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   1 e to propose an integrated model for the fim gene circuit.                                           
     2 cture and biokinetic rates of the underlying gene circuit.                                           
     3  capture the full stochastic behavior of the gene circuit.                                           
     4  of noise arising from any source within the gene circuit.                                           
     5 ontrol transcription from a simple synthetic gene circuit.                                           
     6 e library of components for use in synthetic gene circuits.                                          
     7 ofiles and facilitate mathematical models of gene circuits.                                          
     8 , and experimentally, using simple synthetic gene circuits.                                          
     9 nce of regulatory interactions in endogenous gene circuits.                                          
    10 roposed as mechanisms for decision making in gene circuits.                                          
    11 gical networks and for engineering synthetic gene circuits.                                          
    12 atural networks and designing noise-tolerant gene circuits.                                          
    13 tematic experimental or theoretical study of gene circuits.                                          
    14 rinsic noise within negatively autoregulated gene circuits.                                          
    15 y through the predictive design of synthetic gene circuits.                                          
    16 ibe and predict the behaviours of engineered gene circuits.                                          
    17 ting and expanding the function of synthetic gene circuits.                                          
    18  cell metabolism, cell biology and synthetic gene circuits.                                          
    19 xamine the sources of variability in dynamic gene circuits.                                          
    20 iding new ways to engineer arbitrary complex gene circuits.                                          
    21 onents can be used for large-scale synthetic gene circuits.                                          
    22  'smart bioparticles' controlled by designed gene circuits.                                          
    23 eloped numerous parts for building synthetic gene circuits.                                          
    24 thetic biologists have gone from single-cell gene circuits(8-11) to controlling whole populations usi
  
  
    27 ble circuit performance such as insulating a gene circuit against unwanted interactions with its cont
  
    29 le that adds a layer of control to synthetic gene circuits, allowing dynamic regulation of circuit el
  
    31 oise transmission through this signaling and gene circuit, analyzing data obtained from 43,775 indivi
    32 rgue that f(c) is an intrinsic property of a gene circuit and it varies with circuit parameters and a
    33 urate predictive design of complex synthetic gene circuits and accompanying large sets of quality mod
    34 ew how CRISPR can be used to build synthetic gene circuits and discuss recent advances in CRISPR-medi
    35 regulation of regulator genes in repressible gene circuits and lead to testable predictions, which we
    36 toolkit can be used for programming scalable gene circuits and perturbing endogenous networks for bio
    37 t, facilitating the understanding of natural gene circuits and the design of cell-based therapeutic s
  
    39 tics may serve to 'fill in the gaps' between genes, circuits and behavior, in a manner that should he
    40 f the architecture of the mutual suppression gene circuit, and thus is a design option readily availa
    41 ermination by viruses, dynamics of synthetic gene circuits, and constraints on evolutionary adaptatio
    42 netic switches, rapid prototyping of complex gene circuits, and programmable in vitro diagnostics, in
    43 mics and the noise behavior of autoregulated gene circuits, and this T-based technique provides a sim
    44 tegrated logic and memory by using synthetic gene circuits, and we demonstrated the implementation of
  
    46 se intrinsic to a prototypical two-component gene-circuit architecture composed of interacting positi
  
    48 L and IPTG signals with a synthetic AND gate gene circuit are shown to respond only in the presence o
  
  
  
  
    53 ur of an inducible, negatively autoregulated gene circuit arranged in different transcriptional confi
    54 erturbations that interact directly with the gene circuit as well as for a variety of generic perturb
  
    56 genetic regulatory elements, genes and multi-gene circuits as well as facile development of libraries
  
    58 k advances our quantitative understanding of gene circuit behaviours and also benefits the rational d
  
    60 ynthetic biology devices, such as engineered gene circuits, bring new capabilities to molecular diagn
    61 an regulatory networks including the largest gene circuit built and chromosomally integrated to date 
    62 ntial parameter in the dynamics of synthetic gene circuits but typically is not explicitly considered
    63 n the design and implementation of synthetic gene circuits, but real-world applications of such circu
  
    65    Here we demonstrate that synthetic analog gene circuits can be engineered to execute sophisticated
  
  
    68 st platform for building mammalian synthetic gene circuits capable of precisely modulating cellular b
    69 rder to construct progressively more complex gene circuits capable of processing information in livin
  
    71 mics of a binary fate decision governed by a gene-circuit containing auto-stimulation and cross-inhib
    72 aracterized an inducible, bistable synthetic gene circuit controlling the expression of a bifunctiona
  
  
  
    76 velopments have signalled the emergence of a gene circuit discipline, which provides a framework for 
  
    78 icroscopy is a powerful method for analyzing gene circuit dynamics and heterogeneous cell behavior.  
    79 alysis that remains valid for many important gene circuit elements even as molecular populations appr
  
  
    82 esults suggest that the self-repressing Hes1 gene circuit exploits this phenomenon to generate robust
  
  
    85 ells derived from E. coli strains containing gene circuits for biosensing were able to transduce the 
    86 his framework enables development of complex gene circuits for engineering mammalian cells with unpre
    87 r quick and reliable construction of complex gene circuits for genetically engineering mammalian cell
    88 e emerging field of synthetic biology builds gene circuits for scientific, industrial and therapeutic
  
    90 ning the structure and biokinetic rates of a gene circuit from its noise autocorrelation function.   
  
    92  in the capability of engineering artificial gene circuits from transcription factors (TFs), particul
    93 (TFs) but is capable of evolving any gene-or gene circuit function-that can be linked to conditional 
  
  
  
    97  cytoskeletal force dipoles, and the lamin A gene circuit illustrate the wide range of testable predi
    98 ely address these questions, we engineered a gene circuit in Escherichia coli to control the synthesi
  
  
  
  
   103 mponents and tools available for engineering gene circuits in microbes, including recently developed 
   104 ate large gene cassettes that encode complex gene circuits in order to avoid simultaneous delivery of
   105 pression patterns of nearly 17 million three-gene circuits in order to systematically explore the rel
  
   107  that connect noise, the architecture of the gene circuits in which it is present, and the biological
  
  
  
   111 ure efforts to convert functional multi-copy gene circuits into optimized single-copy circuits for pr
  
   113 ency content is determined by the underlying gene circuits, leading to a mapping between gene circuit
   114 We show that noise-induced oscillations in a gene circuit model display stochastic coherence, that is
  
  
   117 red predictably using exchangeable synthetic gene circuit modules to sense and integrate multiple-inp
  
   119 rk, we demonstrate construction of synthetic gene circuits of up to 64 kb in size comprising 11 trans
  
   121 ts into gene regulation, as perturbations of gene circuit parameters are discernible in the measured 
  
   123  present a proof-of-concept immunomodulatory gene circuit platform that enables tumor-specific expres
  
  
  
   127  dynamical analyses of synthetic and natural gene circuits, providing an essential step toward the pr
  
   129   Engineering of cell fate through synthetic gene circuits requires methods to precisely implement co
   130 or future engineering of synthetic mammalian gene circuits requiring nonlinear responses to HGF signa
  
   132 x, model is proposed for the dynamics of the gene circuit responsible for regulating nitrogen catabol
   133 oretical analyses and simulations of various gene circuits show that the noise regulatory vector is c
   134 ures of E. coli, and verify the link between gene circuit structure and noise spectra by demonstratin
   135  gene circuits, leading to a mapping between gene circuit structure and the noise frequency range.   
   136 The analysis elucidates important aspects of gene circuit structure that control functionality, and m
   137 oscillations, have been found in specialized gene circuits such as the bacteriophage lambda switch an
  
  
  
  
   142 k control, we designed a synthetic mammalian gene circuit that maintains thyroid hormone homeostasis 
   143 olved from an adaptive temperature sensor: a gene circuit that responds only to temperature changes. 
  
  
   146 mework supporting the forward engineering of gene circuits that incorporate RNAi-based regulatory com
   147 nal genetic circuits and describe artificial gene circuits that perform digital and analog computatio
  
  
   150  these insulators are used to join synthetic gene circuits, the behavior of layered circuits can be p
   151 that Tc-eve, Tc-run, and Tc-odd form a three-gene circuit to regulate one another as well as their do
  
   153 Our approach enabled the largest, eukaryotic gene circuits to date and will form the basis for large,
   154  present a framework for building comparator gene circuits to digitize analogue inputs based on diffe
   155 logue-to-digital circuits with other digital gene circuits to enable concentration-dependent logic.  
   156 hat can be harnessed by native and synthetic gene circuits to provide greater control over sRNA activ
  
  
   159     In modeling the system as a parsimonious gene circuit, we show that tension-dependent stabilizati
  
  
   162 involved in gap gene regulation based on gap gene circuits, which are mathematical gene network model
   163 ifferent topologies and verified a synthetic gene circuit with mutual inhibition and auto-activations
  
  
   166 vide one example of how the arrangement of a gene circuit within the genome can affect its behaviour.
  
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