigm for bistable gene expression. However, so far bistable lac induction has only been observed using gratuitous inducers, raising the question about the biological relevance of bistable lac induction in the natural setting with lactose as the inducer. In fact, the existing experimental evidence points to a graded rather than an all-or-none response in the natural lactose uptake system...
May 9, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28461722/systems-biology-study-of-transcriptional-and-post-transcriptional-co-regulatory-network-sheds-light-on-key-regulators-involved-in-important-biological-processes-in-citrus-sinensis
#3
Ehsan Khodadadi, Ali Ashraf Mehrabi, Ali Najafi, Saber Rastad, Ali Masoudi-Nejad
Transcriptional and post-transcriptional regulators including transcription regulator, transcription factor and miRNA are the main endogenous molecular elements which control complex cellular mechanisms such as development, growth and response to biotic and abiotic stresses in a coordinated manner in plants. Utilizing the most recent information on such relationships in a plant species, obtained from high-throughput experimental technologies and advanced computational tools, we can reconstruct its co-regulatory network which consequently sheds light on key regulators involved in its important biological processes...
April 2017: Physiology and Molecular Biology of Plants: An International Journal of Functional Plant Biology
https://www.readbyqxmd.com/read/28459541/decoupling-resource-coupled-gene-expression-in-living-cells
#4
Tatenda Shopera, Lian He, Tolutola Oyetunde, Yinjie J Tang, Tae Seok Moon
Synthetic biology aspires to develop frameworks that enable the construction of complex and reliable gene networks with predictable functionalities. A key limitation is that increasing network complexity increases the demand for cellular resources, potentially causing resource-associated interference among noninteracting circuits. Although recent studies have shown the effects of resource competition on circuit behaviors, mechanisms that decouple such interference remain unclear. Here, we constructed three systems in Escherichia coli, each consisting of two independent circuit modules where the complexity of one module (Circuit 2) was systematically increased while the other (Circuit 1) remained identical...
May 4, 2017: ACS Synthetic Biology
https://www.readbyqxmd.com/read/28455348/a-spectrum-of-modularity-in-multi-functional-gene-circuits
#5
Alba Jiménez, James Cotterell, Andreea Munteanu, James Sharpe
A major challenge in systems biology is to understand the relationship between a circuit's structure and its function, but how is this relationship affected if the circuit must perform multiple distinct functions within the same organism? In particular, to what extent do multi-functional circuits contain modules which reflect the different functions? Here, we computationally survey a range of bi-functional circuits which show no simple structural modularity: They can switch between two qualitatively distinct functions, while both functions depend on all genes of the circuit...
April 27, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28443619/programming-mrna-decay-to-modulate-synthetic-circuit-resource-allocation
#6
Ophelia S Venturelli, Mika Tei, Stefan Bauer, Leanne Jade G Chan, Christopher J Petzold, Adam P Arkin
Synthetic circuits embedded in host cells compete with cellular processes for limited intracellular resources. Here we show how funnelling of cellular resources, after global transcriptome degradation by the sequence-dependent endoribonuclease MazF, to a synthetic circuit can increase production. Target genes are protected from MazF activity by recoding the gene sequence to eliminate recognition sites, while preserving the amino acid sequence. The expression of a protected fluorescent reporter and flux of a high-value metabolite are significantly enhanced using this genome-scale control strategy...
April 26, 2017: Nature Communications
https://www.readbyqxmd.com/read/28437108/design-of-a-toolbox-of-rna-thermometers
#7
Shaunak Sen, Divyansh Apurva, Rohit Satija, Dan Siegal, Richard M Murray
Biomolecular temperature sensors can be used for efficient control of large-volume bioreactors, for spatiotemporal imaging and control of gene expression, and to engineer robustness to temperature in biomolecular circuit design. Although RNA-based sensors, called "thermometers", have been investigated in both natural and synthetic contexts, an important challenge is to design diverse responses to temperature differing in sensitivity and threshold. We address this issue by constructing a library of RNA thermometers based on thermodynamic computations and experimentally measuring their activities in cell-free biomolecular "breadboards"...
May 18, 2017: ACS Synthetic Biology
https://www.readbyqxmd.com/read/28362798/interrogating-the-topological-robustness-of-gene-regulatory-circuits-by-randomization
#8
Bin Huang, Mingyang Lu, Dongya Jia, Eshel Ben-Jacob, Herbert Levine, Jose N Onuchic
One of the most important roles of cells is performing their cellular tasks properly for survival. Cells usually achieve robust functionality, for example, cell-fate decision-making and signal transduction, through multiple layers of regulation involving many genes. Despite the combinatorial complexity of gene regulation, its quantitative behavior has been typically studied on the basis of experimentally verified core gene regulatory circuitry, composed of a small set of important elements. It is still unclear how such a core circuit operates in the presence of many other regulatory molecules and in a crowded and noisy cellular environment...
March 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28361666/towards-targeted-combinatorial-therapy-design-for-the-treatment-of-castration-resistant-prostate-cancer
#9
Osama Ali Arshad, Aniruddha Datta
BACKGROUND: Prostate cancer is one of the most prevalent cancers in males in the United States and amongst the leading causes of cancer related deaths. A particularly virulent form of this disease is castration-resistant prostate cancer (CRPC), where patients no longer respond to medical or surgical castration. CRPC is a complex, multifaceted and heterogeneous malady with limited standard treatment options. RESULTS: The growth and progression of prostate cancer is a complicated process that involves multiple pathways...
March 22, 2017: BMC Bioinformatics
https://www.readbyqxmd.com/read/28355056/deconvolution-of-gene-expression-noise-into-spatial-dynamics-of-transcription-factor-promoter-interplay
#10
Ángel Goñi-Moreno, Ilaria Benedetti, Juhyun Kim, Víctor de Lorenzo
Gene expression noise is not only the mere consequence of stochasticity, but also a signal that reflects the upstream physical dynamics of the cognate molecular machinery. Soil bacteria facing recalcitrant pollutants exploit noise of catabolic promoters to deploy beneficial phenotypes such as metabolic bet-hedging and/or division of biochemical labor. Although the role of upstream promoter-regulator interplay in the origin of this noise is little understood, its specifications are probably ciphered in flow cytometry data patterns...
April 17, 2017: ACS Synthetic Biology
https://www.readbyqxmd.com/read/28350462/automated-design-framework-for-synthetic-biology-exploiting-pareto-optimality
#11
Irene Otero-Muras, Julio R Banga
In this work we consider Pareto optimality for automated design in synthetic biology. We present a generalized framework based on a mixed-integer dynamic optimization formulation that, given design specifications, allows the computation of Pareto optimal sets of designs, that is, the set of best trade-offs for the metrics of interest. We show how this framework can be used for (i) forward design, that is, finding the Pareto optimal set of synthetic designs for implementation, and (ii) reverse design, that is, analyzing and inferring motifs and/or design principles of gene regulatory networks from the Pareto set of optimal circuits...
April 12, 2017: ACS Synthetic Biology
https://www.readbyqxmd.com/read/28346402/large-scale-design-of-robust-genetic-circuits-with-multiple-inputs-and-outputs-for-mammalian-cells
#12
Benjamin H Weinberg, N T Hang Pham, Leidy D Caraballo, Thomas Lozanoski, Adrien Engel, Swapnil Bhatia, Wilson W Wong
Engineered genetic circuits for mammalian cells often require extensive fine-tuning to perform as intended. We present a robust, general, scalable system, called 'Boolean logic and arithmetic through DNA excision' (BLADE), to engineer genetic circuits with multiple inputs and outputs in mammalian cells with minimal optimization. The reliability of BLADE arises from its reliance on recombinases under the control of a single promoter, which integrates circuit signals on a single transcriptional layer. We used BLADE to build 113 circuits in human embryonic kidney and Jurkat T cells and devised a quantitative, vector-proximity metric to evaluate their performance...
May 2017: Nature Biotechnology
https://www.readbyqxmd.com/read/28283561/alteration-of-neuronal-excitability-and-short-term-synaptic-plasticity-in-the-prefrontal-cortex-of-a-mouse-model-of-mental-illness
#13
Gregg W Crabtree, Ziyi Sun, Mirna Kvajo, Jantine A C Broek, Karine Fénelon, Heather McKellar, Lan Xiao, Bin Xu, Sabine Bahn, James M O'Donnell, Joseph A Gogos
Using a genetic mouse model that faithfully recapitulates a DISC1 genetic alteration strongly associated with schizophrenia and other psychiatric disorders, we examined the impact of this mutation within the prefrontal cortex. Although cortical layering, cytoarchitecture, and proteome were found to be largely unaffected, electrophysiological examination of the mPFC revealed both neuronal hyperexcitability and alterations in short-term synaptic plasticity consistent with enhanced neurotransmitter release. Increased excitability of layer II/III pyramidal neurons was accompanied by consistent reductions in voltage-activated potassium currents near the action potential threshold as well as by enhanced recruitment of inputs arising from superficial layers to layer V...
April 12, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28268898/a-large-scale-detailed-neuronal-model-of-electrical-stimulation-of-the-dentate-gyrus-and-perforant-path-as-a-platform-for-electrode-design-and-optimization
#14
Clayton S Bingham, Kyle Loizos, Gene Yu, Andrew Gilbert, Jean-Marie Bouteiller, Dong Song, Gianluca Lazzi, Theodore W Berger
Owing to the dramatic rise in treatment of neurological disorders with electrical micro-stimulation it has become apparent that the major technological limitation in deploying effective devices lies in the process of designing efficient, safe, and outcome specific electrode arrays. The time-consuming and low-fidelity nature of gathering test data using experimental means and the immense control and flexibility of computational models, has prompted us and others to build models of electrical stimulation of neural networks that can be simulated in a computer...
August 2016: Conference Proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society
https://www.readbyqxmd.com/read/28268605/parameter-estimation-for-gene-regulatory-networks-a-two-stage-mcmc-bayesian-approach
#15
Niannan Xue, Wei Pan, Yike Guo
Genetic regulatory networks have emerged as a useful way to elucidate the biochemical pathways for biological functions. Yet, determination of the exact parametric forms for these models remain a major challenge. In this paper, we present a novel computational approach implemented in C++ to solve this inverse problem. This takes the form of an optimization stage first after which Bayesian filtering takes place. The key advantage of such a flexible, general and robust approach is that it provides us with a joint probability distribution of the model parameters instead of single estimates, which we can propagate to final predictions...
August 2016: Conference Proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society
https://www.readbyqxmd.com/read/28256619/a-core-regulatory-circuit-in-glioblastoma-stem-cells-links-mapk-activation-to-a-transcriptional-program-of-neural-stem-cell-identity
#16
Gregory Riddick, Svetlana Kotliarova, Virginia Rodriguez, H S Kim, Amanda Linkous, Andrew J Storaska, Susie Ahn, Jennifer Walling, Galina Belova, Howard A Fine
Glioblastoma, the most common primary malignant brain tumor, harbors a small population of tumor initiating cells (glioblastoma stem cells) that have many properties similar to neural stem cells. To investigate common regulatory networks in both neural and glioblastoma stem cells, we subjected both cell types to in-vitro differentiation conditions and measured global gene-expression changes using gene expression microarrays. Analysis of enriched transcription factor DNA-binding sites in the promoters of differentially expressed genes was used to reconstruct regulatory networks involved in differentiation...
March 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28239411/reliable-measurement-of-e-coli-single-cell-fluorescence-distribution-using-a-standard-microscope-set-up
#17
Marilisa Cortesi, Lucia Bandiera, Alice Pasini, Alessandro Bevilacqua, Alessandro Gherardi, Simone Furini, Emanuele Giordano
BACKGROUND: Quantifying gene expression at single cell level is fundamental for the complete characterization of synthetic gene circuits, due to the significant impact of noise and inter-cellular variability on the system's functionality. Commercial set-ups that allow the acquisition of fluorescent signal at single cell level (flow cytometers or quantitative microscopes) are expensive apparatuses that are hardly affordable by small laboratories. METHODS: A protocol that makes a standard optical microscope able to acquire quantitative, single cell, fluorescent data from a bacterial population transformed with synthetic gene circuitry is presented...
2017: Journal of Biological Engineering
https://www.readbyqxmd.com/read/28231449/synthetic-gene-circuits-learn-to-classify
#18
Andriy Didovyk, Lev S Tsimring
An efficient computational algorithm is developed to design microRNA-based synthetic cell classifiers and to optimize their performance.
February 22, 2017: Cell Systems
https://www.readbyqxmd.com/read/28227099/a-large-scale-detailed-neuronal-model-of-electrical-stimulation-of-the-dentate-gyrus-and-perforant-path-as-a-platform-for-electrode-design-and-optimization
#19
Clayton S Bingham, Kyle Loizos, Gene Yu, Andrew Gilbert, Jean-Marie Bouteiller, Dong Song, Gianluca Lazzi, Theodore W Berger, Clayton S Bingham, Kyle Loizos, Gene Yu, Andrew Gilbert, Jean-Marie Bouteiller, Dong Song, Gianluca Lazzi, Theodore W Berger, Kyle Loizos, Gene Yu, Theodore W Berger, Gianluca Lazzi, Jean-Marie Bouteiller, Clayton S Bingham, Dong Song, Andrew Gilbert
Owing to the dramatic rise in treatment of neurological disorders with electrical micro-stimulation it has become apparent that the major technological limitation in deploying effective devices lies in the process of designing efficient, safe, and outcome specific electrode arrays. The time-consuming and low-fidelity nature of gathering test data using experimental means and the immense control and flexibility of computational models, has prompted us and others to build models of electrical stimulation of neural networks that can be simulated in a computer...
August 2016: Conference Proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society
https://www.readbyqxmd.com/read/28226784/parameter-estimation-for-gene-regulatory-networks-a-two-stage-mcmc-bayesian-approach
#20
Niannan Xue, Wei Pan, Yike Guo, Niannan Xue, Wei Pan, Yike Guo, Wei Pan, Yike Guo, Niannan Xue
Genetic regulatory networks have emerged as a useful way to elucidate the biochemical pathways for biological functions. Yet, determination of the exact parametric forms for these models remain a major challenge. In this paper, we present a novel computational approach implemented in C++ to solve this inverse problem. This takes the form of an optimization stage first after which Bayesian filtering takes place. The key advantage of such a flexible, general and robust approach is that it provides us with a joint probability distribution of the model parameters instead of single estimates, which we can propagate to final predictions...
August 2016: Conference Proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society
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