Computational genes: a tool for molecular diagnosis and therapy of aberrant mutational phenotype

<p>Abstract</p> <p>Background</p> <p>A finite state machine manipulating information-carrying DNA strands can be used to perform autonomous molecular-scale computations at the cellular level.</p> <p>Results</p> <p>We propose a new finite state machine able to detect and correct aberrant molecular phenotype given by mutated genetic transcripts. The aberrant mutations trigger a cascade reaction: specific molecular markers as input are released and induce a spontaneous self-assembly of a wild type protein or peptide, while the mutational disease phenotype is silenced. We experimentally demostrated in <it>in vitro </it>translation system that a viable protein can be autonomously assembled.</p> <p>Conclusion</p> <p>Our work demostrates the basic principles of computational genes and particularly, their potential to detect mutations, and as a response thereafter administer an output that suppresses the aberrant disease phenotype and/or restores the lost physiological function.</p

Inferring Parameters for an Elementary Step Model of DNA Structure Kinetics with Locally Context-Dependent Arrhenius Rates

Models of nucleic acid thermal stability are calibrated to a wide range of experimental observations, and typically predict equilibrium probabilities of nucleic acid secondary structures with reasonable accuracy. By comparison, a similar calibration and evaluation of nucleic acid kinetic models to a broad range of measurements has not been attempted so far. We introduce an Arrhenius model of interacting nucleic acid kinetics that relates the activation energy of a state transition with the immediate local environment of the affected base pair. Our model can be used in stochastic simulations to estimate kinetic properties and is consistent with existing thermodynamic models. We infer parameters for our model using an ensemble Markov chain Monte Carlo (MCMC) approach on a training dataset with 320 kinetic measurements of hairpin closing and opening, helix association and dissociation, bubble closing and toehold-mediated strand exchange. Our new model surpasses the performance of the previously established Metropolis model both on the training set and on a testing set of size 56 composed of toehold-mediated 3-way strand displacement with mismatches and hairpin opening and closing rates: reaction rates are predicted to within a factor of three for 93.4% and 78.5% of reactions for the training and testing sets, respectively

Leak-Resistant Design of DNA Strand Displacement Systems

Although a number of dynamically-controlled nanostructures and programmable DNA Strand Displacement (DSD) systems have been designed using DNA strand displacement, predictability and scalability of these DNA-based systems remain limited due to leakages introduced by spuriously triggered displacement events. We present a systematic design method for implementing leak-resistant DNA strand displacement systems in which each legitimate displacement event requires signal species to bind cooperatively at the two designated toehold binding sites in the protected fuel complexes, and thus inhibits spurious displacement events. To demonstrate the potential of the leak-resistant design approach for the construction of arbitrary complex digital circuits and systems with analog behaviors, we present domain-level designs and displacement pathways of the basic building blocks of the DNA strand displacement cascades, e.g. OR, AND gates, and an elementary bimolecular reaction.Peer reviewe

Attitudes of a group of Brazilian orthodontists towards the diagnosis and management of primary headache (migraine): an electronic-based survey

OBJECTIVES: The aim of this study was to investigate the knowledge and attitudes of orthodontists in the diagnosis and management of migraine without aura. MATERIAL AND METHODS: Participants were dentists, recruited among members of the Brazilian Association of Orthodontics and Facial Orthopedics (ABOR). An e-mail was sent to all ABOR members, with a link to a website, especially prepared for this research. Dentists were presented to a report of a fictional patient fulfilling diagnostic criteria for a primary headache disorder, known as migraine without aura. Participants were asked to describe how they would relieve the patient's pain. Professional procedures were classified as "adequate" or "inadequate" according to the answers given. RESULTS: 161 valid answers were received (18.8% response rate). Of them, 36% of the actions were considered to be "adequate" procedures, while 64% were "inadequate". The results yielded 12 main procedures, based on common characteristics. Eighty-two orthodontists suggested orthodontic treatment with or without orthognathic surgery, and some suggested using stabilization appliances prior to the orthodontic treatment. CONCLUSIONS: The majority of participants proposed inadequate therapies, and 51% suggested orthodontic correction of occlusion, including orthognathic surgery. Educational activities on migraine should also target orthodontists

Programmed folding of DNA origami structures through single-molecule force control

Despite the recent development in the design of DNA origami, its folding yet relies on thermal or chemical annealing methods. We here demonstrate mechanical folding of the DNA origami structure via a pathway that has not been accessible to thermal annealing. Using magnetic tweezers, we stretch a single scaffold DNA with mechanical tension to remove its secondary structures, followed by base pairing of the stretched DNA with staple strands. When the force is subsequently quenched, folding of the DNA nanostructure is completed through displacement between the bound staple strands. Each process in the mechanical folding is well defined and free from kinetic traps, enabling us to complete folding within 10 min. We also demonstrate parallel folding of DNA nanostructures through multiplexed manipulation of the scaffold DNAs. Our results suggest a path towards programmability of the folding pathway of DNA nanostructures