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toggle system

Janica C Wong, Katherine C Krueger, Maria José Costa, Abhishek Aggarwal, Hongqing Du, Tracey L McLaughlin, Brian J Feldman
Obesity is driven by excess caloric intake, which leads to the expansion of adipose tissue by hypertrophy and hyperplasia. Adipose tissue hyperplasia results from the differentiation of adipocyte precursor cells (APCs) that reside in adipose depots. Investigation into this process has elucidated a network of mostly transcription factors that drive APCs through the differentiation process. Using in vitro and in vivo approaches, our study revealed a signaling pathway that inhibited the initiation of the adipocyte differentiation program...
October 25, 2016: Science Signaling
Otti D'Huys, Johannes Lohmann, Nicholas D Haynes, Daniel J Gauthier
Autonomous Boolean networks are commonly used to model the dynamics of gene regulatory networks and allow for the prediction of stable dynamical attractors. However, most models do not account for time delays along the network links and noise, which are crucial features of real biological systems. Concentrating on two paradigmatic motifs, the toggle switch and the repressilator, we develop an experimental testbed that explicitly includes both inter-node time delays and noise using digital logic elements on field-programmable gate arrays...
September 2016: Chaos
Ruben Perez-Carrasco, Pilar Guerrero, James Briscoe, Karen M Page
During tissue development, patterns of gene expression determine the spatial arrangement of cell types. In many cases, gradients of secreted signalling molecules-morphogens-guide this process by controlling downstream transcriptional networks. A mechanism commonly used in these networks to convert the continuous information provided by the gradient into discrete transitions between adjacent cell types is the genetic toggle switch, composed of cross-repressing transcriptional determinants. Previous analyses have emphasised the steady state output of these mechanisms...
October 2016: PLoS Computational Biology
Kaiwen Ivy Liu, Muhammad Nadzim Bin Ramli, Cheok Wei Ariel Woo, Yuanming Wang, Tianyun Zhao, Xiujun Zhang, Guo Rong Daniel Yim, Bao Yi Chong, Ali Gowher, Mervyn Zi Hao Chua, Jonathan Jung, Jia Hui Jane Lee, Meng How Tan
CRISPR-Cas9 has emerged as a powerful technology that enables ready modification of the mammalian genome. The ability to modulate Cas9 activity can reduce off-target cleavage and facilitate precise genome engineering. Here we report the development of a Cas9 variant whose activity can be switched on and off in human cells with 4-hydroxytamoxifen (4-HT) by fusing the Cas9 enzyme with the hormone-binding domain of the estrogen receptor (ERT2). The final optimized variant, termed iCas, showed low endonuclease activity without 4-HT but high editing efficiency at multiple loci with the chemical...
November 2016: Nature Chemical Biology
Yong Xu, Yongge Li, Hao Zhang, Xiaofan Li, Jürgen Kurths
A bistable toggle switch is a paradigmatic model in the field of biology. The dynamics of the system induced by Gaussian noise has been intensively investigated, but Gaussian noise cannot incorporate large bursts typically occurring in real experiments. This paper aims to examine effects of variations from one protein imposed by a non-Gaussian Lévy noise, which is able to describe even large jumps, on the coherent switch and the on/off switch via the steady-state probability density, the joint steady-state probability density, and the mean first passage time...
2016: Scientific Reports
Ashkan Pourkand, Christina Salas, Jasmin Regalado, Krishan Bhakta, Rachel Tufaro, Deana Mercer, David Grow
BACKGROUND: Orthopedics is a motor skills-demanding surgical specialty requiring surgical skills training outside of the operating room. Unfortunately, limited quantitative techniques exist to determine the effectiveness of these surgical skills training programs. Using a variety of drill, surgeon, and specimen mounted sensors, we evaluated orthopedic surgery residents during a surgical skills training course approved by the American Board of Orthopaedic Surgeons (ABOS). This evaluation consisted of quantitative measures of various kinematic and kinetic parameters with the goal of relating these to clinically-significant outcomes...
2016: Iowa Orthopaedic Journal
Harry S Hothi, Andreas C Panagiotopoulos, Robert K Whittaker, Paul J Bills, Rebecca A McMillan, John A Skinner, Alister J Hart
BACKGROUND: Material loss at the taper junction of metal-on-metal total hip arthroplasties has been implicated in their early failure. The mechanisms of material loss are not fully understood; analysis of the patterns of damage at the taper can help us better understand why material loss occurs at this junction. METHODS: We mapped the patterns of material loss in a series of 155 metal-on-metal total hip arthroplasties received at our center by scanning the taper surface using a roundness-measuring machine...
July 7, 2016: Journal of Arthroplasty
Sudhakar Gaikwad, Abir Goswami, Soumen De, Michael Schmittel
The nanomechanical switch 1 with its three orthogonal binding motifs-the zinc(II) porphyrin, azaterpyridine, and shielded phenanthroline binding station-is quantitatively and reversibly toggled back and forth between four different switching states by means of addition and removal of appropriate metal-ion inputs. Two of the four switching stages are able to initiate catalytic transformations (ON1, ON2), while the two others shut down any reaction (OFF1, OFF2). Thus, in a cyclic four-state switching process the sequential transformation A+B+C→AB+C→ABC can be controlled, which proceeds stepwise along the switching states OFF1→ON1 (click reaction: A+B→AB)→OFF2→ON2 (Michael addition: AB+C→ABC)→OFF1...
August 22, 2016: Angewandte Chemie
Marina Frank, Mark D Johnstone, Guido H Clever
This Review covers design strategies, synthetic challenges, host-guest chemistry, and functional properties of interlocked supramolecular cages. Some dynamic covalent organic structures are discussed, as are selected examples of interpenetration in metal-organic frameworks, but the main focus is on discrete coordination architectures, that is, metal-mediated dimers. Factors leading to interpenetration, such as geometry, flexibility and chemical makeup of the ligands, coordination environment, solvent effects, and selection of suitable counter anions and guest molecules, are discussed...
September 26, 2016: Chemistry: a European Journal
Marc Weber, Javier Buceta
Inspired by the Ising model, we introduce a gene regulatory network that induces a phase transition that coordinates robustly the behaviour of cell ensembles. The building blocks of the design are the so-called toggle switch interfaced with two quorum sensing modules, Las and Lux. We show that as a function of the transport rate of signalling molecules across the cell membrane the population undergoes a spontaneous symmetry breaking from cells individually switching their phenotypes to a global collective phenotypic organization...
June 2016: Journal of the Royal Society, Interface
Nikolay Martyushenko, Sigurd Hagen Johansen, Cheol-Min Ghim, Eivind Almaas
BACKGROUND: Genetic switches are ubiquitous in nature, frequently associated with the control of cellular functions and developmental programs. In the realm of synthetic biology, it is of great interest to engineer genetic circuits that can change their mode of operation from monostable to bistable, or even to multistable, based on the experimental fine-tuning of readily accessible parameters. In order to successfully design robust, bistable synthetic circuits to be used as biomolecular probes, or understand modes of operation of such naturally occurring circuits, we must identify parameters that are key in determining their characteristics...
2016: BMC Systems Biology
C E Cameron, I M Moustafa, J J Arnold
Using poliovirus (PV) and its RNA-dependent RNA polymerase (RdRp) as our primary model system, we have advanced knowledge fundamental to the chemistry and fidelity of nucleotide addition by nucleic acid polymerase. Two fidelity checkpoints exist prior to nucleotide addition. The first toggles the enzyme between a nucleotide binding-occluded state and a nucleotide binding-competent state. The second represents an ensemble of conformational states of conserved structural motifs that permits retention of the incoming nucleotide in a state competent for phosphoryl transfer long enough for chemistry to occur...
2016: Enzymes
Alejo M Lifschitz, Ryan M Young, Jose Mendez-Arroyo, C Michael McGuirk, Michael R Wasielewski, Chad A Mirkin
Herein, we report the first allosteric photoredox catalyst regulated via constructively coupled structural and electronic control. While often synergistically exploited in nature, these two types of control mechanisms have only been applied independently in the vast majority of allosteric enzyme mimics and receptors in the literature. By embedding a model of photosystem II in a supramolecular coordination complex that responds to chloride as an allosteric effector, we show that distance and electronic control of light harvesting can be married to maximize allosteric regulation of catalytic activity...
September 6, 2016: Inorganic Chemistry
Hang Chen, Peter Thill, Jianshu Cao
In biochemical systems, intrinsic noise may drive the system switch from one stable state to another. We investigate how kinetic switching between stable states in a bistable network is influenced by dynamic disorder, i.e., fluctuations in the rate coefficients. Using the geometric minimum action method, we first investigate the optimal transition paths and the corresponding minimum actions based on a genetic toggle switch model in which reaction coefficients draw from a discrete probability distribution. For the continuous probability distribution of the rate coefficient, we then consider two models of dynamic disorder in which reaction coefficients undergo different stochastic processes with the same stationary distribution...
May 7, 2016: Journal of Chemical Physics
Evgeni V Nikolaev, Eduardo D Sontag
Synthetic constructs in biotechnology, biocomputing, and modern gene therapy interventions are often based on plasmids or transfected circuits which implement some form of "on-off" switch. For example, the expression of a protein used for therapeutic purposes might be triggered by the recognition of a specific combination of inducers (e.g., antigens), and memory of this event should be maintained across a cell population until a specific stimulus commands a coordinated shut-off. The robustness of such a design is hampered by molecular ("intrinsic") or environmental ("extrinsic") noise, which may lead to spontaneous changes of state in a subset of the population and is reflected in the bimodality of protein expression, as measured for example using flow cytometry...
April 2016: PLoS Computational Biology
Daniel W Bailey, Jason D Spaans, Lalith K Kumaraswamy, Matthew B Podgorsak
Our study aimed to quantify the effect of the Measurement Uncertainty function on planar dosimetry pass rates, as measured and analyzed with the Sun Nuclear Corporation MapCHECK 2 array and its associated software. This optional function is toggled in the program preferences of the software (though turned on by default upon installation), and automatically increases the dose difference tolerance defined by the user for each planar dose comparison. Dose planes from 109 static-gantry IMRT fields and 40 VMAT arcs, of varying modulation complexity, were measured at 5 cm water-equivalent depth in the MapCHECK 2 diode array, and respective calculated dose planes were exported from a commercial treatment planning system...
2016: Journal of Applied Clinical Medical Physics
Anne Press, Lauren McCullagh, Sundas Khan, Andy Schachter, Salvatore Pardo, Thomas McGinn
BACKGROUND: As the electronic health record (EHR) becomes the preferred documentation tool across medical practices, health care organizations are pushing for clinical decision support systems (CDSS) to help bring clinical decision support (CDS) tools to the forefront of patient-physician interactions. A CDSS is integrated into the EHR and allows physicians to easily utilize CDS tools. However, often CDSS are integrated into the EHR without an initial phase of usability testing, resulting in poor adoption rates...
2015: JMIR Human Factors
Rocio Ochoa-Fernandez, Sophia L Samodelov, Simon M Brandl, Elke Wehinger, Konrad Müller, Wilfried Weber, Matias D Zurbriggen
Optogenetic tools to control gene expression have many advantages over the classical chemically inducible systems, overcoming intrinsic limitations of chemical inducers such as solubility, diffusion, and cell toxicity. They offer an unmatched spatiotemporal resolution and permit quantitative and noninvasive control of the gene expression. Here we describe a protocol of a synthetic light-inducible system for the targeted control of gene expression in plants based on the plant photoreceptor phytochrome B and one of its interacting factors (PIF6)...
2016: Methods in Molecular Biology
Oleg Kanakov, Tetyana Laptyeva, Lev Tsimring, Mikhail Ivanchenko
We propose and study models of two distributed synthetic gene circuits, toggle-switch and oscillator, each split between two cell strains and coupled via quorum-sensing signals. The distributed toggle switch relies on mutual repression of the two strains, and oscillator is comprised of two strains, one of which acts as an activator for another that in turn acts as a repressor. Distributed toggle switch can exhibit mobile fronts, switching the system from the weaker to the stronger spatially homogeneous state...
April 1, 2016: Physica D. Nonlinear Phenomena
Leandro Watanabe, Chris J Myers
The Systems Biology Markup Language (SBML) has been widely used for modeling biological systems. Although SBML has been successful in representing a wide variety of biochemical models, the core standard lacks the structure for representing large complex regular systems in a standard way, such as whole-cell and cellular population models. These models require a large number of variables to represent certain aspects of these types of models, such as the chromosome in the whole-cell model and the many identical cell models in a cellular population...
August 19, 2016: ACS Synthetic Biology
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