Nucleic Acid Sequence Design via Efficient Ensemble Defect Optimization

We describe an algorithm for designing the sequence of one or more interacting nucleic acid strands intended to adopt a target secondary structure at equilibrium. Sequence design is formulated as an optimization problem with the goal of reducing the ensemble defect below a user-specified stop condition. For a candidate sequence and a given target secondary structure, the ensemble defect is the average number of incorrectly paired nucleotides at equilibrium evaluated over the ensemble of unpseudoknotted secondary structures. To reduce the computational cost of accepting or rejecting mutations to a random initial sequence, candidate mutations are evaluated on the leaf nodes of a tree-decomposition of the target structure. During leaf optimization, defect-weighted mutation sampling is used to select each candidate mutation position with probability proportional to its contribution to the ensemble defect of the leaf. As subsequences are merged moving up the tree, emergent structural defects resulting from crosstalk between sibling sequences are eliminated via reoptimization within the defective subtree starting from new random subsequences. Using a Θ(N^3) dynamic program to evaluate the ensemble defect of a target structure with N nucleotides, this hierarchical approach implies an asymptotic optimality bound on design time: for sufficiently large N, the cost of sequence design is bounded below by 4/3 the cost of a single evaluation of the ensemble defect for the full sequence. Hence, the design algorithm has time complexity Ω(N^3). For target structures containing N ∈{100,200,400,800,1600,3200} nucleotides and duplex stems ranging from 1 to 30 base pairs, RNA sequence designs at 37°C typically succeed in satisfying a stop condition with ensemble defect less than N/100. Empirically, the sequence design algorithm exhibits asymptotic optimality and the exponent in the time complexity bound is shar

Constrained Multistate Sequence Design for Nucleic Acid Reaction Pathway Engineering

We describe a framework for designing the sequences of multiple nucleic acid strands intended to hybridize in solution via a prescribed reaction pathway. Sequence design is formulated as a multistate optimization problem using a set of target test tubes to represent reactant, intermediate, and product states of the system, as well as to model crosstalk between components. Each target test tube contains a set of desired “on-target” complexes, each with a target secondary structure and target concentration, and a set of undesired “off-target” complexes, each with vanishing target concentration. Optimization of the equilibrium ensemble properties of the target test tubes implements both a positive design paradigm, explicitly designing for on-pathway elementary steps, and a negative design paradigm, explicitly designing against off-pathway crosstalk. Sequence design is performed subject to diverse user-specified sequence constraints including composition constraints, complementarity constraints, pattern prevention constraints, and biological constraints. Constrained multistate sequence design facilitates nucleic acid reaction pathway engineering for diverse applications in molecular programming and synthetic biology. Design jobs can be run online via the NUPACK web application

Generation of broad spectral components from midwave infrared ultrashort pulse laser propagation through ZnSe and ZnS

We investigate the nonlinear optical properties of ZnSe and ZnS using ultrashort (pulse duration approximately 200 fs) midwave infrared laser pulses between 3 and 4 mu m. Multiple harmonic generation in both materials was observed, as well as significant spectral modification of the fundamental pulse. Simulations using a nonlinear polarization model enhanced with ionization compared favorably with experimental data. Random quasi phase matching in the materials is the likely generator of the observed harmonics.SURVICE [S17-095008/DOTC-17-01-INIT0086]; Air Force Office of Scientific Research (AFOSR) [FA9550-16-1-0069]; AFOSR multidisciplinary research program of the university research initiative (MURI) [FA9550-16-1-0013]; AFOSR [FA9550-16-1-0121]This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Minimally Invasive Mitral Valve Surgery I: Patient Selection, Evaluation, and Planning.

Widespread adoption of minimally invasive mitral valve repair and replacement may be fostered by practice consensus and standardization. This expert opinion, first of a 3-part series, outlines current best practices in patient evaluation and selection for minimally invasive mitral valve procedures, and discusses preoperative planning for cannulation and myocardial protection

Minimally Invasive Mitral Valve Surgery II: Surgical Technique and Postoperative Management.

Techniques for minimally invasive mitral valve repair and replacement continue to evolve. This expert opinion, the second of a 3-part series, outlines current best practices for nonrobotic, minimally invasive mitral valve procedures, and for postoperative care after minimally invasive mitral valve surgery

Minimally Invasive Mitral Valve Surgery III: Training and Robotic-Assisted Approaches.

Minimally invasive mitral valve operations are increasingly common in the United States, but robotic-assisted approaches have not been widely adopted for a variety of reasons. This expert opinion reviews the state of the art and defines best practices, training, and techniques for developing a successful robotics program

High-field side scrape-off layer investigation: Plasma profiles and impurity screening behavior in near-double-null configurations

New experiments on Alcator C-Mod reveal that the favorable impurity screening characteristics of the high-field side (HFS) scrape-off layer (SOL), previously reported for single null geometries, is retained in double null configurations, despite the formation of an extremely thin SOL. In balanced double-null, nitrogen injected locally into the HFS SOL is better screened by a factor of 2.5 compared to the same injection into the low field side (LFS) SOL. This result is insensitive to plasma current and Greenwald fraction. Nitrogen injected into the HFS SOL is not as well screened (only a factor of 1.5 improvement over LFS) in unbalanced double-null discharges, when the primary divertor is in the direction of B×∇B. In this configuration, impurity ‘plume’ emission patterns indicate that an opposing E × B drift competes with the parallel impurity flow to the divertor. In balanced double-null plasmas, the dispersal pattern exhibits a dominant E × B motion. Unbalanced discharges with the primary divertor opposite the direction of B×∇B exhibit excellent HFS screening characteristics – a factor of 5 enhancement compared to LFS. These data support the idea that future tokamaks should locate all RF actuators and close-fitting wall structures on the HFS and employ near-double-null magnetic topologies, both to precisely control plasma conditions at the antenna/plasma interface and to maximally mitigate the impact of local impurity sources arising from plasma-material interactions. Keywords: Alcator C-Mod; Impurity screening; Double null; High field side scrape-off layerUnited States. Department of Energy (Contract DE-FC02-99ER54512