Multi-Maneuver Clohessy-Wiltshire Targeting

NASA Technical Reports Server (NTRS)

Dannemiller, David P.

2011-01-01

Orbital rendezvous involves execution of a sequence of maneuvers by a chaser vehicle to bring the chaser to a desired state relative to a target vehicle while meeting intermediate and final relative constraints. Intermediate and final relative constraints are necessary to meet a multitude of requirements such as to control approach direction, ensure relative position is adequate for operation of space-to-space communication systems and relative sensors, provide fail-safe trajectory features, and provide contingency hold points. The effect of maneuvers on constraints is often coupled, so the maneuvers must be solved for as a set. For example, maneuvers that affect orbital energy change both the chaser's height and downrange position relative to the target vehicle. Rendezvous designers use experience and rules-of-thumb to design a sequence of maneuvers and constraints. A non-iterative method is presented for targeting a rendezvous scenario that includes a sequence of maneuvers and relative constraints. This method is referred to as Multi-Maneuver Clohessy-Wiltshire Targeting (MM_CW_TGT). When a single maneuver is targeted to a single relative position, the classic CW targeting solution is obtained. The MM_CW_TGT method involves manipulation of the CW state transition matrix to form a linear system. As a starting point for forming the algorithm, the effects of a series of impulsive maneuvers on the state are derived. Simple and moderately complex examples are used to demonstrate the pattern of the resulting linear system. The general form of the pattern results in an algorithm for formation of the linear system. The resulting linear system relates the effect of maneuver components and initial conditions on relative constraints specified by the rendezvous designer. Solution of the linear system includes the straight-forward inverse of a square matrix. Inversion of the square matrix is assured if the designer poses a controllable scenario - a scenario where the the

Theoretical constraints in the design of multivariable control systems

NASA Technical Reports Server (NTRS)

Rynaski, E. G.; Mook, D. J.

1993-01-01

The theoretical constraints inherent in the design of multivariable control systems were defined and investigated. These constraints are manifested by the system transmission zeros that limit or bound the areas in which closed loop poles and individual transfer function zeros may be placed. These constraints were investigated primarily in the context of system decoupling or non-interaction. It was proven that decoupling requires the placement of closed loop poles at the system transmission zeros. Therefore, the system transmission zeros must be minimum phase to guarantee a stable decoupled system. Once decoupling has been accomplished, the remaining part of the system exhibits transmission zeros at infinity, so nearly complete design freedom is possible in terms of placing both poles and zeros of individual closed loop transfer functions. A general, dynamic inversion model following system architecture was developed that encompasses both the implicit and explicit configuration. Robustness properties are developed along with other attributes of this type of system. Finally, a direct design is developed for the longitudinal-vertical degrees of freedom of aircraft motion to show how a direct lift flap can be used to improve the pitch-heave maneuvering coordination for enhanced flying qualities.

Engineering design constraints of the lunar surface environment

NASA Technical Reports Server (NTRS)

Morrison, D. A.

1992-01-01

Living and working on the lunar surface will be difficult. Design of habitats, machines, tools, and operational scenarios in order to allow maximum flexibility in human activity will require paying attention to certain constraints imposed by conditions at the surface and the characteristics of lunar material. Primary design drivers for habitat, crew health and safety, and crew equipment are: ionizing radiation, the meteoroid flux, and the thermal environment. Secondary constraints for engineering derive from: the physical and chemical properties of lunar surface materials, rock distributions and regolith thicknesses, topography, electromagnetic properties, and seismicity. Protection from ionizing radiation is essential for crew health and safety. The total dose acquired by a crew member will be the sum of the dose acquired during EVA time (when shielding will be least) plus the dose acquired during time spent in the habitat (when shielding will be maximum). Minimizing the dose acquired in the habitat extends the time allowable for EVA's before a dose limit is reached. Habitat shielding is enabling, and higher precision in predicting secondary fluxes produced in shielding material would be desirable. Means for minimizing dose during a solar flare event while on extended EVA will be essential. Early warning of the onset of flare activity (at least a half-hour is feasible) will dictate the time available to take mitigating steps. Warning capability affects design of rovers (or rover tools) and site layout. Uncertainty in solar flare timing is a design constraint that points to the need for quickly accessible or constructible safe havens.

Engineering design constraints of the lunar surface environment

NASA Astrophysics Data System (ADS)

Morrison, D. A.

1992-02-01

Living and working on the lunar surface will be difficult. Design of habitats, machines, tools, and operational scenarios in order to allow maximum flexibility in human activity will require paying attention to certain constraints imposed by conditions at the surface and the characteristics of lunar material. Primary design drivers for habitat, crew health and safety, and crew equipment are: ionizing radiation, the meteoroid flux, and the thermal environment. Secondary constraints for engineering derive from: the physical and chemical properties of lunar surface materials, rock distributions and regolith thicknesses, topography, electromagnetic properties, and seismicity. Protection from ionizing radiation is essential for crew health and safety. The total dose acquired by a crew member will be the sum of the dose acquired during EVA time (when shielding will be least) plus the dose acquired during time spent in the habitat (when shielding will be maximum). Minimizing the dose acquired in the habitat extends the time allowable for EVA's before a dose limit is reached. Habitat shielding is enabling, and higher precision in predicting secondary fluxes produced in shielding material would be desirable. Means for minimizing dose during a solar flare event while on extended EVA will be essential. Early warning of the onset of flare activity (at least a half-hour is feasible) will dictate the time available to take mitigating steps. Warning capability affects design of rovers (or rover tools) and site layout. Uncertainty in solar flare timing is a design constraint that points to the need for quickly accessible or constructible safe havens.

Minimum weight design of rectangular and tapered helicopter rotor blades with frequency constraints

NASA Technical Reports Server (NTRS)

Chattopadhyay, Aditi; Walsh, Joanne L.

1988-01-01

The minimum weight design of a helicopter rotor blade subject to constraints on coupled flap-lag natural frequencies has been studied. A constraint has also been imposed on the minimum value of the autorotational inertia of the blade in order to ensure that it has sufficient inertia to autorotate in the case of engine failure. The program CAMRAD is used for the blade modal analysis and CONMIN is used for the optimization. In addition, a linear approximation analysis involving Taylor series expansion has been used to reduce the analysis effort. The procedure contains a sensitivity analysis which consists of analytical derivatives of the objective function and the autorotational inertia constraint and central finite difference derivatives of the frequency constraints. Optimum designs have been obtained for both rectangular and tapered blades. Design variables include taper ratio, segment weights, and box beam dimensions. It is shown that even when starting with an acceptable baseline design, a significant amount of weight reduction is possible while satisfying all the constraints for both rectangular and tapered blades.

Minimum weight design of rectangular and tapered helicopter rotor blades with frequency constraints

NASA Technical Reports Server (NTRS)

Chattopadhyay, Aditi; Walsh, Joanne L.

1988-01-01

The minimum weight design of a helicopter rotor blade subject to constraints on coupled flap-lag natural frequencies has been studied. A constraint has also been imposed on the minimum value of the autorotational inertia of the blade in order to ensure that it has sufficient inertia to aurorotate in the case of engine failure. The program CAMRAD is used for the blade modal analysis and CONMIN is used for the optimization. In addition, a linear approximation analysis involving Taylor series expansion has been used to reduce the analysis effort. The procedure contains a sensitivity analysis which consists of analytical derivatives of the objective function and the autorotational inertia constraint and central finite difference derivatives of the frequency constraints. Optimum designs have been obtained for both rectangular and tapered blades. Design variables include taper ratio, segment weights, and box beam dimensions. It is shown that even when starting with an acceptable baseline design, a significant amount of weight reduction is possible while satisfying all the constraints for both rectangular and tapered blades.

Finite-horizon differential games for missile-target interception system using adaptive dynamic programming with input constraints

NASA Astrophysics Data System (ADS)

Sun, Jingliang; Liu, Chunsheng

2018-01-01

In this paper, the problem of intercepting a manoeuvring target within a fixed final time is posed in a non-linear constrained zero-sum differential game framework. The Nash equilibrium solution is found by solving the finite-horizon constrained differential game problem via adaptive dynamic programming technique. Besides, a suitable non-quadratic functional is utilised to encode the control constraints into a differential game problem. The single critic network with constant weights and time-varying activation functions is constructed to approximate the solution of associated time-varying Hamilton-Jacobi-Isaacs equation online. To properly satisfy the terminal constraint, an additional error term is incorporated in a novel weight-updating law such that the terminal constraint error is also minimised over time. By utilising Lyapunov's direct method, the closed-loop differential game system and the estimation weight error of the critic network are proved to be uniformly ultimately bounded. Finally, the effectiveness of the proposed method is demonstrated by using a simple non-linear system and a non-linear missile-target interception system, assuming first-order dynamics for the interceptor and target.

Contextual Shaping of Student Design Practices: The Role of Constraint in First-Year Engineering Design

NASA Astrophysics Data System (ADS)

Goncher, Andrea M.

thResearch on engineering design is a core area of concern within engineering education, and a fundamental understanding of how engineering students approach and undertake design is necessary in order to develop effective design models and pedagogies. This dissertation contributes to scholarship on engineering design by addressing a critical, but as yet underexplored, problem: how does the context in which students design shape their design practices? Using a qualitative study comprising of video data of design sessions, focus group interviews with students, and archives of their design work, this research explored how design decisions and actions are shaped by context, specifically the context of higher education. To develop a theoretical explanation for observed behavior, this study used the nested structuration. framework proposed by Perlow, Gittell, & Katz (2004). This framework explicated how teamwork is shaped by mutually reinforcing relationships at the individual, organizational, and institutional levels. I appropriated this framework to look specifically at how engineering students working on a course-related design project identify constraints that guide their design and how these constraints emerge as students interact while working on the project. I first identified and characterized the parameters associated with the design project from the student perspective and then, through multi-case studies of four design teams, I looked at the role these parameters play in student design practices. This qualitative investigation of first-year engineering student design teams revealed mutual and interconnected relationships between students and the organizations and institutions that they are a part of. In addition to contributing to research on engineering design, this work provides guidelines and practices to help design educators develop more effective design projects by incorporating constraints that enable effective design and learning. Moreover, I found

Robust Fusion of Color and Depth Data for RGB-D Target Tracking Using Adaptive Range-Invariant Depth Models and Spatio-Temporal Consistency Constraints.

PubMed

Xiao, Jingjing; Stolkin, Rustam; Gao, Yuqing; Leonardis, Ales

2017-09-06

This paper presents a novel robust method for single target tracking in RGB-D images, and also contributes a substantial new benchmark dataset for evaluating RGB-D trackers. While a target object's color distribution is reasonably motion-invariant, this is not true for the target's depth distribution, which continually varies as the target moves relative to the camera. It is therefore nontrivial to design target models which can fully exploit (potentially very rich) depth information for target tracking. For this reason, much of the previous RGB-D literature relies on color information for tracking, while exploiting depth information only for occlusion reasoning. In contrast, we propose an adaptive range-invariant target depth model, and show how both depth and color information can be fully and adaptively fused during the search for the target in each new RGB-D image. We introduce a new, hierarchical, two-layered target model (comprising local and global models) which uses spatio-temporal consistency constraints to achieve stable and robust on-the-fly target relearning. In the global layer, multiple features, derived from both color and depth data, are adaptively fused to find a candidate target region. In ambiguous frames, where one or more features disagree, this global candidate region is further decomposed into smaller local candidate regions for matching to local-layer models of small target parts. We also note that conventional use of depth data, for occlusion reasoning, can easily trigger false occlusion detections when the target moves rapidly toward the camera. To overcome this problem, we show how combining target information with contextual information enables the target's depth constraint to be relaxed. Our adaptively relaxed depth constraints can robustly accommodate large and rapid target motion in the depth direction, while still enabling the use of depth data for highly accurate reasoning about occlusions. For evaluation, we introduce a new RGB

A Maximin Model for Test Design with Practical Constraints. Project Psychometric Aspects of Item Banking No. 25. Research Report 87-10.

ERIC Educational Resources Information Center

van der Linden, Wim J.; Boekkooi-Timminga, Ellen

A "maximin" model for item response theory based test design is proposed. In this model only the relative shape of the target test information function is specified. It serves as a constraint subject to which a linear programming algorithm maximizes the information in the test. In the practice of test construction there may be several…

Strict Constraint Feasibility in Analysis and Design of Uncertain Systems

NASA Technical Reports Server (NTRS)

Crespo, Luis G.; Giesy, Daniel P.; Kenny, Sean P.

2006-01-01

This paper proposes a methodology for the analysis and design optimization of models subject to parametric uncertainty, where hard inequality constraints are present. Hard constraints are those that must be satisfied for all parameter realizations prescribed by the uncertainty model. Emphasis is given to uncertainty models prescribed by norm-bounded perturbations from a nominal parameter value, i.e., hyper-spheres, and by sets of independently bounded uncertain variables, i.e., hyper-rectangles. These models make it possible to consider sets of parameters having comparable as well as dissimilar levels of uncertainty. Two alternative formulations for hyper-rectangular sets are proposed, one based on a transformation of variables and another based on an infinity norm approach. The suite of tools developed enable us to determine if the satisfaction of hard constraints is feasible by identifying critical combinations of uncertain parameters. Since this practice is performed without sampling or partitioning the parameter space, the resulting assessments of robustness are analytically verifiable. Strategies that enable the comparison of the robustness of competing design alternatives, the approximation of the robust design space, and the systematic search for designs with improved robustness characteristics are also proposed. Since the problem formulation is generic and the solution methods only require standard optimization algorithms for their implementation, the tools developed are applicable to a broad range of problems in several disciplines.

Web-based software tool for constraint-based design specification of synthetic biological systems.

PubMed

Oberortner, Ernst; Densmore, Douglas

2015-06-19

miniEugene provides computational support for solving combinatorial design problems, enabling users to specify and enumerate designs for novel biological systems based on sets of biological constraints. This technical note presents a brief tutorial for biologists and software engineers in the field of synthetic biology on how to use miniEugene. After reading this technical note, users should know which biological constraints are available in miniEugene, understand the syntax and semantics of these constraints, and be able to follow a step-by-step guide to specify the design of a classical synthetic biological system-the genetic toggle switch.1 We also provide links and references to more information on the miniEugene web application and the integration of the miniEugene software library into sophisticated Computer-Aided Design (CAD) tools for synthetic biology ( www.eugenecad.org ).

Theoretical constraints in the design of multivariable control systems

NASA Technical Reports Server (NTRS)

Rynaski, E. G.; Mook, D. Joseph; Depena, Juan

1991-01-01

The research being performed under NASA Grant NAG1-1361 involves a more clear understanding and definition of the constraints involved in the pole-zero placement or assignment process for multiple input, multiple output systems. Complete state feedback to more than a single controller under conditions of complete controllability and observability is redundant if pole placement alone is the design objective. The additional feedback gains, above and beyond those required for pole placement can be used for eignevalue assignment or zero placement of individual closed loop transfer functions. Because both poles and zeros of individual closed loop transfer functions strongly affect the dynamic response to a pilot command input, the pole-zero placement problem is important. When fewer controllers than degrees of freedom of motion are available, complete design freedom is not possible, the transmission zeros constrain the regions of possible pole-zero placement. The effect of transmission zero constraints on the design possibilities, selection of transmission zeros and the avoidance of producing non-minimum phase transfer functions is the subject of the research being performed under this grant.

Optimal Design of General Stiffened Composite Circular Cylinders for Global Buckling with Strength Constraints

NASA Technical Reports Server (NTRS)

Jaunky, N.; Ambur, D. R.; Knight, N. F., Jr.

1998-01-01

A design strategy for optimal design of composite grid-stiffened cylinders subjected to global and local buckling constraints and strength constraints was developed using a discrete optimizer based on a genetic algorithm. An improved smeared stiffener theory was used for the global analysis. Local buckling of skin segments were assessed using a Rayleigh-Ritz method that accounts for material anisotropy. The local buckling of stiffener segments were also assessed. Constraints on the axial membrane strain in the skin and stiffener segments were imposed to include strength criteria in the grid-stiffened cylinder design. Design variables used in this study were the axial and transverse stiffener spacings, stiffener height and thickness, skin laminate stacking sequence and stiffening configuration, where stiffening configuration is a design variable that indicates the combination of axial, transverse and diagonal stiffener in the grid-stiffened cylinder. The design optimization process was adapted to identify the best suited stiffening configurations and stiffener spacings for grid-stiffened composite cylinder with the length and radius of the cylinder, the design in-plane loads and material properties as inputs. The effect of having axial membrane strain constraints in the skin and stiffener segments in the optimization process is also studied for selected stiffening configurations.

Optimal Design of General Stiffened Composite Circular Cylinders for Global Buckling with Strength Constraints

NASA Technical Reports Server (NTRS)

Jaunky, Navin; Knight, Norman F., Jr.; Ambur, Damodar R.

1998-01-01

A design strategy for optimal design of composite grid-stiffened cylinders subjected to global and local buckling constraints and, strength constraints is developed using a discrete optimizer based on a genetic algorithm. An improved smeared stiffener theory is used for the global analysis. Local buckling of skin segments are assessed using a Rayleigh-Ritz method that accounts for material anisotropy. The local buckling of stiffener segments are also assessed. Constraints on the axial membrane strain in the skin and stiffener segments are imposed to include strength criteria in the grid-stiffened cylinder design. Design variables used in this study are the axial and transverse stiffener spacings, stiffener height and thickness, skin laminate stacking sequence, and stiffening configuration, where herein stiffening configuration is a design variable that indicates the combination of axial, transverse, and diagonal stiffener in the grid-stiffened cylinder. The design optimization process is adapted to identify the best suited stiffening configurations and stiffener spacings for grid-stiffened composite cylinder with the length and radius of the cylinder, the design in-plane loads, and material properties as inputs. The effect of having axial membrane strain constraints in the skin and stiffener segments in the optimization process is also studied for selected stiffening configuration.

Generation of Parametric Equivalent-Area Targets for Design of Low-Boom Supersonic Concepts

NASA Technical Reports Server (NTRS)

Li, Wu; Shields, Elwood

2011-01-01

A tool with an Excel visual interface is developed to generate equivalent-area (A(sub e)) targets that satisfy the volume constraints for a low-boom supersonic configuration. The new parametric Ae target explorer allows users to interactively study the tradeoffs between the aircraft volume constraints and the low-boom characteristics (e.g., loudness) of the ground signature. Moreover, numerical optimization can be used to generate the optimal A(sub e) target for given A(sub e) volume constraints. A case study is used to demonstrate how a generated low-boom Ae target can be matched by a supersonic configuration that includes a fuselage, wing, nacelle, pylon, aft pod, horizontal tail, and vertical tail. The low-boom configuration is verified by sonic-boom analysis with an off-body pressure distribution at three body lengths below the configuration

Linear Quadratic Tracking Design for a Generic Transport Aircraft with Structural Load Constraints

NASA Technical Reports Server (NTRS)

Burken, John J.; Frost, Susan A.; Taylor, Brian R.

2011-01-01

When designing control laws for systems with constraints added to the tracking performance, control allocation methods can be utilized. Control allocations methods are used when there are more command inputs than controlled variables. Constraints that require allocators are such task as; surface saturation limits, structural load limits, drag reduction constraints or actuator failures. Most transport aircraft have many actuated surfaces compared to the three controlled variables (such as angle of attack, roll rate & angle of side slip). To distribute the control effort among the redundant set of actuators a fixed mixer approach can be utilized or online control allocation techniques. The benefit of an online allocator is that constraints can be considered in the design whereas the fixed mixer cannot. However, an online control allocator mixer has a disadvantage of not guaranteeing a surface schedule, which can then produce ill defined loads on the aircraft. The load uncertainty and complexity has prevented some controller designs from using advanced allocation techniques. This paper considers actuator redundancy management for a class of over actuated systems with real-time structural load limits using linear quadratic tracking applied to the generic transport model. A roll maneuver example of an artificial load limit constraint is shown and compared to the same no load limitation maneuver.

Water Infrastructure Adaptation in New Urban Design: Possibilities and Constraints

EPA Science Inventory

Natural constraints, including climate change and dynamic socioeconomic development, can significantly impact the way we plan, design, and operate water infrastructure, thus its sustainability to deliver reliable quality water supplies and comply with environmental regulations. ...

Designing Measurement Studies under Budget Constraints: Controlling Error of Measurement and Power.

ERIC Educational Resources Information Center

Marcoulides, George A.

1995-01-01

A methodology is presented for minimizing the mean error variance-covariance component in studies with resource constraints. The method is illustrated using a one-facet multivariate design. Extensions to other designs are discussed. (SLD)

Ideal heat transfer conditions for tubular solar receivers with different design constraints

NASA Astrophysics Data System (ADS)

Kim, Jin-Soo; Potter, Daniel; Gardner, Wilson; Too, Yen Chean Soo; Padilla, Ricardo Vasquez

2017-06-01

The optimum heat transfer condition for a tubular type solar receiver was investigated for various receiver pipe size, heat transfer fluid, and design requirement and constraint(s). Heat transfer of a single plain receiver pipe exposed to concentrated solar energy was modelled along the flow path of the heat transfer fluid. Three different working fluids, molten salt, sodium, and supercritical carbon dioxide (sCO2) were considered in the case studies with different design conditions. The optimized ideal heat transfer condition was identified through fast iterative heat transfer calculations solving for all relevant radiation, conduction and convection heat transfers throughout the entire discretized tubular receiver. The ideal condition giving the best performance was obtained by finding the highest acceptable solar energy flux optimally distributed to meet different constraint(s), such as maximum allowable material temperature of receiver, maximum allowable film temperature of heat transfer fluid, and maximum allowable stress of receiver pipe material. The level of fluid side turbulence (represented by pressure drop in this study) was also optimized to give the highest net power production. As the outcome of the study gives information on the most ideal heat transfer condition, it can be used as a useful guideline for optimal design of a real receiver and solar field in a combined manner. The ideal heat transfer condition is especially important for high temperature tubular receivers (e.g. for supplying heat to high efficiency Brayton cycle turbines) where the system design and performance is tightly constrained by the receiver pipe material strength.

Parallel transmission RF pulse design with strict temperature constraints.

PubMed

Deniz, Cem M; Carluccio, Giuseppe; Collins, Christopher

2017-05-01

RF safety in parallel transmission (pTx) is generally ensured by imposing specific absorption rate (SAR) limits during pTx RF pulse design. There is increasing interest in using temperature to ensure safety in MRI. In this work, we present a local temperature correlation matrix formalism and apply it to impose strict constraints on maximum absolute temperature in pTx RF pulse design for head and hip regions. Electromagnetic field simulations were performed on the head and hip of virtual body models. Temperature correlation matrices were calculated for four different exposure durations ranging between 6 and 24 min using simulated fields and body-specific constants. Parallel transmission RF pulses were designed using either SAR or temperature constraints, and compared with each other and unconstrained RF pulse design in terms of excitation fidelity and safety. The use of temperature correlation matrices resulted in better excitation fidelity compared with the use of SAR in parallel transmission RF pulse design (for the 6 min exposure period, 8.8% versus 21.0% for the head and 28.0% versus 32.2% for the hip region). As RF exposure duration increases (from 6 min to 24 min), the benefit of using temperature correlation matrices on RF pulse design diminishes. However, the safety of the subject is always guaranteed (the maximum temperature was equal to 39°C). This trend was observed in both head and hip regions, where the perfusion rates are very different. Copyright © 2017 John Wiley & Sons, Ltd.

Design constraints of the LST fine guidance sensor

NASA Technical Reports Server (NTRS)

Wissinger, A. B.

1975-01-01

The LST Fine Guidance Sensor design is shaped by the rate of occurrence of suitable guide stars, the competition for telescope focal plane space with the Science Instruments, and the sensitivity of candidate image motion sensors. The relationship between these parameters is presented, and sensitivity to faint stars is shown to be of prime importance. An interferometric technique of image motion sensing is shown to have improved sensitivity and, therefore, a reduced focal plane area requirement in comparison with other candidate techniques (image-splitting prism and image dissector tube techniques). Another design requirement is speed in acquiring the guide star in order to maximize the time available for science observations. The design constraints are shown parametrically, and modelling results are presented.

Application of constraint-based satellite mission planning model in forest fire monitoring

NASA Astrophysics Data System (ADS)

Guo, Bingjun; Wang, Hongfei; Wu, Peng

2017-10-01

In this paper, a constraint-based satellite mission planning model is established based on the thought of constraint satisfaction. It includes target, request, observation, satellite, payload and other elements, with constraints linked up. The optimization goal of the model is to make full use of time and resources, and improve the efficiency of target observation. Greedy algorithm is used in the model solving to make observation plan and data transmission plan. Two simulation experiments are designed and carried out, which are routine monitoring of global forest fire and emergency monitoring of forest fires in Australia. The simulation results proved that the model and algorithm perform well. And the model is of good emergency response capability. Efficient and reasonable plan can be worked out to meet users' needs under complex cases of multiple payloads, multiple targets and variable priorities with this model.

Implementing Target Value Design.

PubMed

Alves, Thais da C L; Lichtig, Will; Rybkowski, Zofia K

2017-04-01

An alternative to the traditional way of designing projects is the process of target value design (TVD), which takes different departure points to start the design process. The TVD process starts with the client defining an allowable cost that needs to be met by the design and construction teams. An expected cost in the TVD process is defined through multiple interactions between multiple stakeholders who define wishes and others who define ways of achieving these wishes. Finally, a target cost is defined based on the expected profit the design and construction teams are expecting to make. TVD follows a series of continuous improvement efforts aimed at reaching the desired goals for the project and its associated target value cost. The process takes advantage of rapid cycles of suggestions, analyses, and implementation that starts with the definition of value for the client. In the traditional design process, the goal is to identify user preferences and find solutions that meet the needs of the client's expressed preferences. In the lean design process, the goal is to educate users about their values and advocate for a better facility over the long run; this way owners can help contractors and designers to identify better solutions. This article aims to inform the healthcare community about tools and techniques commonly used during the TVD process and how they can be used to educate and support project participants in developing better solutions to meet their needs now as well as in the future.

Modified Fully Utilized Design (MFUD) Method for Stress and Displacement Constraints

NASA Technical Reports Server (NTRS)

Patnaik, Surya; Gendy, Atef; Berke, Laszlo; Hopkins, Dale

1997-01-01

The traditional fully stressed method performs satisfactorily for stress-limited structural design. When this method is extended to include displacement limitations in addition to stress constraints, it is known as the fully utilized design (FUD). Typically, the FUD produces an overdesign, which is the primary limitation of this otherwise elegant method. We have modified FUD in an attempt to alleviate the limitation. This new method, called the modified fully utilized design (MFUD) method, has been tested successfully on a number of designs that were subjected to multiple loads and had both stress and displacement constraints. The solutions obtained with MFUD compare favorably with the optimum results that can be generated by using nonlinear mathematical programming techniques. The MFUD method appears to have alleviated the overdesign condition and offers the simplicity of a direct, fully stressed type of design method that is distinctly different from optimization and optimality criteria formulations. The MFUD method is being developed for practicing engineers who favor traditional design methods rather than methods based on advanced calculus and nonlinear mathematical programming techniques. The Integrated Force Method (IFM) was found to be the appropriate analysis tool in the development of the MFUD method. In this paper, the MFUD method and its optimality are presented along with a number of illustrative examples.

Rubber airplane: Constraint-based component-modeling for knowledge representation in computer-aided conceptual design

NASA Technical Reports Server (NTRS)

Kolb, Mark A.

1990-01-01

Viewgraphs on Rubber Airplane: Constraint-based Component-Modeling for Knowledge Representation in Computer Aided Conceptual Design are presented. Topics covered include: computer aided design; object oriented programming; airfoil design; surveillance aircraft; commercial aircraft; aircraft design; and launch vehicles.

Effect of leading-edge load constraints on the design and performance of supersonic wings

NASA Technical Reports Server (NTRS)

Darden, C. M.

1985-01-01

A theoretical and experimental investigation was conducted to assess the effect of leading-edge load constraints on supersonic wing design and performance. In the effort to delay flow separation and the formation of leading-edge vortices, two constrained, linear-theory optimization approaches were used to limit the loadings on the leading edge of a variable-sweep planform design. Experimental force and moment tests were made on two constrained camber wings, a flat uncambered wing, and an optimum design with no constraints. Results indicate that vortex strength and separation regions were mildest on the severely and moderately constrained wings.

Multidisciplinary design optimization of aircraft wing structures with aeroelastic and aeroservoelastic constraints

NASA Astrophysics Data System (ADS)

Jung, Sang-Young

Design procedures for aircraft wing structures with control surfaces are presented using multidisciplinary design optimization. Several disciplines such as stress analysis, structural vibration, aerodynamics, and controls are considered simultaneously and combined for design optimization. Vibration data and aerodynamic data including those in the transonic regime are calculated by existing codes. Flutter analyses are performed using those data. A flutter suppression method is studied using control laws in the closed-loop flutter equation. For the design optimization, optimization techniques such as approximation, design variable linking, temporary constraint deletion, and optimality criteria are used. Sensitivity derivatives of stresses and displacements for static loads, natural frequency, flutter characteristics, and control characteristics with respect to design variables are calculated for an approximate optimization. The objective function is the structural weight. The design variables are the section properties of the structural elements and the control gain factors. Existing multidisciplinary optimization codes (ASTROS* and MSC/NASTRAN) are used to perform single and multiple constraint optimizations of fully built up finite element wing structures. Three benchmark wing models are developed and/or modified for this purpose. The models are tested extensively.

Structural design optimization with survivability dependent constraints application: Primary wing box of a multi-role fighter

NASA Technical Reports Server (NTRS)

Dolvin, Douglas J.

1992-01-01

The superior survivability of a multirole fighter is dependent upon balanced integration of technologies for reduced vulnerability and susceptability. The objective is to develop a methodology for structural design optimization with survivability dependent constraints. The design criteria for optimization will be survivability in a tactical laser environment. The following analyses are studied to establish a dependent design relationship between structural weight and survivability: (1) develop a physically linked global design model of survivability variables; and (2) apply conventional constraints to quantify survivability dependent design. It was not possible to develop an exact approach which would include all aspects of survivability dependent design, therefore guidelines are offered for solving similar problems.

Conceptual Design Optimization of an Augmented Stability Aircraft Incorporating Dynamic Response Performance Constraints

NASA Technical Reports Server (NTRS)

Welstead, Jason

2014-01-01

This research focused on incorporating stability and control into a multidisciplinary de- sign optimization on a Boeing 737-class advanced concept called the D8.2b. A new method of evaluating the aircraft handling performance using quantitative evaluation of the sys- tem to disturbances, including perturbations, continuous turbulence, and discrete gusts, is presented. A multidisciplinary design optimization was performed using the D8.2b transport air- craft concept. The con guration was optimized for minimum fuel burn using a design range of 3,000 nautical miles. Optimization cases were run using xed tail volume coecients, static trim constraints, and static trim and dynamic response constraints. A Cessna 182T model was used to test the various dynamic analysis components, ensuring the analysis was behaving as expected. Results of the optimizations show that including stability and con- trol in the design process drastically alters the optimal design, indicating that stability and control should be included in conceptual design to avoid system level penalties later in the design process.

MRPrimerW: a tool for rapid design of valid high-quality primers for multiple target qPCR experiments

PubMed Central

Kim, Hyerin; Kang, NaNa; An, KyuHyeon; Koo, JaeHyung; Kim, Min-Soo

2016-01-01

Design of high-quality primers for multiple target sequences is essential for qPCR experiments, but is challenging due to the need to consider both homology tests on off-target sequences and the same stringent filtering constraints on the primers. Existing web servers for primer design have major drawbacks, including requiring the use of BLAST-like tools for homology tests, lack of support for ranking of primers, TaqMan probes and simultaneous design of primers against multiple targets. Due to the large-scale computational overhead, the few web servers supporting homology tests use heuristic approaches or perform homology tests within a limited scope. Here, we describe the MRPrimerW, which performs complete homology testing, supports batch design of primers for multi-target qPCR experiments, supports design of TaqMan probes and ranks the resulting primers to return the top-1 best primers to the user. To ensure high accuracy, we adopted the core algorithm of a previously reported MapReduce-based method, MRPrimer, but completely redesigned it to allow users to receive query results quickly in a web interface, without requiring a MapReduce cluster or a long computation. MRPrimerW provides primer design services and a complete set of 341 963 135 in silico validated primers covering 99% of human and mouse genes. Free access: http://MRPrimerW.com. PMID:27154272

Concurrent design of composite materials and structures considering thermal conductivity constraints

NASA Astrophysics Data System (ADS)

Jia, J.; Cheng, W.; Long, K.

2017-08-01

This article introduces thermal conductivity constraints into concurrent design. The influence of thermal conductivity on macrostructure and orthotropic composite material is extensively investigated using the minimum mean compliance as the objective function. To simultaneously control the amounts of different phase materials, a given mass fraction is applied in the optimization algorithm. Two phase materials are assumed to compete with each other to be distributed during the process of maximizing stiffness and thermal conductivity when the mass fraction constraint is small, where phase 1 has superior stiffness and thermal conductivity whereas phase 2 has a superior ratio of stiffness to density. The effective properties of the material microstructure are computed by a numerical homogenization technique, in which the effective elasticity matrix is applied to macrostructural analyses and the effective thermal conductivity matrix is applied to the thermal conductivity constraint. To validate the effectiveness of the proposed optimization algorithm, several three-dimensional illustrative examples are provided and the features under different boundary conditions are analysed.

Automated design optimization of supersonic airplane wing structures under dynamic constraints

NASA Technical Reports Server (NTRS)

Fox, R. L.; Miura, H.; Rao, S. S.

1972-01-01

The problems of the preliminary and first level detail design of supersonic aircraft wings are stated as mathematical programs and solved using automated optimum design techniques. The problem is approached in two phases: the first is a simplified equivalent plate model in which the envelope, planform and structural parameters are varied to produce a design, the second is a finite element model with fixed configuration in which the material distribution is varied. Constraints include flutter, aeroelastically computed stresses and deflections, natural frequency and a variety of geometric limitations.

Robust attitude control design for spacecraft under assigned velocity and control constraints.

PubMed

Hu, Qinglei; Li, Bo; Zhang, Youmin

2013-07-01

A novel robust nonlinear control design under the constraints of assigned velocity and actuator torque is investigated for attitude stabilization of a rigid spacecraft. More specifically, a nonlinear feedback control is firstly developed by explicitly taking into account the constraints on individual angular velocity components as well as external disturbances. Considering further the actuator misalignments and magnitude deviation, a modified robust least-squares based control allocator is employed to deal with the problem of distributing the previously designed three-axis moments over the available actuators, in which the focus of this control allocation is to find the optimal control vector of actuators by minimizing the worst-case residual error using programming algorithms. The attitude control performance using the controller structure is evaluated through a numerical example. Copyright © 2013 ISA. Published by Elsevier Ltd. All rights reserved.

State estimation with incomplete nonlinear constraint

NASA Astrophysics Data System (ADS)

Huang, Yuan; Wang, Xueying; An, Wei

2017-10-01

A problem of state estimation with a new constraints named incomplete nonlinear constraint is considered. The targets are often move in the curve road, if the width of road is neglected, the road can be considered as the constraint, and the position of sensors, e.g., radar, is known in advance, this info can be used to enhance the performance of the tracking filter. The problem of how to incorporate the priori knowledge is considered. In this paper, a second-order sate constraint is considered. A fitting algorithm of ellipse is adopted to incorporate the priori knowledge by estimating the radius of the trajectory. The fitting problem is transformed to the nonlinear estimation problem. The estimated ellipse function is used to approximate the nonlinear constraint. Then, the typical nonlinear constraint methods proposed in recent works can be used to constrain the target state. Monte-Carlo simulation results are presented to illustrate the effectiveness proposed method in state estimation with incomplete constraint.

Integrating ergonomics knowledge into business-driven design projects: The shaping of resource constraints in engineering consultancy.

PubMed

Hall-Andersen, Lene Bjerg; Neumann, Patrick; Broberg, Ole

2016-10-17

The integration of ergonomics knowledge into engineering projects leads to both healthier and more efficient workplaces. There is a lack of knowledge about integrating ergonomic knowledge into the design practice in engineering consultancies. This study explores how organizational resources can pose constraints for the integration of ergonomics knowledge into engineering design projects in a business-driven setting, and how ergonomists cope with these resource constraints. An exploratory case study in an engineering consultancy was conducted. A total of 27 participants were interviewed. Data were collected applying semi-structured interviews, observations, and documentary studies. Interviews were transcribed, coded, and categorized into themes. From the analysis five overall themes emerged as major constituents of resource constraints: 1) maximizing project revenue, 2) payment for ergonomics services, 3) value of ergonomic services, 4) role of the client, and 5) coping strategies to overcome resource constraints. We hypothesize that resource constraints were shaped due to sub-optimization of costs in design projects. The economical contribution of ergonomics measures was not evaluated in the entire life cycle of a designed workplace. Coping strategies included teaming up with engineering designers in the sales process or creating an alliance with ergonomists in the client organization.

MRPrimerW: a tool for rapid design of valid high-quality primers for multiple target qPCR experiments.

PubMed

Kim, Hyerin; Kang, NaNa; An, KyuHyeon; Koo, JaeHyung; Kim, Min-Soo

2016-07-08

Design of high-quality primers for multiple target sequences is essential for qPCR experiments, but is challenging due to the need to consider both homology tests on off-target sequences and the same stringent filtering constraints on the primers. Existing web servers for primer design have major drawbacks, including requiring the use of BLAST-like tools for homology tests, lack of support for ranking of primers, TaqMan probes and simultaneous design of primers against multiple targets. Due to the large-scale computational overhead, the few web servers supporting homology tests use heuristic approaches or perform homology tests within a limited scope. Here, we describe the MRPrimerW, which performs complete homology testing, supports batch design of primers for multi-target qPCR experiments, supports design of TaqMan probes and ranks the resulting primers to return the top-1 best primers to the user. To ensure high accuracy, we adopted the core algorithm of a previously reported MapReduce-based method, MRPrimer, but completely redesigned it to allow users to receive query results quickly in a web interface, without requiring a MapReduce cluster or a long computation. MRPrimerW provides primer design services and a complete set of 341 963 135 in silico validated primers covering 99% of human and mouse genes. Free access: http://MRPrimerW.com. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Sliding mode control based impact angle control guidance considering the seeker׳s field-of-view constraint.

PubMed

Wang, Xingliang; Zhang, Youan; Wu, Huali

2016-03-01

The problem of impact angle control guidance for a field-of-view constrained missile against non-maneuvering or maneuvering targets is solved by using the sliding mode control theory. The existing impact angle control guidance laws with field-of-view constraint are only applicable against stationary targets and most of them suffer abrupt-jumping of guidance command due to the application of additional guidance mode switching logic. In this paper, the field-of-view constraint is handled without using any additional switching logic. In particular, a novel time-varying sliding surface is first designed to achieve zero miss distance and zero impact angle error without violating the field-of-view constraint during the sliding mode phase. Then a control integral barrier Lyapunov function is used to design the reaching law so that the sliding mode can be reached within finite time and the field-of-view constraint is not violated during the reaching phase as well. A nonlinear extended state observer is constructed to estimate the disturbance caused by unknown target maneuver, and the undesirable chattering is alleviated effectively by using the estimation as a compensation item in the guidance law. The performance of the proposed guidance law is illustrated with simulations. Copyright © 2016 ISA. Published by Elsevier Ltd. All rights reserved.

Branch target buffer design and optimization

NASA Technical Reports Server (NTRS)

Perleberg, Chris H.; Smith, Alan J.

1993-01-01

Consideration is given to two major issues in the design of branch target buffers (BTBs), with the goal of achieving maximum performance for a given number of bits allocated to the BTB design. The first issue is BTB management; the second is what information to keep in the BTB. A number of solutions to these problems are reviewed, and various optimizations in the design of BTBs are discussed. Design target miss ratios for BTBs are developed, making it possible to estimate the performance of BTBs for real workloads.

Design of ligand-targeted nanoparticles for enhanced cancer targeting

NASA Astrophysics Data System (ADS)

Stefanick, Jared F.

Ligand-targeted nanoparticles are increasingly used as drug delivery vehicles for cancer therapy, yet have not consistently produced successful clinical outcomes. Although these inconsistencies may arise from differences in disease models and target receptors, nanoparticle design parameters can significantly influence therapeutic efficacy. By employing a multifaceted synthetic strategy to prepare peptide-targeted nanoparticles with high purity, reproducibility, and precisely controlled stoichiometry of functionalities, this work evaluates the roles of polyethylene glycol (PEG) coating, ethylene glycol (EG) peptide-linker length, peptide hydrophilicity, peptide density, and nanoparticle size on tumor targeting in a systematic manner. These parameters were analyzed in multiple disease models by targeting human epidermal growth factor receptor 2 (HER2) in breast cancer and very late antigen-4 (VLA-4) in multiple myeloma to demonstrate the widespread applicability of this approach. By increasing the hydrophilicity of the targeting peptide sequence and simultaneously optimizing the EG peptide-linker length, the in vitro cellular uptake of targeted liposomes was significantly enhanced. Specifically, including a short oligolysine chain adjacent to the targeting peptide sequence effectively increased cellular uptake ~80-fold using an EG6 peptide-linker compared to ~10-fold using an EG45 linker. In vivo, targeted liposomes prepared in a traditional manner lacking the oligolysine chain demonstrated similar biodistribution and tumor uptake to non-targeted liposomes. However, by including the oligolysine chain, targeted liposomes using an EG45 linker significantly improved tumor uptake ~8-fold over non-targeted liposomes, while the use of an EG6 linker decreased tumor accumulation and uptake, owing to differences in cellular uptake kinetics, clearance mechanisms, and binding site barrier effects. To further improve tumor targeting and enhance the selectivity of targeted

Coverage-based constraints for IMRT optimization

NASA Astrophysics Data System (ADS)

Mescher, H.; Ulrich, S.; Bangert, M.

2017-09-01

Radiation therapy treatment planning requires an incorporation of uncertainties in order to guarantee an adequate irradiation of the tumor volumes. In current clinical practice, uncertainties are accounted for implicitly with an expansion of the target volume according to generic margin recipes. Alternatively, it is possible to account for uncertainties by explicit minimization of objectives that describe worst-case treatment scenarios, the expectation value of the treatment or the coverage probability of the target volumes during treatment planning. In this note we show that approaches relying on objectives to induce a specific coverage of the clinical target volumes are inevitably sensitive to variation of the relative weighting of the objectives. To address this issue, we introduce coverage-based constraints for intensity-modulated radiation therapy (IMRT) treatment planning. Our implementation follows the concept of coverage-optimized planning that considers explicit error scenarios to calculate and optimize patient-specific probabilities q(\\hat{d}, \\hat{v}) of covering a specific target volume fraction \\hat{v} with a certain dose \\hat{d} . Using a constraint-based reformulation of coverage-based objectives we eliminate the trade-off between coverage and competing objectives during treatment planning. In-depth convergence tests including 324 treatment plan optimizations demonstrate the reliability of coverage-based constraints for varying levels of probability, dose and volume. General clinical applicability of coverage-based constraints is demonstrated for two cases. A sensitivity analysis regarding penalty variations within this planing study based on IMRT treatment planning using (1) coverage-based constraints, (2) coverage-based objectives, (3) probabilistic optimization, (4) robust optimization and (5) conventional margins illustrates the potential benefit of coverage-based constraints that do not require tedious adjustment of target volume objectives.

Bioengineering Strategies for Designing Targeted Cancer Therapies

PubMed Central

Wen, Xuejun

2014-01-01

The goals of bioengineering strategies for targeted cancer therapies are (1) to deliver a high dose of an anticancer drug directly to a cancer tumor, (2) to enhance drug uptake by malignant cells, and (3) to minimize drug uptake by nonmalignant cells. Effective cancer-targeting therapies will require both passive- and active targeting strategies and a thorough understanding of physiologic barriers to targeted drug delivery. Designing a targeted therapy includes the selection and optimization of a nanoparticle delivery vehicle for passive accumulation in tumors, a targeting moiety for active receptor-mediated uptake, and stimuli-responsive polymers for control of drug release. The future direction of cancer targeting is a combinatorial approach, in which targeting therapies are designed to use multiple targeting strategies. The combinatorial approach will enable combination therapy for delivery of multiple drugs and dual ligand targeting to improve targeting specificity. Targeted cancer treatments in development and the new combinatorial approaches show promise for improving targeted anticancer drug delivery and improving treatment outcomes. PMID:23768509

Design and Implementation of the Automated Rendezvous Targeting Algorithms for Orion

NASA Technical Reports Server (NTRS)

DSouza, Christopher; Weeks, Michael

2010-01-01

The Orion vehicle will be designed to perform several rendezvous missions: rendezvous with the ISS in Low Earth Orbit (LEO), rendezvous with the EDS/Altair in LEO, a contingency rendezvous with the ascent stage of the Altair in Low Lunar Orbit (LLO) and a contingency rendezvous in LLO with the ascent and descent stage in the case of an aborted lunar landing. Therefore, it is not difficult to realize that each of these scenarios imposes different operational, timing, and performance constraints on the GNC system. To this end, a suite of on-board guidance and targeting algorithms have been designed to meet the requirement to perform the rendezvous independent of communications with the ground. This capability is particularly relevant for the lunar missions, some of which may occur on the far side of the moon. This paper will describe these algorithms which are designed to be structured and arranged in such a way so as to be flexible and able to safely perform a wide variety of rendezvous trajectories. The goal of the algorithms is not to merely fly one specific type of canned rendezvous profile. Conversely, it was designed from the start to be general enough such that any type of trajectory profile can be flown.(i.e. a coelliptic profile, a stable orbit rendezvous profile, and a expedited LLO rendezvous profile, etc) all using the same rendezvous suite of algorithms. Each of these profiles makes use of maneuver types which have been designed with dual goals of robustness and performance. They are designed to converge quickly under dispersed conditions and they are designed to perform many of the functions performed on the ground today. The targeting algorithms consist of a phasing maneuver (NC), an altitude adjust maneuver (NH), and plane change maneuver (NPC), a coelliptic maneuver (NSR), a Lambert targeted maneuver, and several multiple-burn targeted maneuvers which combine one of more of these algorithms. The derivation and implementation of each of these

NIF Target Designs and OMEGA Experiments for Shock-Ignition Inertial Confinement Fusion

NASA Astrophysics Data System (ADS)

Anderson, K. S.

2012-10-01

Shock ignition (SI)footnotetextR. Betti et al., Phys. Rev. Lett. 98, 155001 (2007). is being pursued as a viable option to achieve ignition on the National Ignition Facility (NIF). Shock-ignition target designs require the addition of a high-intensity (˜5 x 10^15 W/cm^2) laser spike at the end of a low-adiabat assembly pulse to launch a spherically convergent strong shock to ignite the imploding capsule. Achieving ignition with SI requires the laser spike to generate an ignitor shock with a launching pressure typically in excess of ˜300 Mbar. At the high laser intensities required during the spike pulse, stimulated Raman (SRS) and Brillouin scattering (SBS) could reflect a significant fraction of the incident light. In addition, SRS and the two-plasmon-decay instability can accelerate hot electrons into the shell and preheat the fuel. Since the high-power spike occurs at the end of the pulse when the areal density of the shell is several tens of mg/cm^2, shock-ignition fuel layers are shielded against hot electrons with energies below 150 keV. This paper will present data for a set of OMEGA experiments that were designed to study laser--plasma interactions during the spike pulse. In addition, these experiments were used to demonstrate that high-pressure shocks can be produced in long-scale-length plasmas with SI-relevant intensities. Within the constraints imposed by the hydrodynamics of strong shock generation and the laser--plasma instabilities, target designs for SI experiments on the NIF will be presented. Two-dimensional radiation--hydrodynamic simulations of SI target designs for the NIF predict ignition in the polar-drive beam configuration at sub-MJ laser energies. Design robustness to various 1-D effects and 2-D nonuniformities has been characterized. This work was supported by the U.S. Department of Energy Office of Inertial Confinement Fusion under Cooperative Agreement No. DE-FC52-08NA28302.

Global Optimization of Low-Thrust Interplanetary Trajectories Subject to Operational Constraints

NASA Technical Reports Server (NTRS)

Englander, Jacob A.; Vavrina, Matthew A.; Hinckley, David

2016-01-01

Low-thrust interplanetary space missions are highly complex and there can be many locally optimal solutions. While several techniques exist to search for globally optimal solutions to low-thrust trajectory design problems, they are typically limited to unconstrained trajectories. The operational design community in turn has largely avoided using such techniques and has primarily focused on accurate constrained local optimization combined with grid searches and intuitive design processes at the expense of efficient exploration of the global design space. This work is an attempt to bridge the gap between the global optimization and operational design communities by presenting a mathematical framework for global optimization of low-thrust trajectories subject to complex constraints including the targeting of planetary landing sites, a solar range constraint to simplify the thermal design of the spacecraft, and a real-world multi-thruster electric propulsion system that must switch thrusters on and off as available power changes over the course of a mission.

A Model To Address Design Constraints of Training Delivered via Satellite. Study Number Eight.

ERIC Educational Resources Information Center

Montler, Joseph; Geroy, Gary D.

This document: summarizes how some companies are addressing the design constraints involved in using satellite technology to deliver training, presents a model aimed at examining cost effectiveness of the satellite option, and includes a guide to designing instructional materials for delivery by satellite. A survey of 39 organizations, 12…

RNAiFold2T: Constraint Programming design of thermo-IRES switches.

PubMed

Garcia-Martin, Juan Antonio; Dotu, Ivan; Fernandez-Chamorro, Javier; Lozano, Gloria; Ramajo, Jorge; Martinez-Salas, Encarnacion; Clote, Peter

2016-06-15

RNA thermometers (RNATs) are cis-regulatory elements that change secondary structure upon temperature shift. Often involved in the regulation of heat shock, cold shock and virulence genes, RNATs constitute an interesting potential resource in synthetic biology, where engineered RNATs could prove to be useful tools in biosensors and conditional gene regulation. Solving the 2-temperature inverse folding problem is critical for RNAT engineering. Here we introduce RNAiFold2T, the first Constraint Programming (CP) and Large Neighborhood Search (LNS) algorithms to solve this problem. Benchmarking tests of RNAiFold2T against existent programs (adaptive walk and genetic algorithm) inverse folding show that our software generates two orders of magnitude more solutions, thus allowing ample exploration of the space of solutions. Subsequently, solutions can be prioritized by computing various measures, including probability of target structure in the ensemble, melting temperature, etc. Using this strategy, we rationally designed two thermosensor internal ribosome entry site (thermo-IRES) elements, whose normalized cap-independent translation efficiency is approximately 50% greater at 42 °C than 30 °C, when tested in reticulocyte lysates. Translation efficiency is lower than that of the wild-type IRES element, which on the other hand is fully resistant to temperature shift-up. This appears to be the first purely computational design of functional RNA thermoswitches, and certainly the first purely computational design of functional thermo-IRES elements. RNAiFold2T is publicly available as part of the new release RNAiFold3.0 at https://github.com/clotelab/RNAiFold and http://bioinformatics.bc.edu/clotelab/RNAiFold, which latter has a web server as well. The software is written in C ++ and uses OR-Tools CP search engine. clote@bc.edu Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press.

An investigation of constraint-based component-modeling for knowledge representation in computer-aided conceptual design

NASA Technical Reports Server (NTRS)

Kolb, Mark A.

1990-01-01

Originally, computer programs for engineering design focused on detailed geometric design. Later, computer programs for algorithmically performing the preliminary design of specific well-defined classes of objects became commonplace. However, due to the need for extreme flexibility, it appears unlikely that conventional programming techniques will prove fruitful in developing computer aids for engineering conceptual design. The use of symbolic processing techniques, such as object-oriented programming and constraint propagation, facilitate such flexibility. Object-oriented programming allows programs to be organized around the objects and behavior to be simulated, rather than around fixed sequences of function- and subroutine-calls. Constraint propagation allows declarative statements to be understood as designating multi-directional mathematical relationships among all the variables of an equation, rather than as unidirectional assignments to the variable on the left-hand side of the equation, as in conventional computer programs. The research has concentrated on applying these two techniques to the development of a general-purpose computer aid for engineering conceptual design. Object-oriented programming techniques are utilized to implement a user-extensible database of design components. The mathematical relationships which model both geometry and physics of these components are managed via constraint propagation. In addition, to this component-based hierarchy, special-purpose data structures are provided for describing component interactions and supporting state-dependent parameters. In order to investigate the utility of this approach, a number of sample design problems from the field of aerospace engineering were implemented using the prototype design tool, Rubber Airplane. The additional level of organizational structure obtained by representing design knowledge in terms of components is observed to provide greater convenience to the program user, and to

Design of the LBNF Beamline Target Station

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tariq, S.; Ammigan, K.; Anderson, K.

2016-10-01

The Long Baseline Neutrino Facility (LBNF) project will build a beamline located at Fermilab to create and aim an intense neutrino beam of appropriate energy range toward the DUNE detectors at the SURF facility in Lead, South Dakota. Neutrino production starts in the Target Station, which consists of a solid target, magnetic focusing horns, and the associated sub-systems and shielding infrastructure. Protons hit the target producing mesons which are then focused by the horns into a helium-filled decay pipe where they decay into muons and neutrinos. The target and horns are encased in actively cooled steel and concrete shielding inmore » a chamber called the target chase. The reference design chase is filled with air, but nitrogen and helium are being evaluated as alternatives. A replaceable beam window separates the decay pipe from the target chase. The facility is designed for initial operation at 1.2 MW, with the ability to upgrade to 2.4 MW, and is taking advantage of the experience gained by operating Fermilab’s NuMI facility. We discuss here the design status, associated challenges, and ongoing R&D and physics-driven component optimization of the Target Station.« less

Analytical design of an industrial two-term controller for optimal regulatory control of open-loop unstable processes under operational constraints.

PubMed

Tchamna, Rodrigue; Lee, Moonyong

2018-01-01

This paper proposes a novel optimization-based approach for the design of an industrial two-term proportional-integral (PI) controller for the optimal regulatory control of unstable processes subjected to three common operational constraints related to the process variable, manipulated variable and its rate of change. To derive analytical design relations, the constrained optimal control problem in the time domain was transformed into an unconstrained optimization problem in a new parameter space via an effective parameterization. The resulting optimal PI controller has been verified to yield optimal performance and stability of an open-loop unstable first-order process under operational constraints. The proposed analytical design method explicitly takes into account the operational constraints in the controller design stage and also provides useful insights into the optimal controller design. Practical procedures for designing optimal PI parameters and a feasible constraint set exclusive of complex optimization steps are also proposed. The proposed controller was compared with several other PI controllers to illustrate its performance. The robustness of the proposed controller against plant-model mismatch has also been investigated. Copyright © 2018 ISA. Published by Elsevier Ltd. All rights reserved.

Powered Descent Guidance with General Thrust-Pointing Constraints

NASA Technical Reports Server (NTRS)

Carson, John M., III; Acikmese, Behcet; Blackmore, Lars

2013-01-01

The Powered Descent Guidance (PDG) algorithm and software for generating Mars pinpoint or precision landing guidance profiles has been enhanced to incorporate thrust-pointing constraints. Pointing constraints would typically be needed for onboard sensor and navigation systems that have specific field-of-view requirements to generate valid ground proximity and terrain-relative state measurements. The original PDG algorithm was designed to enforce both control and state constraints, including maximum and minimum thrust bounds, avoidance of the ground or descent within a glide slope cone, and maximum speed limits. The thrust-bound and thrust-pointing constraints within PDG are non-convex, which in general requires nonlinear optimization methods to generate solutions. The short duration of Mars powered descent requires guaranteed PDG convergence to a solution within a finite time; however, nonlinear optimization methods have no guarantees of convergence to the global optimal or convergence within finite computation time. A lossless convexification developed for the original PDG algorithm relaxed the non-convex thrust bound constraints. This relaxation was theoretically proven to provide valid and optimal solutions for the original, non-convex problem within a convex framework. As with the thrust bound constraint, a relaxation of the thrust-pointing constraint also provides a lossless convexification that ensures the enhanced relaxed PDG algorithm remains convex and retains validity for the original nonconvex problem. The enhanced PDG algorithm provides guidance profiles for pinpoint and precision landing that minimize fuel usage, minimize landing error to the target, and ensure satisfaction of all position and control constraints, including thrust bounds and now thrust-pointing constraints.

LBNF 1.2 MW Target: Conceptual Design & Fabrication

DOE Office of Scientific and Technical Information (OSTI.GOV)

Crowley, C.; Ammigan, K.; Anderson, K.

2015-06-01

Fermilab’s Long-Baseline Neutrino Facility (LBNF) will utilize a modified design based on the NuMI low energy target that is reconfigured to accommodate beam operation at 1.2 MW. Achieving this power with a graphite target material and ancillary systems originally rated for 400 kW requires several design changes and R&D efforts related to material bonding and electrical isolation. Target cooling, structural design, and fabrication techniques must address higher stresses and heat loads that will be present during 1.2 MW operation, as the assembly will be subject to cyclic loads and thermal expansion. Mitigations must be balanced against compromises in neutrino yield.more » Beam monitoring and subsystem instrumentation will be updated and added to ensure confidence in target positioning and monitoring. Remote connection to the target hall support structure must provide for the eventual upgrade to a 2.4 MW target design, without producing excessive radioactive waste or unreasonable exposure to technicians during reconfiguration. Current designs and assembly layouts will be presented, in addition to current findings on processes and possibilities for prototype and final assembly fabrication.« less

LBNF 1.2 MW TARGET: CONCEPTUAL DESIGN & FABRICATION

DOE Office of Scientific and Technical Information (OSTI.GOV)

Crowley, Cory F.; Ammigan, K.; Anderson, K.

2015-06-29

Fermilab’s Long-Baseline Neutrino Facility (LBNF) will utilize a modified design based on the NuMI low energy target that is reconfigured to accommodate beam operation at 1.2 MW. Achieving this power with a graphite target material and ancillary systems originally rated for 400 kW requires several design changes and R&D efforts related to material bonding and electrical isolation. Target cooling, structural design, and fabrication techniques must address higher stresses and heat loads that will be present during 1.2 MW operation, as the assembly will be subject to cyclic loads and thermal expansion. Mitigations must be balanced against compromises in neutrino yield.more » Beam monitoring and subsystem instrumentation will be updated and added to ensure confidence in target positioning and monitoring. Remote connection to the target hall support structure must provide for the eventual upgrade to a 2.4 MW target design, without producing excessive radioactive waste or unreasonable exposure to technicians during reconfiguration. Current designs and assembly layouts will be presented, in addition to current findings on processes and possibilities for prototype and final assembly fabrication.« less

Disassemblability modeling technology of configurable product based on disassembly constraint relation weighted design structure matrix(DSM)

NASA Astrophysics Data System (ADS)

Qiu, Lemiao; Liu, Xiaojian; Zhang, Shuyou; Sun, Liangfeng

2014-05-01

The current research of configurable product disassemblability focuses on disassemblability evaluation and disassembly sequence planning. Little work has been done on quantitative analysis of configurable product disassemblability. The disassemblability modeling technology for configurable product based on disassembly constraint relation weighted design structure matrix (DSM) is proposed. Major factors affecting the disassemblability of configurable product are analyzed, and the disassembling degrees between components in configurable product are obtained by calculating disassembly entropies such as joint type, joint quantity, disassembly path, disassembly accessibility and material compatibility. The disassembly constraint relation weighted DSM of configurable product is constructed and configuration modules are formed by matrix decomposition and tearing operations. The disassembly constraint relation in configuration modules is strong coupling, and the disassembly constraint relation between modules is weak coupling, and the disassemblability configuration model is constructed based on configuration module. Finally, taking a hydraulic forging press as an example, the decomposed weak coupling components are used as configuration modules alone, components with a strong coupling are aggregated into configuration modules, and the disassembly sequence of components inside configuration modules is optimized by tearing operation. A disassemblability configuration model of the hydraulic forging press is constructed. By researching the disassemblability modeling technology of product configuration design based on disassembly constraint relation weighted DSM, the disassembly property in maintenance, recycling and reuse of configurable product are optimized.

A novel guidance law using fast terminal sliding mode control with impact angle constraints.

PubMed

Sun, Lianghua; Wang, Weihong; Yi, Ran; Xiong, Shaofeng

2016-09-01

This paper is concerned with the question of, for a missile interception with impact angle constraints, how to design a guidance law. Firstly, missile interception with impact angle constraints is modeled; secondly, a novel guidance law using fast terminal sliding mode control based on extended state observer is proposed to optimize the trajectory and time of interception; finally, for stationary targets, constant velocity targets and maneuvering targets, the guidance law and the stability of the closed loop system is analyzed and the stability of the closed loop system is analyzed, respectively. Simulation results show that when missile and target are on a collision course, the novel guidance law using fast terminal sliding mode control with extended state observer has more optimized trajectory and effectively reduces the time of interception which has a great significance in modern warfare. Copyright © 2016 ISA. Published by Elsevier Ltd. All rights reserved.

Mission Implementation Constraints on Planetary Muon Radiography

NASA Technical Reports Server (NTRS)

Jones, Cathleen E.; Kedar, Sharon; Naudet, Charles; Webb, Frank

2011-01-01

Cost: Use heritage hardware, especially use a tested landing system to reduce cost (Phoenix or MSL EDL stage). The sky crane technology delivers higher mass to the surface and enables reaching targets at higher elevation, but at a higher mission cost. Rover vs. Stationary Lander: Rover-mounted instrument enables tomography, but the increased weight of the rover reduces the allowable payload weight. Mass is the critical design constraint for an instrument for a planetary mission. Many factors that are minor factors or do not enter into design considerations for terrestrial operation are important for a planetary application. (Landing site, diurnal temperature variation, instrument portability, shock/vibration)

Design of a Covert RFID Tag Network for Target Discovery and Target Information Routing

PubMed Central

Pan, Qihe; Narayanan, Ram M.

2011-01-01

Radio frequency identification (RFID) tags are small electronic devices working in the radio frequency range. They use wireless radio communications to automatically identify objects or people without the need for line-of-sight or contact, and are widely used in inventory tracking, object location, environmental monitoring. This paper presents a design of a covert RFID tag network for target discovery and target information routing. In the design, a static or very slowly moving target in the field of RFID tags transmits a distinct pseudo-noise signal, and the RFID tags in the network collect the target information and route it to the command center. A map of each RFID tag’s location is saved at command center, which can determine where a RFID tag is located based on each RFID tag’s ID. We propose the target information collection method with target association and clustering, and we also propose the information routing algorithm within the RFID tag network. The design and operation of the proposed algorithms are illustrated through examples. Simulation results demonstrate the effectiveness of the design. PMID:22163693

Design of a covert RFID tag network for target discovery and target information routing.

PubMed

Pan, Qihe; Narayanan, Ram M

2011-01-01

Radio frequency identification (RFID) tags are small electronic devices working in the radio frequency range. They use wireless radio communications to automatically identify objects or people without the need for line-of-sight or contact, and are widely used in inventory tracking, object location, environmental monitoring. This paper presents a design of a covert RFID tag network for target discovery and target information routing. In the design, a static or very slowly moving target in the field of RFID tags transmits a distinct pseudo-noise signal, and the RFID tags in the network collect the target information and route it to the command center. A map of each RFID tag's location is saved at command center, which can determine where a RFID tag is located based on each RFID tag's ID. We propose the target information collection method with target association and clustering, and we also propose the information routing algorithm within the RFID tag network. The design and operation of the proposed algorithms are illustrated through examples. Simulation results demonstrate the effectiveness of the design.

Constraints complicate centrifugal compressor depressurization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Key, B.; Colbert, F.L.

1993-05-10

Blowdown of a centrifugal compressor is complicated by process constraints that might require slowing the depressurization rate and by mechanical constraints for which a faster rate might be preferred. The paper describes design constraints such as gas leaks; thrust-bearing overload; system constraints; flare extinguishing; heat levels; and pressure drop.

WINDOWAC (Wing Design Optimization With Aeroelastic Constraints): Program manual

NASA Technical Reports Server (NTRS)

Haftka, R. T.; Starnes, J. H., Jr.

1974-01-01

User and programer documentation for the WIDOWAC programs is given. WIDOWAC may be used for the design of minimum mass wing structures subjected to flutter, strength, and minimum gage constraints. The wing structure is modeled by finite elements, flutter conditions may be both subsonic and supersonic, and mathematical programing methods are used for the optimization procedure. The user documentation gives general directions on how the programs may be used and describes their limitations; in addition, program input and output are described, and example problems are presented. A discussion of computational algorithms and flow charts of the WIDOWAC programs and major subroutines is also given.

Design Constraints on a Synthetic Metabolism

PubMed Central

Bilgin, Tugce; Wagner, Andreas

2012-01-01

A metabolism is a complex network of chemical reactions that converts sources of energy and chemical elements into biomass and other molecules. To design a metabolism from scratch and to implement it in a synthetic genome is almost within technological reach. Ideally, a synthetic metabolism should be able to synthesize a desired spectrum of molecules at a high rate, from multiple different nutrients, while using few chemical reactions, and producing little or no waste. Not all of these properties are achievable simultaneously. We here use a recently developed technique to create random metabolic networks with pre-specified properties to quantify trade-offs between these and other properties. We find that for every additional molecule to be synthesized a network needs on average three additional reactions. For every additional carbon source to be utilized, it needs on average two additional reactions. Networks able to synthesize 20 biomass molecules from each of 20 alternative sole carbon sources need to have at least 260 reactions. This number increases to 518 reactions for networks that can synthesize more than 60 molecules from each of 80 carbon sources. The maximally achievable rate of biosynthesis decreases by approximately 5 percent for every additional molecule to be synthesized. Biochemically related molecules can be synthesized at higher rates, because their synthesis produces less waste. Overall, the variables we study can explain 87 percent of variation in network size and 84 percent of the variation in synthesis rate. The constraints we identify prescribe broad boundary conditions that can help to guide synthetic metabolism design. PMID:22768162

A methodology for the efficient integration of transient constraints in the design of aircraft dynamic systems

NASA Astrophysics Data System (ADS)

Phan, Leon L.

The motivation behind this thesis mainly stems from previous work performed at Hispano-Suiza (Safran Group) in the context of the European research project "Power Optimised Aircraft". Extensive testing on the COPPER Bird RTM, a test rig designed to characterize aircraft electrical networks, demonstrated the relevance of transient regimes in the design and development of dynamic systems. Transient regimes experienced by dynamic systems may have severe impacts on the operation of the aircraft. For example, the switching on of a high electrical load might cause a network voltage drop inducing a loss of power available to critical aircraft systems. These transient behaviors are thus often regulated by dynamic constraints, requiring the dynamic signals to remain within bounds whose values vary with time. The verification of these peculiar types of constraints, which generally requires high-fidelity time-domain simulation, intervenes late in the system development process, thus potentially causing costly design iterations. The research objective of this thesis is to develop a methodology that integrates the verification of dynamic constraints in the early specification of dynamic systems. In order to circumvent the inefficiencies of time-domain simulation, multivariate dynamic surrogate models of the original time-domain simulation models are generated, building on a nonlinear system identification technique using wavelet neural networks (or wavenets), which allow the multiscale nature of transient signals to be captured. However, training multivariate wavenets can become computationally prohibitive as the number of design variables increases. Therefore, an alternate approach is formulated, in which dynamic surrogate models using sigmoid-based neural networks are used to emulate the transient behavior of the envelopes of the time-domain response. Thus, in order to train the neural network, the envelopes are extracted by first separating the scales of the dynamic response

An efficient constraint to account for mistuning effects in the optimal design of engine rotors

NASA Technical Reports Server (NTRS)

Murthy, Durbha V.; Pierre, Christophe; Ottarsson, Gisli

1992-01-01

Blade-to-blade differences in structural properties, unavoidable in practice due to manufacturing tolerances, can have significant influence on the vibratory response of engine rotor blade. Accounting for these differences, also known as mistuning, in design and in optimization procedures is generally not possible. This note presents an easily calculated constraint that can be used in design and optimization procedures to control the sensitivity of final designs to mistuning.

A Method for the Constrained Design of Natural Laminar Flow Airfoils

NASA Technical Reports Server (NTRS)

Green, Bradford E.; Whitesides, John L.; Campbell, Richard L.; Mineck, Raymond E.

1996-01-01

A fully automated iterative design method has been developed by which an airfoil with a substantial amount of natural laminar flow can be designed, while maintaining other aerodynamic and geometric constraints. Drag reductions have been realized using the design method over a range of Mach numbers, Reynolds numbers and airfoil thicknesses. The thrusts of the method are its ability to calculate a target N-Factor distribution that forces the flow to undergo transition at the desired location; the target-pressure-N-Factor relationship that is used to reduce the N-Factors in order to prolong transition; and its ability to design airfoils to meet lift, pitching moment, thickness and leading-edge radius constraints while also being able to meet the natural laminar flow constraint. The method uses several existing CFD codes and can design a new airfoil in only a few days using a Silicon Graphics IRIS workstation.

Impact of structural optimization with aeroelastic/multidisciplinary constraints on helicopter rotor design

NASA Technical Reports Server (NTRS)

Friedmann, Peretz P.

1992-01-01

This paper presents a review of the state-of-the-art in the field of structural optimization when applied to vibration reduction of helicopters in forward flight with aeroelastic and multidisciplinary constraints. It emphasizes the application of the modern approach where the optimization is formulated as a mathematical programming problem and the objective function consists of the vibration levels at the hub and behavior constraints are imposed on the blade frequencies, aeroelastic stability margins as well as on a number of additional ingredients which can have a significant effect on the overall performance and flight mechanics of the helicopter. It is shown that the integrated multidisciplinary optimization of rotorcraft offers the potential for substantial improvements which can be achieved by careful preliminary design and analysis without requiring additional hardware such as rotor vibration absorbers or isolation systems.

Designing divertor targets for uniform power load

NASA Astrophysics Data System (ADS)

Dekeyser, W.; Reiter, D.; Baelmans, M.

2015-08-01

Divertor design for next step fusion reactors heavily relies on 2D edge plasma modeling with codes as e.g. B2-EIRENE. While these codes are typically used in a design-by-analysis approach, in previous work we have shown that divertor design can alternatively be posed as a mathematical optimization problem, and solved very efficiently using adjoint methods adapted from computational aerodynamics. This approach has been applied successfully to divertor target shape design for more uniform power load. In this paper, the concept is further extended to include all contributions to the target power load, with particular focus on radiation. In a simplified test problem, we show the potential benefits of fully including the radiation load in the design cycle as compared to only assessing this load in a post-processing step.

Shock Ignition Target Design for Inertial Fusion Energy

DTIC Science & Technology

2010-01-01

Shock ignition target design for inertial fusion energy Andrew J. Schmitt,1, a) Jason W. Bates,1 Steven P. Obenschain,1 Steven T. Zalesak,2 and David...2010 to 00-00-2010 4. TITLE AND SUBTITLE Shock ignition target design for inertial fusion energy 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM

Nanogel Carrier Design for Targeted Drug Delivery

PubMed Central

Eckmann, D. M.; Composto, R. J.; Tsourkas, A.; Muzykantov, V. R.

2014-01-01

Polymer-based nanogel formulations offer features attractive for drug delivery, including ease of synthesis, controllable swelling and viscoelasticity as well as drug loading and release characteristics, passive and active targeting, and the ability to formulate nanogel carriers that can respond to biological stimuli. These unique features and low toxicity make the nanogels a favorable option for vascular drug targeting. In this review, we address key chemical and biological aspects of nanogel drug carrier design. In particular, we highlight published studies of nanogel design, descriptions of nanogel functional characteristics and their behavior in biological models. These studies form a compendium of information that supports the scientific and clinical rationale for development of this carrier for targeted therapeutic interventions. PMID:25485112

Optimal Design of Gradient Materials and Bi-Level Optimization of Topology Using Targets (BOTT)

NASA Astrophysics Data System (ADS)

Garland, Anthony

The objective of this research is to understand the fundamental relationships necessary to develop a method to optimize both the topology and the internal gradient material distribution of a single object while meeting constraints and conflicting objectives. Functionally gradient material (FGM) objects possess continuous varying material properties throughout the object, and they allow an engineer to tailor individual regions of an object to have specific mechanical properties by locally modifying the internal material composition. A variety of techniques exists for topology optimization, and several methods exist for FGM optimization, but combining the two together is difficult. Understanding the relationship between topology and material gradient optimization enables the selection of an appropriate model and the development of algorithms, which allow engineers to design high-performance parts that better meet design objectives than optimized homogeneous material objects. For this research effort, topology optimization means finding the optimal connected structure with an optimal shape. FGM optimization means finding the optimal macroscopic material properties within an object. Tailoring the material constitutive matrix as a function of position results in gradient properties. Once, the target macroscopic properties are known, a mesostructure or a particular material nanostructure can be found which gives the target material properties at each macroscopic point. This research demonstrates that topology and gradient materials can both be optimized together for a single part. The algorithms use a discretized model of the domain and gradient based optimization algorithms. In addition, when considering two conflicting objectives the algorithms in this research generate clear 'features' within a single part. This tailoring of material properties within different areas of a single part (automated design of 'features') using computational design tools is a novel benefit

Reliability Assessment of a Robust Design Under Uncertainty for a 3-D Flexible Wing

NASA Technical Reports Server (NTRS)

Gumbert, Clyde R.; Hou, Gene J. -W.; Newman, Perry A.

2003-01-01

The paper presents reliability assessment results for the robust designs under uncertainty of a 3-D flexible wing previously reported by the authors. Reliability assessments (additional optimization problems) of the active constraints at the various probabilistic robust design points are obtained and compared with the constraint values or target constraint probabilities specified in the robust design. In addition, reliability-based sensitivity derivatives with respect to design variable mean values are also obtained and shown to agree with finite difference values. These derivatives allow one to perform reliability based design without having to obtain second-order sensitivity derivatives. However, an inner-loop optimization problem must be solved for each active constraint to find the most probable point on that constraint failure surface.

Role of Bioreactor Technology in Tissue Engineering for Clinical Use and Therapeutic Target Design.

PubMed

Selden, Clare; Fuller, Barry

2018-04-24

Micro and small bioreactors are well described for use in bioprocess development in pre-production manufacture, using ultra-scale down and microfluidic methodology. However, the use of bioreactors to understand normal and pathophysiology by definition must be very different, and the constraints of the physiological environment influence such bioreactor design. This review considers the key elements necessary to enable bioreactors to address three main areas associated with biological systems. All entail recreation of the in vivo cell niche as faithfully as possible, so that they may be used to study molecular and cellular changes in normal physiology, with a view to creating tissue-engineered grafts for clinical use; understanding the pathophysiology of disease at the molecular level; defining possible therapeutic targets; and enabling appropriate pharmaceutical testing on a truly representative organoid, thus enabling better drug design, and simultaneously creating the potential to reduce the numbers of animals in research. The premise explored is that not only cellular signalling cues, but also mechano-transduction from mechanical cues, play an important role.

Targeting targeted agents: open issues for clinical trial design.

PubMed

Bria, Emilio; Di Maio, Massimo; Carlini, Paolo; Cuppone, Federica; Giannarelli, Diana; Cognetti, Francesco; Milella, Michele

2009-05-22

Molecularly targeted agents for the treatment of solid tumors had entered the market in the last 5 years, with a great impact upon both the scientific community and the society. Many randomized phase III trials conducted in recent years with new targeted agents, despite previous data coming from preclinical research and from phase II trials were often promising, have produced disappointingly negative results. Some other trials have actually met their primary endpoint, demonstrating a statistically significant result favouring the experimental treatment. Unfortunately, with a few relevant exceptions, this advantage is often small, if not negligible, in absolute terms. The difference between statistical significance and clinical relevance should always be considered when translating clinical trials' results in the practice. The reason why this 'revolution' did not significantly impact on cancer treatment to displace chemotherapy from the patient' bedside is in part due to complicated, and in many cases, unknown, mechanisms of action of such drugs; indeed, the traditional way the clinical investigators were used to test the efficacy of 'older' chemotherapeutics, has become 'out of date' from the methodological perspective. As these drugs should be theoretically tailored upon featured bio-markers expressed by the patients, the clinical trial design should follow new rules based upon stronger hypotheses than those developed so far. Indeed, the early phases of basic and clinical drug development are crucial in the correct process which is able to correctly identify the target (when present). Targeted trial designs can result in easier studies, with less, better selected, and supported by stronger proofs of response evidences, patients, in order to not waste time and resources.

An approach to constrained aerodynamic design with application to airfoils

NASA Technical Reports Server (NTRS)

Campbell, Richard L.

1992-01-01

An approach was developed for incorporating flow and geometric constraints into the Direct Iterative Surface Curvature (DISC) design method. In this approach, an initial target pressure distribution is developed using a set of control points. The chordwise locations and pressure levels of these points are initially estimated either from empirical relationships and observed characteristics of pressure distributions for a given class of airfoils or by fitting the points to an existing pressure distribution. These values are then automatically adjusted during the design process to satisfy the flow and geometric constraints. The flow constraints currently available are lift, wave drag, pitching moment, pressure gradient, and local pressure levels. The geometric constraint options include maximum thickness, local thickness, leading-edge radius, and a 'glove' constraint involving inner and outer bounding surfaces. This design method was also extended to include the successive constraint release (SCR) approach to constrained minimization.

Optical design of the National Ignition Facility main laser and switchyard/target area beam transport systems

NASA Astrophysics Data System (ADS)

Miller, John L.; English, R. Edward, Jr.; Korniski, Ronald J.; Rodgers, J. Michael

1999-07-01

The optical design of the main laser and transport mirror sections of the National Ignition Facility are described. For the main laser the configuration, layout constraints, multiple beam arrangement, pinhole layout and beam paths, clear aperture budget, ray trace models, alignment constraints, lens designs, wavefront performance, and pupil aberrations are discussed. For the transport mirror system the layout, alignment controls and clear aperture budget are described.

Changing paradigm from one target one ligand towards multi target directed ligand design for key drug targets of Alzheimer disease: An important role of Insilco methods in multi target directed ligands design.

PubMed

Kumar, Akhil; Tiwari, Ashish; Sharma, Ashok

2018-03-15

Alzheimer disease (AD) is now considered as a multifactorial neurodegenerative disorder and rapidly increasing to an alarming situation and causing higher death rate. One target one ligand hypothesis is not able to provide complete solution of AD due to multifactorial nature of disease and one target one drug seems to fail to provide better treatment against AD. Moreover, current available treatments are limited and most of the upcoming treatments under clinical trials are based on modulating single target. So the current AD drug discovery research shifting towards new approach for better solution that simultaneously modulate more than one targets in the neurodegenerative cascade. This can be achieved by network pharmacology, multi-modal therapies, multifaceted, and/or the more recently proposed term "multi-targeted designed drugs. Drug discovery project is tedious, costly and long term project. Moreover, multi target AD drug discovery added extra challenges such as good binding affinity of ligands for multiple targets, optimal ADME/T properties, no/less off target side effect and crossing of the blood brain barrier. These hurdles may be addressed by insilico methods for efficient solution in less time and cost as computational methods successfully applied to single target drug discovery project. Here we are summarizing some of the most prominent and computationally explored single target against AD and further we discussed successful example of dual or multiple inhibitors for same targets. Moreover we focused on ligand and structure based computational approach to design MTDL against AD. However is not an easy task to balance dual activity in a single molecule but computational approach such as virtual screening docking, QSAR, simulation and free energy are useful in future MTDLs drug discovery alone or in combination with fragment based method. However, rational and logical implementations of computational drug designing methods are capable of assisting AD drug

Circular revisit orbits design for responsive mission over a single target

NASA Astrophysics Data System (ADS)

Li, Taibo; Xiang, Junhua; Wang, Zhaokui; Zhang, Yulin

2016-10-01

The responsive orbits play a key role in addressing the mission of Operationally Responsive Space (ORS) because of their capabilities. These capabilities are usually focused on supporting specific targets as opposed to providing global coverage. One subtype of responsive orbits is repeat coverage orbit which is nearly circular in most remote sensing applications. This paper deals with a special kind of repeating ground track orbit, referred to as circular revisit orbit. Different from traditional repeat coverage orbits, a satellite on circular revisit orbit can visit a target site at both the ascending and descending stages in one revisit cycle. This typology of trajectory allows a halving of the traditional revisit time and does a favor to get useful information for responsive applications. However the previous reported numerical methods in some references often cost lots of computation or fail to obtain such orbits. To overcome this difficulty, an analytical method to determine the existence conditions of the solutions to revisit orbits is presented in this paper. To this end, the mathematical model of circular revisit orbit is established under the central gravity model and the J2 perturbation. A constraint function of the circular revisit orbit is introduced, and the monotonicity of that function has been studied. The existent conditions and the number of such orbits are naturally worked out. Taking the launch cost into consideration, optimal design model of circular revisit orbit is established to achieve a best orbit which visits a target twice a day in the morning and in the afternoon respectively for several days. The result shows that it is effective to apply circular revisit orbits in responsive application such as reconnoiter of natural disaster.

Direct handling of equality constraints in multilevel optimization

NASA Technical Reports Server (NTRS)

Renaud, John E.; Gabriele, Gary A.

1990-01-01

In recent years there have been several hierarchic multilevel optimization algorithms proposed and implemented in design studies. Equality constraints are often imposed between levels in these multilevel optimizations to maintain system and subsystem variable continuity. Equality constraints of this nature will be referred to as coupling equality constraints. In many implementation studies these coupling equality constraints have been handled indirectly. This indirect handling has been accomplished using the coupling equality constraints' explicit functional relations to eliminate design variables (generally at the subsystem level), with the resulting optimization taking place in a reduced design space. In one multilevel optimization study where the coupling equality constraints were handled directly, the researchers encountered numerical difficulties which prevented their multilevel optimization from reaching the same minimum found in conventional single level solutions. The researchers did not explain the exact nature of the numerical difficulties other than to associate them with the direct handling of the coupling equality constraints. The coupling equality constraints are handled directly, by employing the Generalized Reduced Gradient (GRG) method as the optimizer within a multilevel linear decomposition scheme based on the Sobieski hierarchic algorithm. Two engineering design examples are solved using this approach. The results show that the direct handling of coupling equality constraints in a multilevel optimization does not introduce any problems when the GRG method is employed as the internal optimizer. The optimums achieved are comparable to those achieved in single level solutions and in multilevel studies where the equality constraints have been handled indirectly.

Adaptive bi-level programming for optimal gene knockouts for targeted overproduction under phenotypic constraints

PubMed Central

2013-01-01

Background Optimization procedures to identify gene knockouts for targeted biochemical overproduction have been widely in use in modern metabolic engineering. Flux balance analysis (FBA) framework has provided conceptual simplifications for genome-scale dynamic analysis at steady states. Based on FBA, many current optimization methods for targeted bio-productions have been developed under the maximum cell growth assumption. The optimization problem to derive gene knockout strategies recently has been formulated as a bi-level programming problem in OptKnock for maximum targeted bio-productions with maximum growth rates. However, it has been shown that knockout mutants in fact reach the steady states with the minimization of metabolic adjustment (MOMA) from the corresponding wild-type strains instead of having maximal growth rates after genetic or metabolic intervention. In this work, we propose a new bi-level computational framework--MOMAKnock--which can derive robust knockout strategies under the MOMA flux distribution approximation. Methods In this new bi-level optimization framework, we aim to maximize the production of targeted chemicals by identifying candidate knockout genes or reactions under phenotypic constraints approximated by the MOMA assumption. Hence, the targeted chemical production is the primary objective of MOMAKnock while the MOMA assumption is formulated as the inner problem of constraining the knockout metabolic flux to be as close as possible to the steady-state phenotypes of wide-type strains. As this new inner problem becomes a quadratic programming problem, a novel adaptive piecewise linearization algorithm is developed in this paper to obtain the exact optimal solution to this new bi-level integer quadratic programming problem for MOMAKnock. Results Our new MOMAKnock model and the adaptive piecewise linearization solution algorithm are tested with a small E. coli core metabolic network and a large-scale iAF1260 E. coli metabolic network

Adaptive bi-level programming for optimal gene knockouts for targeted overproduction under phenotypic constraints.

PubMed

Ren, Shaogang; Zeng, Bo; Qian, Xiaoning

2013-01-01

Optimization procedures to identify gene knockouts for targeted biochemical overproduction have been widely in use in modern metabolic engineering. Flux balance analysis (FBA) framework has provided conceptual simplifications for genome-scale dynamic analysis at steady states. Based on FBA, many current optimization methods for targeted bio-productions have been developed under the maximum cell growth assumption. The optimization problem to derive gene knockout strategies recently has been formulated as a bi-level programming problem in OptKnock for maximum targeted bio-productions with maximum growth rates. However, it has been shown that knockout mutants in fact reach the steady states with the minimization of metabolic adjustment (MOMA) from the corresponding wild-type strains instead of having maximal growth rates after genetic or metabolic intervention. In this work, we propose a new bi-level computational framework--MOMAKnock--which can derive robust knockout strategies under the MOMA flux distribution approximation. In this new bi-level optimization framework, we aim to maximize the production of targeted chemicals by identifying candidate knockout genes or reactions under phenotypic constraints approximated by the MOMA assumption. Hence, the targeted chemical production is the primary objective of MOMAKnock while the MOMA assumption is formulated as the inner problem of constraining the knockout metabolic flux to be as close as possible to the steady-state phenotypes of wide-type strains. As this new inner problem becomes a quadratic programming problem, a novel adaptive piecewise linearization algorithm is developed in this paper to obtain the exact optimal solution to this new bi-level integer quadratic programming problem for MOMAKnock. Our new MOMAKnock model and the adaptive piecewise linearization solution algorithm are tested with a small E. coli core metabolic network and a large-scale iAF1260 E. coli metabolic network. The derived knockout

Forming Uniform Deuterium-Ice Layers in Cryogenic Targets: Experiences Using the OMEGA Cryogenic Target Handling System

NASA Astrophysics Data System (ADS)

Harding, D. R.; Wittman, M. D.; Elasky, L.; Iwan, L. S.; Lund, L.

2001-10-01

The OMEGA Cryogenic Target Handling System (OCTHS) allows variable-thickness ice layers (nominal 100-μm) to be formed inside OMEGA-size (1-mm-diam., 3-μm-wall) plastic shells. The OCTHS design provides the most straightforward thermal environment for layering targets: permeation filled spherical targets are in a spherical isothermal environment. The layered target can be rotated 360^o to acquire multiple views of the ice layer. However, the capability of providing cryogenic targets for implosion experiments imposes constraints that do not exist in test systems dedicated to ice-layering studies. Most affected is the ability to characterize the target: space constraints and the need for multiple sets of windows limit the viewing access to f/5 optics, which affects the image quality. With these features, the OCTS provides the most relevant test system, to date, for layering targets and quantifying the overall ice roughness. No single layering protocol provides repeatable ice smoothness. All techniques require extensive operator interaction, and the layering process is lengthy. Typical ice rms smoothness varied from 5 to 10 μm for all targets studied. Characterizing the ice layer from different views shows a ~30% variation in the ice rms smoothness and a greater difference in the power spectra, depending on the view axis. This work was supported by the U.S. DOE Office of Inertial Confinement Fusion under Cooperative Agreement No. DE-FC03-92SF19460.

A Novel Fixed-Target Task to Determine Articulatory Speed Constraints in Persons with Amyotrophic Lateral Sclerosis

PubMed Central

Mefferd, Antje S.; Green, Jordan R.; Pattee, Gary

2011-01-01

Purpose The goal of this study was to determine if talkers with ALS are limited in their ability to increase lower lip and jaw speed at an early stage of the disease when their speaking rate and intelligibility are only minimally or not affected. Method A novel metronome paced fixed-target task was used to assess movement speed capacities during lower lip and jaw oscillations in seven talkers with ALS and seven age and gender matched controls. Results Lower lip peak speeds were significantly lower in talkers with mild ALS than in healthy talkers suggesting a lower lip speed constraint in talkers with mild ALS. Jaw peak speeds tended to be lower, but jaw displacements tended to be larger in talkers with mild ALS than in healthy talkers. Because greater speeds are typically expected for larger displacements, outcomes also suggest a jaw speed constraint in talkers with mild ALS. Conclusions Lower lip and jaw peak speeds may be sensitive measures to identify bulbar motor performance decline at an early stage of the disease when speaking rate and intelligibility are only minimally affected. PMID:22000045

Spacecraft rendezvous operational considerations affecting vehicle systems design and configuration

NASA Astrophysics Data System (ADS)

Prust, Ellen E.

One lesson learned from Orbiting Maneuvering Vehicle (OMV) program experience is that Design Reference Missions must include an appropriate balance of operations and performance inputs to effectively drive vehicle systems design and configuration. Rendezvous trajectory design is based on vehicle characteristics (e.g., mass, propellant tank size, and mission duration capability) and operational requirements, which have evolved through the Gemini, Apollo, and STS programs. Operational constraints affecting the rendezvous final approach are summarized. The two major objectives of operational rendezvous design are vehicle/crew safety and mission success. Operational requirements on the final approach which support these objectives include: tracking/targeting/communications; trajectory dispersion and navigation uncertainty handling; contingency protection; favorable sunlight conditions; acceptable relative state for proximity operations handover; and compliance with target vehicle constraints. A discussion of the ways each of these requirements may constrain the rendezvous trajectory follows. Although the constraints discussed apply to all rendezvous, the trajectory presented in 'Cargo Transfer Vehicle Preliminary Reference Definition' (MSFC, May 1991) was used as the basis for the comments below.

Dual Target Design for CLAS12

NASA Astrophysics Data System (ADS)

Alam, Omair; Gilfoyle, Gerard; Christo, Steve

2015-10-01

An experiment to measure the neutron magnetic form factor (GnM) is planned for the new CLAS12 detector in Hall B at Jefferson Lab. This form factor will be extracted from the ratio of the quasielastic electron-neutron to electron-proton scattering off a liquid deuterium (LD2) target. A collinear liquid hydrogen (LH2) target will be used to measure efficiencies at the same time as production data is collected from the LD2 target. To test target designs we have simulated CLAS12 and the target geometry. Electron-nucleon events are produced first with the QUasiElastic Event Generator (QUEEG) which models the internal motion of the nucleons in deuterium.1 The results are used as input to the CLAS12 Monte Caro code gemc; a Geant4-based program that simulates the particle's interactions with each component of CLAS12 including the target material. The dual target geometry has been added to gemc including support structures and cryogenic transport systems. A Perl script was written to define the target materials and geometries. The output of the script is a set of database entries read by gemc at runtime. An initial study of the impact of this dual-target structure revealed limited effects on the electron momentum and angular resolutions. Work supported by the University of Richmond and the US Department of Energy.

Optimum design of a composite structure with ply-interleaving constraints

NASA Technical Reports Server (NTRS)

Wang, Bo Ping; Costin, Daniel P.

1990-01-01

The application of composite materials to aircraft construction has provided the designer with increased flexibility. The orientation of plies can be tailored to provide additional aeroelastic performance unobtainable with an isotropic material. A tailored laminate is made up of plies of several orientations, usually 0 deg, 45 deg, -45 deg, and 90 deg. The direction of the 0 deg plies, does not need to be oriented with the leading edge, but can be varied to obtain a wide variety of structural properties. Also, the number of plies of each orientation varies from one zone to another on the planform. Thus, a thick laminate with mainly 0 deg plies may form the root zone, and a thinner laminate with mainly +45 deg plies may form the leading edge zone. Tailored laminates were designed using complicated optimization programs. Unfortunately, many tailored designs must be modified before they are manufactured. The modification adds weight and decreases performance. One type of modification is ply interleaving, an overlap of plies between zones on the laminate. These interleaves are added to ensure that zones with varying ply percentages can be connected without loss of strength. In this paper, the constraints needed to eliminate interleaves in the laminate optimization process will be described and implemented in a structural optimization problem. The method used has the potential to prevent changes to composite laminates late in the design cycle.

Designing a mixture experiment when the components are subject to a nonlinear multiple-component constraint

DOE Office of Scientific and Technical Information (OSTI.GOV)

Piepel, Greg F.; Cooley, Scott K.; Vienna, John D.

This article presents a case study of developing an experimental design for a constrained mixture experiment when the experimental region is defined by single-component constraints (SCCs), linear multiple-component constraints (MCCs), and a nonlinear MCC. Traditional methods and software for designing constrained mixture experiments with SCCs and linear MCCs are not directly applicable because of the nonlinear MCC. A modification of existing methodology to account for the nonlinear MCC was developed and is described in this article. The case study involves a 15-component nuclear waste glass example in which SO3 is one of the components. SO3 has a solubility limit inmore » glass that depends on the composition of the balance of the glass. A goal was to design the experiment so that SO3 would not exceed its predicted solubility limit for any of the experimental glasses. The SO3 solubility limit had previously been modeled by a partial quadratic mixture (PQM) model expressed in the relative proportions of the 14 other components. The PQM model was used to construct a nonlinear MCC in terms of all 15 components. In addition, there were SCCs and linear MCCs. This article discusses the waste glass example and how a layered design was generated to (i) account for the SCCs, linear MCCs, and nonlinear MCC and (ii) meet the goals of the study.« less

Quantifying design trade-offs of beryllium targets on NIF

NASA Astrophysics Data System (ADS)

Yi, S. A.; Zylstra, A. B.; Kline, J. L.; Loomis, E. N.; Kyrala, G. A.; Shah, R. C.; Perry, T. S.; Kanzleiter, R. J.; Batha, S. H.; MacLaren, S. A.; Ralph, J. E.; Masse, L. P.; Salmonson, J. D.; Tipton, R. E.; Callahan, D. A.; Hurricane, O. A.

2017-10-01

An important determinant of target performance is implosion kinetic energy, which scales with the capsule size. The maximum achievable performance for a given laser is thus related to the largest capsule that can be imploded symmetrically, constrained by drive uniformity. A limiting factor for symmetric radiation drive is the ratio of hohlraum to capsule radii, or case-to-capsule ratio (CCR). For a fixed laser energy, a larger hohlraum allows for driving bigger capsules symmetrically at the cost of reduced peak radiation temperature (Tr). Beryllium ablators may thus allow for unique target design trade-offs due to their higher ablation efficiency at lower Tr. By utilizing larger hohlraum sizes than most modern NIF designs, beryllium capsules thus have the potential to operate in unique regions of the target design parameter space. We present design simulations of beryllium targets with a large CCR = 4.3 3.7 . These are scaled surrogates of large hohlraum low Tr beryllium targets, with the goal of quantifying symmetry tunability as a function of CCR. This work performed under the auspices of the U.S. DOE by LANL under contract DE-AC52- 06NA25396, and by LLNL under Contract DE-AC52-07NA27344.

Target selection and comparison of mission design for space debris removal by DLR's advanced study group

NASA Astrophysics Data System (ADS)

van der Pas, Niels; Lousada, Joao; Terhes, Claudia; Bernabeu, Marc; Bauer, Waldemar

2014-09-01

Space debris is a growing problem. Models show that the Kessler syndrome, the exponential growth of debris due to collisions, has become unavoidable unless an active debris removal program is initiated. The debris population in LEO with inclination between 60° and 95° is considered as the most critical zone. In order to stabilize the debris population in orbit, especially in LEO, 5 to 10 objects will need to be removed every year. The unique circumstances of such a mission could require that several objects are removed with a single launch. This will require a mission to rendezvous with a multitude of objects orbiting on different altitudes, inclinations and planes. Removal models have assumed that the top priority targets will be removed first. However this will lead to a suboptimal mission design and increase the ΔV-budget. Since there is a multitude of targets to choose from, the targets can be selected for an optimal mission design. In order to select a group of targets for a removal mission the orbital parameters and political constraints should also be taken into account. Within this paper a number of the target selection criteria are presented. The possible mission targets and their order of retrieval is dependent on the mission architecture. A comparison between several global mission architectures is given. Under consideration are 3 global missions of which a number of parameters are varied. The first mission launches multiple separate deorbit kits. The second launches a mother craft with deorbit kits. The third launches an orbital tug which pulls the debris in a lower orbit, after which a deorbit kit performs the final deorbit burn. A RoM mass and cost comparison is presented. The research described in this paper has been conducted as part of an active debris removal study by the Advanced Study Group (ASG). The ASG is an interdisciplinary student group working at the DLR, analyzing existing technologies and developing new ideas into preliminary

Designing a Constraint Based Parser for Sanskrit

NASA Astrophysics Data System (ADS)

Kulkarni, Amba; Pokar, Sheetal; Shukl, Devanand

Verbal understanding (śā bdabodha) of any utterance requires the knowledge of how words in that utterance are related to each other. Such knowledge is usually available in the form of cognition of grammatical relations. Generative grammars describe how a language codes these relations. Thus the knowledge of what information various grammatical relations convey is available from the generation point of view and not the analysis point of view. In order to develop a parser based on any grammar one should then know precisely the semantic content of the grammatical relations expressed in a language string, the clues for extracting these relations and finally whether these relations are expressed explicitly or implicitly. Based on the design principles that emerge from this knowledge, we model the parser as finding a directed Tree, given a graph with nodes representing the words and edges representing the possible relations between them. Further, we also use the Mīmā ṃsā constraint of ākā ṅkṣā (expectancy) to rule out non-solutions and sannidhi (proximity) to prioritize the solutions. We have implemented a parser based on these principles and its performance was found to be satisfactory giving us a confidence to extend its functionality to handle the complex sentences.

Constraint-based Data Mining

NASA Astrophysics Data System (ADS)

Boulicaut, Jean-Francois; Jeudy, Baptiste

Knowledge Discovery in Databases (KDD) is a complex interactive process. The promising theoretical framework of inductive databases considers this is essentially a querying process. It is enabled by a query language which can deal either with raw data or patterns which hold in the data. Mining patterns turns to be the so-called inductive query evaluation process for which constraint-based Data Mining techniques have to be designed. An inductive query specifies declaratively the desired constraints and algorithms are used to compute the patterns satisfying the constraints in the data. We survey important results of this active research domain. This chapter emphasizes a real breakthrough for hard problems concerning local pattern mining under various constraints and it points out the current directions of research as well.

Benchmarking CRISPR on-target sgRNA design.

PubMed

Yan, Jifang; Chuai, Guohui; Zhou, Chi; Zhu, Chenyu; Yang, Jing; Zhang, Chao; Gu, Feng; Xu, Han; Wei, Jia; Liu, Qi

2017-02-15

CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-based gene editing has been widely implemented in various cell types and organisms. A major challenge in the effective application of the CRISPR system is the need to design highly efficient single-guide RNA (sgRNA) with minimal off-target cleavage. Several tools are available for sgRNA design, while limited tools were compared. In our opinion, benchmarking the performance of the available tools and indicating their applicable scenarios are important issues. Moreover, whether the reported sgRNA design rules are reproducible across different sgRNA libraries, cell types and organisms remains unclear. In our study, a systematic and unbiased benchmark of the sgRNA predicting efficacy was performed on nine representative on-target design tools, based on six benchmark data sets covering five different cell types. The benchmark study presented here provides novel quantitative insights into the available CRISPR tools. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

PrimerDesign-M: A multiple-alignment based multiple-primer design tool for walking across variable genomes

DOE PAGES

Yoon, Hyejin; Leitner, Thomas

2014-12-17

Analyses of entire viral genomes or mtDNA requires comprehensive design of many primers across their genomes. In addition, simultaneous optimization of several DNA primer design criteria may improve overall experimental efficiency and downstream bioinformatic processing. To achieve these goals, we developed PrimerDesign-M. It includes several options for multiple-primer design, allowing researchers to efficiently design walking primers that cover long DNA targets, such as entire HIV-1 genomes, and that optimizes primers simultaneously informed by genetic diversity in multiple alignments and experimental design constraints given by the user. PrimerDesign-M can also design primers that include DNA barcodes and minimize primer dimerization. PrimerDesign-Mmore » finds optimal primers for highly variable DNA targets and facilitates design flexibility by suggesting alternative designs to adapt to experimental conditions.« less

An Approach to the Constrained Design of Natural Laminar Flow Airfoils

NASA Technical Reports Server (NTRS)

Green, Bradford E.

1997-01-01

A design method has been developed by which an airfoil with a substantial amount of natural laminar flow can be designed, while maintaining other aerodynamic and geometric constraints. After obtaining the initial airfoil's pressure distribution at the design lift coefficient using an Euler solver coupled with an integral turbulent boundary layer method, the calculations from a laminar boundary layer solver are used by a stability analysis code to obtain estimates of the transition location (using N-Factors) for the starting airfoil. A new design method then calculates a target pressure distribution that will increase the laminar flow toward the desired amount. An airfoil design method is then iteratively used to design an airfoil that possesses that target pressure distribution. The new airfoil's boundary layer stability characteristics are determined, and this iterative process continues until an airfoil is designed that meets the laminar flow requirement and as many of the other constraints as possible.

An approach to the constrained design of natural laminar flow airfoils

NASA Technical Reports Server (NTRS)

Green, Bradford Earl

1995-01-01

A design method has been developed by which an airfoil with a substantial amount of natural laminar flow can be designed, while maintaining other aerodynamic and geometric constraints. After obtaining the initial airfoil's pressure distribution at the design lift coefficient using an Euler solver coupled with an integml turbulent boundary layer method, the calculations from a laminar boundary layer solver are used by a stability analysis code to obtain estimates of the transition location (using N-Factors) for the starting airfoil. A new design method then calculates a target pressure distribution that will increase the larninar flow toward the desired amounl An airfoil design method is then iteratively used to design an airfoil that possesses that target pressure distribution. The new airfoil's boundary layer stability characteristics are determined, and this iterative process continues until an airfoil is designed that meets the laminar flow requirement and as many of the other constraints as possible.

Transoptr — A second order beam transport design code with optimization and constraints

NASA Astrophysics Data System (ADS)

Heighway, E. A.; Hutcheon, R. M.

1981-08-01

This code was written initially to design an achromatic and isochronous reflecting magnet and has been extended to compete in capability (for constrained problems) with TRANSPORT. Its advantage is its flexibility in that the user writes a routine to describe his transport system. The routine allows the definition of general variables from which the system parameters can be derived. Further, the user can write any constraints he requires as algebraic equations relating the parameters. All variables may be used in either a first or second order optimization.

Instructional Constraints Faced by Learners with Muscular Dystrophy: A Case of Joytown Special Primary School, Thika, Kenya

ERIC Educational Resources Information Center

Wang'ang'a, Annrose Wanjiku; Wamocho, Franciscah Irangi; Kioy, Paul

2015-01-01

The purpose of this study was to investigate the instructional constraints facing learners with muscular dystrophy in Joy Town special primary school, Thika, Kenya. Descriptive design was used for this study. The target population were all the 20 learners suffering from muscular dystrophy from S.A Joy Town Special Primary School. The total target…

Designing multi-targeted agents: An emerging anticancer drug discovery paradigm.

PubMed

Fu, Rong-Geng; Sun, Yuan; Sheng, Wen-Bing; Liao, Duan-Fang

2017-08-18

The dominant paradigm in drug discovery is to design ligands with maximum selectivity to act on individual drug targets. With the target-based approach, many new chemical entities have been discovered, developed, and further approved as drugs. However, there are a large number of complex diseases such as cancer that cannot be effectively treated or cured only with one medicine to modulate the biological function of a single target. As simultaneous intervention of two (or multiple) cancer progression relevant targets has shown improved therapeutic efficacy, the innovation of multi-targeted drugs has become a promising and prevailing research topic and numerous multi-targeted anticancer agents are currently at various developmental stages. However, most multi-pharmacophore scaffolds are usually discovered by serendipity or screening, while rational design by combining existing pharmacophore scaffolds remains an enormous challenge. In this review, four types of multi-pharmacophore modes are discussed, and the examples from literature will be used to introduce attractive lead compounds with the capability of simultaneously interfering with different enzyme or signaling pathway of cancer progression, which will reveal the trends and insights to help the design of the next generation multi-targeted anticancer agents. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Hard Constraints in Optimization Under Uncertainty

NASA Technical Reports Server (NTRS)

Crespo, Luis G.; Giesy, Daniel P.; Kenny, Sean P.

2008-01-01

This paper proposes a methodology for the analysis and design of systems subject to parametric uncertainty where design requirements are specified via hard inequality constraints. Hard constraints are those that must be satisfied for all parameter realizations within a given uncertainty model. Uncertainty models given by norm-bounded perturbations from a nominal parameter value, i.e., hyper-spheres, and by sets of independently bounded uncertain variables, i.e., hyper-rectangles, are the focus of this paper. These models, which are also quite practical, allow for a rigorous mathematical treatment within the proposed framework. Hard constraint feasibility is determined by sizing the largest uncertainty set for which the design requirements are satisfied. Analytically verifiable assessments of robustness are attained by comparing this set with the actual uncertainty model. Strategies that enable the comparison of the robustness characteristics of competing design alternatives, the description and approximation of the robust design space, and the systematic search for designs with improved robustness are also proposed. Since the problem formulation is generic and the tools derived only require standard optimization algorithms for their implementation, this methodology is applicable to a broad range of engineering problems.

Concentric Tube Robot Design and Optimization Based on Task and Anatomical Constraints

PubMed Central

Bergeles, Christos; Gosline, Andrew H.; Vasilyev, Nikolay V.; Codd, Patrick J.; del Nido, Pedro J.; Dupont, Pierre E.

2015-01-01

Concentric tube robots are catheter-sized continuum robots that are well suited for minimally invasive surgery inside confined body cavities. These robots are constructed from sets of pre-curved superelastic tubes and are capable of assuming complex 3D curves. The family of 3D curves that the robot can assume depends on the number, curvatures, lengths and stiffnesses of the tubes in its tube set. The robot design problem involves solving for a tube set that will produce the family of curves necessary to perform a surgical procedure. At a minimum, these curves must enable the robot to smoothly extend into the body and to manipulate tools over the desired surgical workspace while respecting anatomical constraints. This paper introduces an optimization framework that utilizes procedureor patient-specific image-based anatomical models along with surgical workspace requirements to generate robot tube set designs. The algorithm searches for designs that minimize robot length and curvature and for which all paths required for the procedure consist of stable robot configurations. Two mechanics-based kinematic models are used. Initial designs are sought using a model assuming torsional rigidity. These designs are then refined using a torsionally-compliant model. The approach is illustrated with clinically relevant examples from neurosurgery and intracardiac surgery. PMID:26380575

Targeted polymeric therapeutic nanoparticles: design, development and clinical translation†

PubMed Central

Kamaly, Nazila; Xiao, Zeyu; Valencia, Pedro M.; Radovic-Moreno, Aleksandar F.; Farokhzad, Omid C.

2013-01-01

Polymeric materials have been used in a range of pharmaceutical and biotechnology products for more than 40 years. These materials have evolved from their earlier use as biodegradable products such as resorbable sutures, orthopaedic implants, macroscale and microscale drug delivery systems such as microparticles and wafers used as controlled drug release depots, to multifunctional nanoparticles (NPs) capable of targeting, and controlled release of therapeutic and diagnostic agents. These newer generations of targeted and controlled release polymeric NPs are now engineered to navigate the complex in vivo environment, and incorporate functionalities for achieving target specificity, control of drug concentration and exposure kinetics at the tissue, cell, and subcellular levels. Indeed this optimization of drug pharmacology as aided by careful design of multifunctional NPs can lead to improved drug safety and efficacy, and may be complimentary to drug enhancements that are traditionally achieved by medicinal chemistry. In this regard, polymeric NPs have the potential to result in a highly differentiated new class of therapeutics, distinct from the original active drugs used in their composition, and distinct from first generation NPs that largely facilitated drug formulation. A greater flexibility in the design of drug molecules themselves may also be facilitated following their incorporation into NPs, as drug properties (solubility, metabolism, plasma binding, biodistribution, target tissue accumulation) will no longer be constrained to the same extent by drug chemical composition, but also become in-part the function of the physicochemical properties of the NP. The combination of optimally designed drugs with optimally engineered polymeric NPs opens up the possibility of improved clinical outcomes that may not be achievable with the administration of drugs in their conventional form. In this critical review, we aim to provide insights into the design and development

Robust synergetic control design under inputs and states constraints

NASA Astrophysics Data System (ADS)

Rastegar, Saeid; Araújo, Rui; Sadati, Jalil

2018-03-01

In this paper, a novel robust-constrained control methodology for discrete-time linear parameter-varying (DT-LPV) systems is proposed based on a synergetic control theory (SCT) approach. It is shown that in DT-LPV systems without uncertainty, and for any unmeasured bounded additive disturbance, the proposed controller accomplishes the goal of stabilising the system by asymptotically driving the error of the controlled variable to a bounded set containing the origin and then maintaining it there. Moreover, given an uncertain DT-LPV system jointly subject to unmeasured and constrained additive disturbances, and constraints in states, input commands and reference signals (set points), then invariant set theory is used to find an appropriate polyhedral robust invariant region in which the proposed control framework is guaranteed to robustly stabilise the closed-loop system. Furthermore, this is achieved even for the case of varying non-zero control set points in such uncertain DT-LPV systems. The controller is characterised to have a simple structure leading to an easy implementation, and a non-complex design process. The effectiveness of the proposed method and the implications of the controller design on feasibility and closed-loop performance are demonstrated through application examples on the temperature control on a continuous-stirred tank reactor plant, on the control of a real-coupled DC motor plant, and on an open-loop unstable system example.

Massively parallel de novo protein design for targeted therapeutics.

PubMed

Chevalier, Aaron; Silva, Daniel-Adriano; Rocklin, Gabriel J; Hicks, Derrick R; Vergara, Renan; Murapa, Patience; Bernard, Steffen M; Zhang, Lu; Lam, Kwok-Ho; Yao, Guorui; Bahl, Christopher D; Miyashita, Shin-Ichiro; Goreshnik, Inna; Fuller, James T; Koday, Merika T; Jenkins, Cody M; Colvin, Tom; Carter, Lauren; Bohn, Alan; Bryan, Cassie M; Fernández-Velasco, D Alejandro; Stewart, Lance; Dong, Min; Huang, Xuhui; Jin, Rongsheng; Wilson, Ian A; Fuller, Deborah H; Baker, David

2017-10-05

De novo protein design holds promise for creating small stable proteins with shapes customized to bind therapeutic targets. We describe a massively parallel approach for designing, manufacturing and screening mini-protein binders, integrating large-scale computational design, oligonucleotide synthesis, yeast display screening and next-generation sequencing. We designed and tested 22,660 mini-proteins of 37-43 residues that target influenza haemagglutinin and botulinum neurotoxin B, along with 6,286 control sequences to probe contributions to folding and binding, and identified 2,618 high-affinity binders. Comparison of the binding and non-binding design sets, which are two orders of magnitude larger than any previously investigated, enabled the evaluation and improvement of the computational model. Biophysical characterization of a subset of the binder designs showed that they are extremely stable and, unlike antibodies, do not lose activity after exposure to high temperatures. The designs elicit little or no immune response and provide potent prophylactic and therapeutic protection against influenza, even after extensive repeated dosing.

Massively parallel de novo protein design for targeted therapeutics

NASA Astrophysics Data System (ADS)

Chevalier, Aaron; Silva, Daniel-Adriano; Rocklin, Gabriel J.; Hicks, Derrick R.; Vergara, Renan; Murapa, Patience; Bernard, Steffen M.; Zhang, Lu; Lam, Kwok-Ho; Yao, Guorui; Bahl, Christopher D.; Miyashita, Shin-Ichiro; Goreshnik, Inna; Fuller, James T.; Koday, Merika T.; Jenkins, Cody M.; Colvin, Tom; Carter, Lauren; Bohn, Alan; Bryan, Cassie M.; Fernández-Velasco, D. Alejandro; Stewart, Lance; Dong, Min; Huang, Xuhui; Jin, Rongsheng; Wilson, Ian A.; Fuller, Deborah H.; Baker, David

2017-10-01

De novo protein design holds promise for creating small stable proteins with shapes customized to bind therapeutic targets. We describe a massively parallel approach for designing, manufacturing and screening mini-protein binders, integrating large-scale computational design, oligonucleotide synthesis, yeast display screening and next-generation sequencing. We designed and tested 22,660 mini-proteins of 37-43 residues that target influenza haemagglutinin and botulinum neurotoxin B, along with 6,286 control sequences to probe contributions to folding and binding, and identified 2,618 high-affinity binders. Comparison of the binding and non-binding design sets, which are two orders of magnitude larger than any previously investigated, enabled the evaluation and improvement of the computational model. Biophysical characterization of a subset of the binder designs showed that they are extremely stable and, unlike antibodies, do not lose activity after exposure to high temperatures. The designs elicit little or no immune response and provide potent prophylactic and therapeutic protection against influenza, even after extensive repeated dosing.

Massively parallel de novo protein design for targeted therapeutics

PubMed Central

Chevalier, Aaron; Silva, Daniel-Adriano; Rocklin, Gabriel J.; Hicks, Derrick R.; Vergara, Renan; Murapa, Patience; Bernard, Steffen M.; Zhang, Lu; Lam, Kwok-Ho; Yao, Guorui; Bahl, Christopher D.; Miyashita, Shin-Ichiro; Goreshnik, Inna; Fuller, James T.; Koday, Merika T.; Jenkins, Cody M.; Colvin, Tom; Carter, Lauren; Bohn, Alan; Bryan, Cassie M.; Fernández-Velasco, D. Alejandro; Stewart, Lance; Dong, Min; Huang, Xuhui; Jin, Rongsheng; Wilson, Ian A.; Fuller, Deborah H.; Baker, David

2018-01-01

De novo protein design holds promise for creating small stable proteins with shapes customized to bind therapeutic targets. We describe a massively parallel approach for designing, manufacturing and screening mini-protein binders, integrating large-scale computational design, oligonucleotide synthesis, yeast display screening and next-generation sequencing. We designed and tested 22,660 mini-proteins of 37–43 residues that target influenza haemagglutinin and botulinum neurotoxin B, along with 6,286 control sequences to probe contributions to folding and binding, and identified 2,618 high-affinity binders. Comparison of the binding and non-binding design sets, which are two orders of magnitude larger than any previously investigated, enabled the evaluation and improvement of the computational model. Biophysical characterization of a subset of the binder designs showed that they are extremely stable and, unlike antibodies, do not lose activity after exposure to high temperatures. The designs elicit little or no immune response and provide potent prophylactic and therapeutic protection against influenza, even after extensive repeated dosing. PMID:28953867

Geometric constraints for shape and topology optimization in architectural design

NASA Astrophysics Data System (ADS)

Dapogny, Charles; Faure, Alexis; Michailidis, Georgios; Allaire, Grégoire; Couvelas, Agnes; Estevez, Rafael

2017-06-01

This work proposes a shape and topology optimization framework oriented towards conceptual architectural design. A particular emphasis is put on the possibility for the user to interfere on the optimization process by supplying information about his personal taste. More precisely, we formulate three novel constraints on the geometry of shapes; while the first two are mainly related to aesthetics, the third one may also be used to handle several fabrication issues that are of special interest in the device of civil structures. The common mathematical ingredient to all three models is the signed distance function to a domain, and its sensitivity analysis with respect to perturbations of this domain; in the present work, this material is extended to the case where the ambient space is equipped with an anisotropic metric tensor. Numerical examples are discussed in two and three space dimensions.

Level-Set Topology Optimization with Aeroelastic Constraints

NASA Technical Reports Server (NTRS)

Dunning, Peter D.; Stanford, Bret K.; Kim, H. Alicia

2015-01-01

Level-set topology optimization is used to design a wing considering skin buckling under static aeroelastic trim loading, as well as dynamic aeroelastic stability (flutter). The level-set function is defined over the entire 3D volume of a transport aircraft wing box. Therefore, the approach is not limited by any predefined structure and can explore novel configurations. The Sequential Linear Programming (SLP) level-set method is used to solve the constrained optimization problems. The proposed method is demonstrated using three problems with mass, linear buckling and flutter objective and/or constraints. A constraint aggregation method is used to handle multiple buckling constraints in the wing skins. A continuous flutter constraint formulation is used to handle difficulties arising from discontinuities in the design space caused by a switching of the critical flutter mode.

Topological Constraints and Their Conformational Entropic Penalties on RNA Folds.

PubMed

Mak, Chi H; Phan, Ethan N H

2018-05-08

Functional RNAs can fold into intricate structures using a number of different secondary and tertiary structural motifs. Many factors contribute to the overall free energy of the target fold. This study aims at quantifying the entropic costs coming from the loss of conformational freedom when the sugar-phosphate backbone is subjected to constraints imposed by secondary and tertiary contacts. Motivated by insights from topology theory, we design a diagrammatic scheme to represent different types of RNA structures so that constraints associated with a folded structure may be segregated into mutually independent subsets, enabling the total conformational entropy loss to be easily calculated as a sum of independent terms. We used high-throughput Monte Carlo simulations to simulate large ensembles of single-stranded RNA sequences in solution to validate the assumptions behind our diagrammatic scheme, examining the entropic costs for hairpin initiation and formation of many multiway junctions. Our diagrammatic scheme aids in the factorization of secondary/tertiary constraints into distinct topological classes and facilitates the discovery of interrelationships among multiple constraints on RNA folds. This perspective, which to our knowledge is novel, leads to useful insights into the inner workings of some functional RNA sequences, demonstrating how they might operate by transforming their structures among different topological classes. Copyright © 2018 Biophysical Society. Published by Elsevier Inc. All rights reserved.

The effect of contextual constraint on parafoveal processing in reading

PubMed Central

Schotter, Elizabeth R.; Lee, Michelle; Reiderman, Michael; Rayner, Keith

2015-01-01

Semantic preview benefit in reading is an elusive and controversial effect because empirical studies do not always (but sometimes) find evidence for it. Its presence seems to depend on (at least) the language being read, visual properties of the text (e.g., initial letter capitalization), the type of relationship between preview and target, and as shown here, semantic constraint generated by the prior sentence context. Schotter (2013) reported semantic preview benefit for synonyms, but not semantic associates when the preview/target was embedded in a neutral sentence context. In Experiment 1, we embedded those same previews/targets into constrained sentence contexts and in Experiment 2 we replicated the effects reported by Schotter (2013; in neutral sentence contexts) and Experiment 1 (in constrained contexts) in a within-subjects design. In both experiments, we found an early (i.e., first-pass) apparent preview benefit for semantically associated previews in constrained contexts that went away in late measures (e.g., total time). These data suggest that sentence constraint (at least as manipulated in the current study) does not operate by making a single word form expected, but rather generates expectations about what kinds of words are likely to appear. Furthermore, these data are compatible with the assumption of the E-Z Reader model that early oculomotor decisions reflect “hedged bets” that a word will be identifiable and, when wrong, lead the system to identify the wrong word, triggering regressions. PMID:26257469

A flexible computer aid for conceptual design based on constraint propagation and component-modeling. [of aircraft in three dimensions

NASA Technical Reports Server (NTRS)

Kolb, Mark A.

1988-01-01

The Rubber Airplane program, which combines two symbolic processing techniques with a component-based database of design knowledge, is proposed as a computer aid for conceptual design. Using object-oriented programming, programs are organized around the objects and behavior to be simulated, and using constraint propagation, declarative statements designate mathematical relationships among all the equation variables. It is found that the additional level of organizational structure resulting from the arrangement of the design information in terms of design components provides greater flexibility and convenience.

CEM-designer: design of custom expression microarrays in the post-ENCODE Era.

PubMed

Arnold, Christian; Externbrink, Fabian; Hackermüller, Jörg; Reiche, Kristin

2014-11-10

Microarrays are widely used in gene expression studies, and custom expression microarrays are popular to monitor expression changes of a customer-defined set of genes. However, the complexity of transcriptomes uncovered recently make custom expression microarray design a non-trivial task. Pervasive transcription and alternative processing of transcripts generate a wealth of interweaved transcripts that requires well-considered probe design strategies and is largely neglected in existing approaches. We developed the web server CEM-Designer that facilitates microarray platform independent design of custom expression microarrays for complex transcriptomes. CEM-Designer covers (i) the collection and generation of a set of unique target sequences from different sources and (ii) the selection of a set of sensitive and specific probes that optimally represents the target sequences. Probe design itself is left to third party software to ensure that probes meet provider-specific constraints. CEM-Designer is available at http://designpipeline.bioinf.uni-leipzig.de. Copyright © 2014 Elsevier B.V. All rights reserved.

Oak Ridge Spallation Neutron Source (ORSNS) target station design integration

DOE Office of Scientific and Technical Information (OSTI.GOV)

McManamy, T.; Booth, R.; Cleaves, J.

1996-06-01

The conceptual design for a 1- to 3-MW short pulse spallation source with a liquid mercury target has been started recently. The design tools and methods being developed to define requirements, integrate the work, and provide early cost guidance will be presented with a summary of the current target station design status. The initial design point was selected with performance and cost estimate projections by a systems code. This code was developed recently using cost estimates from the Brookhaven Pulsed Spallation Neutron Source study and experience from the Advanced Neutron Source Project`s conceptual design. It will be updated and improvedmore » as the design develops. Performance was characterized by a simplified figure of merit based on a ratio of neutron production to costs. A work breakdown structure was developed, with simplified systems diagrams used to define interfaces and system responsibilities. A risk assessment method was used to identify potential problems, to identify required research and development (R&D), and to aid contingency development. Preliminary 3-D models of the target station are being used to develop remote maintenance concepts and to estimate costs.« less

Reinforcement-Learning-Based Robust Controller Design for Continuous-Time Uncertain Nonlinear Systems Subject to Input Constraints.

PubMed

Liu, Derong; Yang, Xiong; Wang, Ding; Wei, Qinglai

2015-07-01

The design of stabilizing controller for uncertain nonlinear systems with control constraints is a challenging problem. The constrained-input coupled with the inability to identify accurately the uncertainties motivates the design of stabilizing controller based on reinforcement-learning (RL) methods. In this paper, a novel RL-based robust adaptive control algorithm is developed for a class of continuous-time uncertain nonlinear systems subject to input constraints. The robust control problem is converted to the constrained optimal control problem with appropriately selecting value functions for the nominal system. Distinct from typical action-critic dual networks employed in RL, only one critic neural network (NN) is constructed to derive the approximate optimal control. Meanwhile, unlike initial stabilizing control often indispensable in RL, there is no special requirement imposed on the initial control. By utilizing Lyapunov's direct method, the closed-loop optimal control system and the estimated weights of the critic NN are proved to be uniformly ultimately bounded. In addition, the derived approximate optimal control is verified to guarantee the uncertain nonlinear system to be stable in the sense of uniform ultimate boundedness. Two simulation examples are provided to illustrate the effectiveness and applicability of the present approach.

Ligand-based virtual screening under partial shape constraints.

PubMed

von Behren, Mathias M; Rarey, Matthias

2017-04-01

Ligand-based virtual screening has proven to be a viable technology during the search for new lead structures in drug discovery. Despite the rapidly increasing number of published methods, meaningful shape matching as well as ligand and target flexibility still remain open challenges. In this work, we analyze the influence of knowledge-based sterical constraints on the performance of the recently published ligand-based virtual screening method mRAISE. We introduce the concept of partial shape matching enabling a more differentiated view on chemical structure. The new method is integrated into the LBVS tool mRAISE providing multiple options for such constraints. The applied constraints can either be derived automatically from a protein-ligand complex structure or by manual selection of ligand atoms. In this way, the descriptor directly encodes the fit of a ligand into the binding site. Furthermore, the conservation of close contacts between the binding site surface and the query ligand can be enforced. We validated our new method on the DUD and DUD-E datasets. Although the statistical performance remains on the same level, detailed analysis reveal that for certain and especially very flexible targets a significant improvement can be achieved. This is further highlighted looking at the quality of calculated molecular alignments using the recently introduced mRAISE dataset. The new partial shape constraints improved the overall quality of molecular alignments especially for difficult targets with highly flexible or different sized molecules. The software tool mRAISE is freely available on Linux operating systems for evaluation purposes and academic use (see http://www.zbh.uni-hamburg.de/raise ).

Ligand-based virtual screening under partial shape constraints

NASA Astrophysics Data System (ADS)

von Behren, Mathias M.; Rarey, Matthias

2017-04-01

Ligand-based virtual screening has proven to be a viable technology during the search for new lead structures in drug discovery. Despite the rapidly increasing number of published methods, meaningful shape matching as well as ligand and target flexibility still remain open challenges. In this work, we analyze the influence of knowledge-based sterical constraints on the performance of the recently published ligand-based virtual screening method mRAISE. We introduce the concept of partial shape matching enabling a more differentiated view on chemical structure. The new method is integrated into the LBVS tool mRAISE providing multiple options for such constraints. The applied constraints can either be derived automatically from a protein-ligand complex structure or by manual selection of ligand atoms. In this way, the descriptor directly encodes the fit of a ligand into the binding site. Furthermore, the conservation of close contacts between the binding site surface and the query ligand can be enforced. We validated our new method on the DUD and DUD-E datasets. Although the statistical performance remains on the same level, detailed analysis reveal that for certain and especially very flexible targets a significant improvement can be achieved. This is further highlighted looking at the quality of calculated molecular alignments using the recently introduced mRAISE dataset. The new partial shape constraints improved the overall quality of molecular alignments especially for difficult targets with highly flexible or different sized molecules. The software tool mRAISE is freely available on Linux operating systems for evaluation purposes and academic use (see http://www.zbh.uni-hamburg.de/raise).

Autonomous Rover Traverse and Precise Arm Placement on Remotely Designated Targets

NASA Technical Reports Server (NTRS)

Nesnas, Issa A.; Pivtoraiko, Mihail N.; Kelly, Alonzo; Fleder, Michael

2012-01-01

This software controls a rover platform to traverse rocky terrain autonomously, plan paths, and avoid obstacles using its stereo hazard and navigation cameras. It does so while continuously tracking a target of interest selected from 10 20 m away. The rover drives and tracks the target until it reaches the vicinity of the target. The rover then positions itself to approach the target, deploys its robotic arm, and places the end effector instrument on the designated target to within 2-3-cm accuracy of the originally selected target. This software features continuous navigation in a fairly rocky field in an outdoor environment and the ability to enable the rover to avoid large rocks and traverse over smaller ones. Using point-and-click mouse commands, a scientist designates targets in the initial imagery acquired from the rover s mast cameras. The navigation software uses stereo imaging, traversability analysis, path planning, trajectory generation, and trajectory execution. It also includes visual target tracking of a designated target selected from 10 m away while continuously navigating the rocky terrain. Improvements in this design include steering while driving, which uses continuous curvature paths. There are also several improvements to the traversability analyzer, including improved data fusion of traversability maps that result from pose estimation uncertainties, dealing with boundary effects to enable tighter maneuvers, and handling a wider range of obstacles. This work advances what has been previously developed and integrated on the Mars Exploration Rovers by using algorithms that are capable of traversing more rock-dense terrains, enabling tight, thread-the-needle maneuvers. These algorithms were integrated on the newly refurbished Athena Mars research rover, and were fielded in the JPL Mars Yard. Forty-three runs were conducted with targets at distances ranging from 5 to 15 m, and a success rate of 93% was achieved for placement of the instrument within

Autonomous Rover Traverse and Precise Arm Placement on Remotely Designated Targets

NASA Technical Reports Server (NTRS)

Felder, Michael; Nesnas, Issa A.; Pivtoraiko, Mihail; Kelly, Alonzo; Volpe, Richard

2011-01-01

Exploring planetary surfaces typically involves traversing challenging and unknown terrain and acquiring in-situ measurements at designated locations using arm-mounted instruments. We present field results for a new implementation of an autonomous capability that enables a rover to traverse and precisely place an arm-mounted instrument on remote targets. Using point-and-click mouse commands, a scientist designates targets in the initial imagery acquired from the rover's mast cameras. The rover then autonomously traverse the rocky terrain for a distance of 10 - 15 m, tracks the target(s) of interest during the traverse, positions itself for approaching the target, and then precisely places an arm-mounted instrument within 2-3 cm from the originally designated target. The rover proceeds to acquire science measurements with the instrument. This work advances what has been previously developed and integrated on the Mars Exploration Rovers by using algorithms that are capable of traversing more rock-dense terrains, enabling tight thread-the-needle maneuvers. We integrated these algorithms on the newly refurbished Athena Mars research rover and fielded them in the JPL Mars Yard. We conducted 43 runs with targets at distances ranging from 5 m to 15 m and achieved a success rate of 93% for placement of the instrument within 2-3 cm.

RNAblueprint: flexible multiple target nucleic acid sequence design.

PubMed

Hammer, Stefan; Tschiatschek, Birgit; Flamm, Christoph; Hofacker, Ivo L; Findeiß, Sven

2017-09-15

Realizing the value of synthetic biology in biotechnology and medicine requires the design of molecules with specialized functions. Due to its close structure to function relationship, and the availability of good structure prediction methods and energy models, RNA is perfectly suited to be synthetically engineered with predefined properties. However, currently available RNA design tools cannot be easily adapted to accommodate new design specifications. Furthermore, complicated sampling and optimization methods are often developed to suit a specific RNA design goal, adding to their inflexibility. We developed a C ++  library implementing a graph coloring approach to stochastically sample sequences compatible with structural and sequence constraints from the typically very large solution space. The approach allows to specify and explore the solution space in a well defined way. Our library also guarantees uniform sampling, which makes optimization runs performant by not only avoiding re-evaluation of already found solutions, but also by raising the probability of finding better solutions for long optimization runs. We show that our software can be combined with any other software package to allow diverse RNA design applications. Scripting interfaces allow the easy adaption of existing code to accommodate new scenarios, making the whole design process very flexible. We implemented example design approaches written in Python to demonstrate these advantages. RNAblueprint , Python implementations and benchmark datasets are available at github: https://github.com/ViennaRNA . s.hammer@univie.ac.at, ivo@tbi.univie.ac.at or sven@tbi.univie.ac.at. Supplementary data are available at Bioinformatics online. © The Author(s) 2017. Published by Oxford University Press.

Understanding spearfishing in a coral reef fishery: Fishers' opportunities, constraints, and decision-making.

PubMed

Pavlowich, Tyler; Kapuscinski, Anne R

2017-01-01

Social and ecological systems come together during the act of fishing. However, we often lack a deep understanding of the fishing process, despite its importance for understanding and managing fisheries. A quantitative, mechanistic understanding of the opportunities fishers encounter, the constraints they face, and how they make decisions within the context of opportunities and constraints will enhance the design of fisheries management strategies to meet linked ecological and social objectives and will improve scientific capacity to predict impacts of different strategies. We examined the case of spearfishing in a Caribbean coral reef fishery. We mounted cameras on fishers' spearguns to observe the fish they encountered, what limited their ability to catch fish, and how they made decisions about which fish to target. We observed spearfishers who dove with and without the assistance of compressed air, and compared the fishing process of each method using content analysis of videos and decision models of fishers' targeting selections. Compressor divers encountered more fish, took less time to catch each fish, and had a higher rate of successful pursuits. We also analyzed differences among taxa in this multispecies fishery, because some taxa are known to be ecologically or economically more valuable than others. Parrotfish are ecologically indispensable for healthy coral reefs, and they were encountered and captured more frequently than any other taxon. Fishers made decisions about which fish to target based on a fish's market value, proximity to the fisher, and taxon. The information uncovered on fishers' opportunities, constraints, and decision making has implications for managing this fishery and others. Moreover, it demonstrates the value of pursuing an improved understanding of the fishing process from the perspective of the fishers.

Selection and trajectory design to mission secondary targets

NASA Astrophysics Data System (ADS)

Victorino Sarli, Bruno; Kawakatsu, Yasuhiro

2017-02-01

Recently, with new trajectory design techniques and use of low-thrust propulsion systems, missions have become more efficient and cheaper with respect to propellant. As a way to increase the mission's value and scientific return, secondary targets close to the main trajectory are often added with a small change in the transfer trajectory. As a result of their large number, importance and facility to perform a flyby, asteroids are commonly used as such targets. This work uses the Primer Vector theory to define the direction and magnitude of the thrust for a minimum fuel consumption problem. The design of a low-thrust trajectory with a midcourse asteroid flyby is not only challenging for the low-thrust problem solution, but also with respect to the selection of a target and its flyby point. Currently more than 700,000 minor bodies have been identified, which generates a very large number of possible flyby points. This work uses a combination of reachability, reference orbit, and linear theory to select appropriate candidates, drastically reducing the simulation time, to be later included in the main trajectory and optimized. Two test cases are presented using the aforementioned selection process and optimization to add and design a secondary flyby to a mission with the primary objective of 3200 Phaethon flyby and 25143 Itokawa rendezvous.

Conceptual Design Optimization of an Augmented Stability Aircraft Incorporating Dynamic Response and Actuator Constraints

NASA Technical Reports Server (NTRS)

Welstead, Jason; Crouse, Gilbert L., Jr.

2014-01-01

Empirical sizing guidelines such as tail volume coefficients have long been used in the early aircraft design phases for sizing stabilizers, resulting in conservatively stable aircraft. While successful, this results in increased empty weight, reduced performance, and greater procurement and operational cost relative to an aircraft with optimally sized surfaces. Including flight dynamics in the conceptual design process allows the design to move away from empirical methods while implementing modern control techniques. A challenge of flight dynamics and control is the numerous design variables, which are changing fluidly throughout the conceptual design process, required to evaluate the system response to some disturbance. This research focuses on addressing that challenge not by implementing higher order tools, such as computational fluid dynamics, but instead by linking the lower order tools typically used within the conceptual design process so each discipline feeds into the other. In thisresearch, flight dynamics and control was incorporated into the conceptual design process along with the traditional disciplines of vehicle sizing, weight estimation, aerodynamics, and performance. For the controller, a linear quadratic regulator structure with constant gains has been specified to reduce the user input. Coupling all the disciplines in the conceptual design phase allows the aircraft designer to explore larger design spaces where stabilizers are sized according to dynamic response constraints rather than historical static margin and volume coefficient guidelines.

Design of the next generation target at Lujan center, LANSCE.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ferres, Laurent

2016-07-27

This is a presentation given at Los Alamos National Laboratory (LANL) on the design of the next generation target at Lujan center, LANSCE. The motivation for this design is to enable new nuclear physics experiments (defense program applications (DANCE)) that are currently limited by neutron intensity or energy resolution available at LANSCE. The target is being redesigned so that the Flight Paths in the upper tier provide a higher intensity in the epithermal and medium energy ranges.

Advanced Divertor Design and Application under Modern Superconducting Tokamak Constraints

NASA Astrophysics Data System (ADS)

Covele, Brent; Kotschenreuther, Mike; Mahajan, Swadesh; Valanju, Prashant

2013-10-01

With current ITER projections already predicting divertor exhaust heat loads in the 5-10 MW/m2 range, i.e. at the maximum tolerance, it is clear that the divertor heat load problem will only be exacerbated for future superconducting tokamaks, as well as perhaps some modern tokamaks today. Thus, an advanced divertor, such as the X-Divertor (XD), Super-X Divertor (SXD), or Snowflake (SF) will become a virtual necessity to reduce incident heat flux at the target plates. Using the 2D magnetic equilibrium code CORSICA, we explore the possibilities of creating an advanced divertor for a next-generation superconducting tokamak (Ip = 15 MA, BT = 5.3 T, R = 6.2 m) under nominal engineering constraints. Advanced divertors were achieved with no in-vessel PF coils, PF current densities below 30 MA/m2, and vertical maintenance access, all of which are favorable conditions for tokamaks today. Both the XD and SF divertors are readily achievable while maintaining core plasma performance, and the advantages and disadvantages of each are discussed in turn. Some thought is given as to how the divertor cassette will need to be modified to accommodate advanced divertors. Work supported under US-DOE projects DE-FG02-04ER54742 and DE-FG02-04ER54754.

RobOKoD: microbial strain design for (over)production of target compounds.

PubMed

Stanford, Natalie J; Millard, Pierre; Swainston, Neil

2015-01-01

Sustainable production of target compounds such as biofuels and high-value chemicals for pharmaceutical, agrochemical, and chemical industries is becoming an increasing priority given their current dependency upon diminishing petrochemical resources. Designing these strains is difficult, with current methods focusing primarily on knocking-out genes, dismissing other vital steps of strain design including the overexpression and dampening of genes. The design predictions from current methods also do not translate well-into successful strains in the laboratory. Here, we introduce RobOKoD (Robust, Overexpression, Knockout and Dampening), a method for predicting strain designs for overproduction of targets. The method uses flux variability analysis to profile each reaction within the system under differing production percentages of target-compound and biomass. Using these profiles, reactions are identified as potential knockout, overexpression, or dampening targets. The identified reactions are ranked according to their suitability, providing flexibility in strain design for users. The software was tested by designing a butanol-producing Escherichia coli strain, and was compared against the popular OptKnock and RobustKnock methods. RobOKoD shows favorable design predictions, when predictions from these methods are compared to a successful butanol-producing experimentally-validated strain. Overall RobOKoD provides users with rankings of predicted beneficial genetic interventions with which to support optimized strain design.

A target design for irradiation of NaI at high beam current.

NASA Technical Reports Server (NTRS)

Blue, J. W.; Sodd, V. J.

1972-01-01

A solution to the targetry problems encountered when the iodine nucleus is a target for cyclotron irradiation is given as a new target design. A target based on this design has been used in 30 microampere irradiations of 46 MeV alpha particles for one-half hour without significant damage. Such an irradiation produces 6 to 7 mCi of Cs-129, an isotope useful in nuclear medicine. This target should also be considered for cyclotron production of the radioisotopes Cs-127, I-123, and Xe-127.

High-efficiency-release targets for use at ISOL facilities: computational design

NASA Astrophysics Data System (ADS)

Liu, Y.; Alton, G. D.

1999-12-01

This report describes efforts made at the Oak Ridge National Laboratory to design high-efficiency-release targets that simultaneously incorporate the short diffusion lengths, high permeabilities, controllable temperatures, and heat-removal properties required for the generation of useful radioactive ion beam (RIB) intensities for nuclear physics and astrophysics research using the isotope separation on-line (ISOL) technique. Short diffusion lengths are achieved either by using thin fibrous target materials or by coating thin layers of selected target material onto low-density carbon fibers such as reticulated-vitreous-carbon fiber (RVCF) or carbon-bonded-carbon fiber (CBCF) to form highly permeable composite target matrices. Computational studies that simulate the generation and removal of primary beam deposited heat from target materials have been conducted to optimize the design of target/heat-sink systems for generating RIBs. The results derived from diffusion release-rate simulation studies for selected targets and thermal analyses of temperature distributions within a prototype target/heat-sink system subjected to primary ion beam irradiation are presented in this report.

Optimization of Wireless Transceivers under Processing Energy Constraints

NASA Astrophysics Data System (ADS)

Wang, Gaojian; Ascheid, Gerd; Wang, Yanlu; Hanay, Oner; Negra, Renato; Herrmann, Matthias; Wehn, Norbert

2017-09-01

Focus of the article is on achieving maximum data rates under a processing energy constraint. For a given amount of processing energy per information bit, the overall power consumption increases with the data rate. When targeting data rates beyond 100 Gb/s, the system's overall power consumption soon exceeds the power which can be dissipated without forced cooling. To achieve a maximum data rate under this power constraint, the processing energy per information bit must be minimized. Therefore, in this article, suitable processing efficient transmission schemes together with energy efficient architectures and their implementations are investigated in a true cross-layer approach. Target use cases are short range wireless transmitters working at carrier frequencies around 60 GHz and bandwidths between 1 GHz and 10 GHz.

Dynamic Financial Constraints: Distinguishing Mechanism Design from Exogenously Incomplete Regimes*

PubMed Central

Karaivanov, Alexander; Townsend, Robert M.

2014-01-01

We formulate and solve a range of dynamic models of constrained credit/insurance that allow for moral hazard and limited commitment. We compare them to full insurance and exogenously incomplete financial regimes (autarky, saving only, borrowing and lending in a single asset). We develop computational methods based on mechanism design, linear programming, and maximum likelihood to estimate, compare, and statistically test these alternative dynamic models with financial/information constraints. Our methods can use both cross-sectional and panel data and allow for measurement error and unobserved heterogeneity. We estimate the models using data on Thai households running small businesses from two separate samples. We find that in the rural sample, the exogenously incomplete saving only and borrowing regimes provide the best fit using data on consumption, business assets, investment, and income. Family and other networks help consumption smoothing there, as in a moral hazard constrained regime. In contrast, in urban areas, we find mechanism design financial/information regimes that are decidedly less constrained, with the moral hazard model fitting best combined business and consumption data. We perform numerous robustness checks in both the Thai data and in Monte Carlo simulations and compare our maximum likelihood criterion with results from other metrics and data not used in the estimation. A prototypical counterfactual policy evaluation exercise using the estimation results is also featured. PMID:25246710

Spatial, socio-economic, and ecological implications of incorporating minimum size constraints in marine protected area network design.

PubMed

Metcalfe, Kristian; Vaughan, Gregory; Vaz, Sandrine; Smith, Robert J

2015-12-01

Marine protected areas (MPAs) are the cornerstone of most marine conservation strategies, but the effectiveness of each one partly depends on its size and distance to other MPAs in a network. Despite this, current recommendations on ideal MPA size and spacing vary widely, and data are lacking on how these constraints might influence the overall spatial characteristics, socio-economic impacts, and connectivity of the resultant MPA networks. To address this problem, we tested the impact of applying different MPA size constraints in English waters. We used the Marxan spatial prioritization software to identify a network of MPAs that met conservation feature targets, whilst minimizing impacts on fisheries; modified the Marxan outputs with the MinPatch software to ensure each MPA met a minimum size; and used existing data on the dispersal distances of a range of species found in English waters to investigate the likely impacts of such spatial constraints on the region's biodiversity. Increasing MPA size had little effect on total network area or the location of priority areas, but as MPA size increased, fishing opportunity cost to stakeholders increased. In addition, as MPA size increased, the number of closely connected sets of MPAs in networks and the average distance between neighboring MPAs decreased, which consequently increased the proportion of the planning region that was isolated from all MPAs. These results suggest networks containing large MPAs would be more viable for the majority of the region's species that have small dispersal distances, but dispersal between MPA sets and spill-over of individuals into unprotected areas would be reduced. These findings highlight the importance of testing the impact of applying different MPA size constraints because there are clear trade-offs that result from the interaction of size, number, and distribution of MPAs in a network. © 2015 Society for Conservation Biology.

Targeting legume loci: A comparison of three methods for target enrichment bait design in Leguminosae phylogenomics.

PubMed

Vatanparast, Mohammad; Powell, Adrian; Doyle, Jeff J; Egan, Ashley N

2018-03-01

The development of pipelines for locus discovery has spurred the use of target enrichment for plant phylogenomics. However, few studies have compared pipelines from locus discovery and bait design, through validation, to tree inference. We compared three methods within Leguminosae (Fabaceae) and present a workflow for future efforts. Using 30 transcriptomes, we compared Hyb-Seq, MarkerMiner, and the Yang and Smith (Y&S) pipelines for locus discovery, validated 7501 baits targeting 507 loci across 25 genera via Illumina sequencing, and inferred gene and species trees via concatenation- and coalescent-based methods. Hyb-Seq discovered loci with the longest mean length. MarkerMiner discovered the most conserved loci with the least flagged as paralogous. Y&S offered the most parsimony-informative sites and putative orthologs. Target recovery averaged 93% across taxa. We optimized our targeted locus set based on a workflow designed to minimize paralog/ortholog conflation and thus present 423 loci for legume phylogenomics. Methods differed across criteria important for phylogenetic marker development. We recommend Hyb-Seq as a method that may be useful for most phylogenomic projects. Our targeted locus set is a resource for future, community-driven efforts to reconstruct the legume tree of life.

Methods to enable the design of bioactive small molecules targeting RNA.

PubMed

Disney, Matthew D; Yildirim, Ilyas; Childs-Disney, Jessica L

2014-02-21

RNA is an immensely important target for small molecule therapeutics or chemical probes of function. However, methods that identify, annotate, and optimize RNA-small molecule interactions that could enable the design of compounds that modulate RNA function are in their infancies. This review describes recent approaches that have been developed to understand and optimize RNA motif-small molecule interactions, including structure-activity relationships through sequencing (StARTS), quantitative structure-activity relationships (QSAR), chemical similarity searching, structure-based design and docking, and molecular dynamics (MD) simulations. Case studies described include the design of small molecules targeting RNA expansions, the bacterial A-site, viral RNAs, and telomerase RNA. These approaches can be combined to afford a synergistic method to exploit the myriad of RNA targets in the transcriptome.

Grammatical constraints on phonological encoding in speech production.

PubMed

Heller, Jordana R; Goldrick, Matthew

2014-12-01

To better understand the influence of grammatical encoding on the retrieval and encoding of phonological word-form information during speech production, we examine how grammatical class constraints influence the activation of phonological neighbors (words phonologically related to the target--e.g., MOON, TWO for target TUNE). Specifically, we compare how neighbors that share a target's grammatical category (here, nouns) influence its planning and retrieval, assessed by picture naming latencies, and phonetic encoding, assessed by word productions in picture names, when grammatical constraints are strong (in sentence contexts) versus weak (bare naming). Within-category (noun) neighbors influenced planning time and phonetic encoding more strongly in sentence contexts. This suggests that grammatical encoding constrains phonological processing; the influence of phonological neighbors is grammatically dependent. Moreover, effects on planning times could not fully account for phonetic effects, suggesting that phonological interaction affects articulation after speech onset. These results support production theories integrating grammatical, phonological, and phonetic processes.

Test Information Targeting Strategies for Adaptive Multistage Testing Designs.

ERIC Educational Resources Information Center

Luecht, Richard M.; Burgin, William

Adaptive multistage testlet (MST) designs appear to be gaining popularity for many large-scale computer-based testing programs. These adaptive MST designs use a modularized configuration of preconstructed testlets and embedded score-routing schemes to prepackage different forms of an adaptive test. The conditional information targeting (CIT)…

Design of the polar neutron-imaging aperture for use at the National Ignition Facility.

PubMed

Fatherley, V E; Barker, D A; Fittinghoff, D N; Hibbard, R L; Martinez, J I; Merrill, F E; Oertel, J A; Schmidt, D W; Volegov, P L; Wilde, C H

2016-11-01

The installation of a neutron imaging diagnostic with a polar view at the National Ignition Facility (NIF) required design of a new aperture, an extended pinhole array (PHA). This PHA is different from the pinhole array for the existing equatorial system due to significant changes in the alignment and recording systems. The complex set of component requirements, as well as significant space constraints in its intended location, makes the design of this aperture challenging. In addition, lessons learned from development of prior apertures mandate careful aperture metrology prior to first use. This paper discusses the PHA requirements, constraints, and the final design. The PHA design is complex due to size constraints, machining precision, assembly tolerances, and design requirements. When fully assembled, the aperture is a 15 mm × 15 mm × 200 mm tungsten and gold assembly. The PHA body is made from 2 layers of tungsten and 11 layers of gold. The gold layers include 4 layers containing penumbral openings, 4 layers containing pinholes and 3 spacer layers. In total, there are 64 individual, triangular pinholes with a field of view (FOV) of 200 μm and 6 penumbral apertures. Each pinhole is pointed to a slightly different location in the target plane, making the effective FOV of this PHA a 700 μm square in the target plane. The large FOV of the PHA reduces the alignment requirements both for the PHA and the target, allowing for alignment with a laser tracking system at NIF.

Translating Genetic Research into Preventive Intervention: The Baseline Target Moderated Mediator Design.

PubMed

Howe, George W; Beach, Steven R H; Brody, Gene H; Wyman, Peter A

2015-01-01

In this paper we present and discuss a novel research approach, the baseline target moderated mediation (BTMM) design, that holds substantial promise for advancing our understanding of how genetic research can inform prevention research. We first discuss how genetically informed research on developmental psychopathology can be used to identify potential intervention targets. We then describe the BTMM design, which employs moderated mediation within a longitudinal study to test whether baseline levels of intervention targets moderate the impact of the intervention on change in that target, and whether change in those targets mediates causal impact of preventive or treatment interventions on distal health outcomes. We next discuss how genetically informed BTMM designs can be applied to both microtrials and full-scale prevention trials. We use simulated data to illustrate a BTMM, and end with a discussion of some of the advantages and limitations of this approach.

Translating Genetic Research into Preventive Intervention: The Baseline Target Moderated Mediator Design

PubMed Central

Howe, George W.; Beach, Steven R. H.; Brody, Gene H.; Wyman, Peter A.

2016-01-01

In this paper we present and discuss a novel research approach, the baseline target moderated mediation (BTMM) design, that holds substantial promise for advancing our understanding of how genetic research can inform prevention research. We first discuss how genetically informed research on developmental psychopathology can be used to identify potential intervention targets. We then describe the BTMM design, which employs moderated mediation within a longitudinal study to test whether baseline levels of intervention targets moderate the impact of the intervention on change in that target, and whether change in those targets mediates causal impact of preventive or treatment interventions on distal health outcomes. We next discuss how genetically informed BTMM designs can be applied to both microtrials and full-scale prevention trials. We use simulated data to illustrate a BTMM, and end with a discussion of some of the advantages and limitations of this approach. PMID:26779062

Designing oral vaccines targeting intestinal dendritic cells.

PubMed

Devriendt, Bert; De Geest, Bruno G; Cox, Eric

2011-04-01

Most pathogens colonize and invade the host at mucosal surfaces, such as the lung and the intestine. To combat intestinal pathogens the induction of local adaptive immune responses is required, which is mainly achieved through oral vaccination. However, most vaccines are ineffective when given orally owing to the hostile environment in the gastrointestinal tract. The encapsulation of antigens in biodegradable microparticulate delivery systems enhances their immunogenicity; however, the uptake of these delivery systems by intestinal immune cells is rather poor. Surface decoration of the particulates with targeting ligands could increase the uptake and mediate the selective targeting of the vaccine to intestinal antigen-presenting cells, including dendritic cells. In this review, current knowledge on dendritic cell subsets is discussed, along with progress in the development of selective antigen targeting to these cells, in addition to focusing on data obtained in mice and, where possible, the pig, as a non-rodent animal model for humans. Moreover, the potential use and benefits of Fcγ receptor-mediated targeting of antigen delivery systems are highlighted. In conclusion, dendritic cell targeting ligands grafted on antigen carrier systems should preferably bind to a conserved endocytotic receptor, facilitating the design of a multispecies vaccine platform, which could elicit robust protective immune responses against enteric pathogens.

Constraints on global temperature target overshoot.

PubMed

Ricke, K L; Millar, R J; MacMartin, D G

2017-11-07

In the aftermath of the Paris Agreement, the climate science and policy communities are beginning to assess the feasibility and potential benefits of limiting global warming to 1.5 °C or 2 °C above preindustrial. Understanding the dependence of the magnitude and duration of possible temporary exceedance (i.e., "overshoot") of temperature targets on sustainable energy decarbonization futures and carbon dioxide (CO 2 ) removal rates will be an important contribution to this policy discussion. Drawing upon results from the mitigation literature and the IPCC Working Group 3 (WG3) scenario database, we examine the global mean temperature implications of differing, independent pathways for the decarbonization of global energy supply and the implementation of negative emissions technologies. We find that within the scope of scenarios broadly-consistent with the WG3 database, the magnitude of temperature overshoot is more sensitive to the rate of decarbonization. However, limiting the duration of overshoot to less than two centuries requires ambitious deployment of both decarbonization and negative emissions technology. The dependencies of temperature target overshoot's properties upon currently untested negative emissions technologies suggests that it will be important to consider how climate impacts depend on both the magnitude and duration of overshoot, not just long term residual warming.

Dead-blow hammer design applied to a calibration target mechanism to dampen excessive rebound

NASA Technical Reports Server (NTRS)

Lim, Brian Y.

1991-01-01

An existing rotary electromagnetic driver was specified to be used to deploy and restow a blackbody calibration target inside of a spacecraft infrared science instrument. However, this target was much more massive than any other previously inherited design applications. The target experienced unacceptable bounce when reaching its stops. Without any design modification, the momentum generated by the driver caused the target to bounce back to its starting position. Initially, elastomeric dampers were used between the driver and the target. However, this design could not prevent the bounce, and it compromised the positional accuracy of the calibration target. A design that successfully met all the requirements incorporated a sealed pocket 85 percent full of 0.75 mm diameter stainless steel balls in the back of the target to provide the effect of a dead-blow hammer. The energy dissipation resulting from the collision of balls in the pocket successfully dampened the excess momentum generated during the target deployment. The disastrous effects of new requirements on a design with a successful flight history, the modifications that were necessary to make the device work, and the tests performed to verify its functionality are described.

RobOKoD: microbial strain design for (over)production of target compounds

PubMed Central

Stanford, Natalie J.; Millard, Pierre; Swainston, Neil

2015-01-01

Sustainable production of target compounds such as biofuels and high-value chemicals for pharmaceutical, agrochemical, and chemical industries is becoming an increasing priority given their current dependency upon diminishing petrochemical resources. Designing these strains is difficult, with current methods focusing primarily on knocking-out genes, dismissing other vital steps of strain design including the overexpression and dampening of genes. The design predictions from current methods also do not translate well-into successful strains in the laboratory. Here, we introduce RobOKoD (Robust, Overexpression, Knockout and Dampening), a method for predicting strain designs for overproduction of targets. The method uses flux variability analysis to profile each reaction within the system under differing production percentages of target-compound and biomass. Using these profiles, reactions are identified as potential knockout, overexpression, or dampening targets. The identified reactions are ranked according to their suitability, providing flexibility in strain design for users. The software was tested by designing a butanol-producing Escherichia coli strain, and was compared against the popular OptKnock and RobustKnock methods. RobOKoD shows favorable design predictions, when predictions from these methods are compared to a successful butanol-producing experimentally-validated strain. Overall RobOKoD provides users with rankings of predicted beneficial genetic interventions with which to support optimized strain design. PMID:25853130

A heuristic constraint programmed planner for deep space exploration problems

NASA Astrophysics Data System (ADS)

Jiang, Xiao; Xu, Rui; Cui, Pingyuan

2017-10-01

In recent years, the increasing numbers of scientific payloads and growing constraints on the probe have made constraint processing technology a hotspot in the deep space planning field. In the procedure of planning, the ordering of variables and values plays a vital role. This paper we present two heuristic ordering methods for variables and values. On this basis a graphplan-like constraint-programmed planner is proposed. In the planner we convert the traditional constraint satisfaction problem to a time-tagged form with different levels. Inspired by the most constrained first principle in constraint satisfaction problem (CSP), the variable heuristic is designed by the number of unassigned variables in the constraint and the value heuristic is designed by the completion degree of the support set. The simulation experiments show that the planner proposed is effective and its performance is competitive with other kind of planners.

Methods to enable the design of bioactive small molecules targeting RNA

PubMed Central

Disney, Matthew D.; Yildirim, Ilyas; Childs-Disney, Jessica L.

2014-01-01

RNA is an immensely important target for small molecule therapeutics or chemical probes of function. However, methods that identify, annotate, and optimize RNA-small molecule interactions that could enable the design of compounds that modulate RNA function are in their infancies. This review describes recent approaches that have been developed to understand and optimize RNA motif-small molecule interactions, including Structure-Activity Relationships Through Sequencing (StARTS), quantitative structure-activity relationships (QSAR), chemical similarity searching, structure-based design and docking, and molecular dynamics (MD) simulations. Case studies described include the design of small molecules targeting RNA expansions, the bacterial A-site, viral RNAs, and telomerase RNA. These approaches can be combined to afford a synergistic method to exploit the myriad of RNA targets in the transcriptome. PMID:24357181

Design of a three-dimensional scramjet nozzle considering lateral expansion and geometric constraints

NASA Astrophysics Data System (ADS)

Lv, Zheng; Xu, Jinglei; Mo, Jianwei

2017-12-01

A new method based on quasi two-dimensional supersonic flow and maximum thrust theory to design a three-dimensional nozzle while considering lateral expansion and geometric constraints is presented in this paper. To generate the configuration of the three-dimensional nozzle, the inviscid flowfield is calculated through the method of characteristics, and the reference temperature method is applied to correct the boundary layer thickness. The computational fluid dynamics approach is used to obtain the aerodynamic performance of the nozzle. Results show that the initial arc radius slightly influences the axial thrust coefficient, whereas the variations in the lateral expansion contour, the length and initial expansion angle of the lower cowl significantly affect the axial thrust coefficient. The three-dimensional nozzle designed by streamline tracing technique is also investigated for comparison to verify the superiority of the new method. The proposed nozzle shows increases in the axial thrust coefficient, lift, and pitching moment of 6.86%, 203.15%, and 642.86%, respectively, at the design point, compared with the nozzle designed by streamline tracing approach. In addition, the lateral expansion accounts for 22.46% of the entire axial thrust, while it has no contribution to the lift and pitching moment in the proposed nozzle.

Injector design for liner-on-target gas-puff experiments

NASA Astrophysics Data System (ADS)

Valenzuela, J. C.; Krasheninnikov, I.; Conti, F.; Wessel, F.; Fadeev, V.; Narkis, J.; Ross, M. P.; Rahman, H. U.; Ruskov, E.; Beg, F. N.

2017-11-01

We present the design of a gas-puff injector for liner-on-target experiments. The injector is composed of an annular high atomic number (e.g., Ar and Kr) gas and an on-axis plasma gun that delivers an ionized deuterium target. The annular supersonic nozzle injector has been studied using Computational Fluid Dynamics (CFD) simulations to produce a highly collimated (M > 5), ˜1 cm radius gas profile that satisfies the theoretical requirement for best performance on ˜1-MA current generators. The CFD simulations allowed us to study output density profiles as a function of the nozzle shape, gas pressure, and gas composition. We have performed line-integrated density measurements using a continuous wave (CW) He-Ne laser to characterize the liner gas density. The measurements agree well with the CFD values. We have used a simple snowplow model to study the plasma sheath acceleration in a coaxial plasma gun to help us properly design the target injector.

Injector design for liner-on-target gas-puff experiments.

PubMed

Valenzuela, J C; Krasheninnikov, I; Conti, F; Wessel, F; Fadeev, V; Narkis, J; Ross, M P; Rahman, H U; Ruskov, E; Beg, F N

2017-11-01

We present the design of a gas-puff injector for liner-on-target experiments. The injector is composed of an annular high atomic number (e.g., Ar and Kr) gas and an on-axis plasma gun that delivers an ionized deuterium target. The annular supersonic nozzle injector has been studied using Computational Fluid Dynamics (CFD) simulations to produce a highly collimated (M > 5), ∼1 cm radius gas profile that satisfies the theoretical requirement for best performance on ∼1-MA current generators. The CFD simulations allowed us to study output density profiles as a function of the nozzle shape, gas pressure, and gas composition. We have performed line-integrated density measurements using a continuous wave (CW) He-Ne laser to characterize the liner gas density. The measurements agree well with the CFD values. We have used a simple snowplow model to study the plasma sheath acceleration in a coaxial plasma gun to help us properly design the target injector.

The WFIRST Interim Design Reference Mission: Capabilities, Constraints, and Open Questions

NASA Technical Reports Server (NTRS)

Kruk, Jeffrey W.

2012-01-01

The Project Office and Science Definition Team for the Wide-Field Infrared Survey Telescope (WFIRST) are in the midst of a pre-Phase A study to establish a Design Reference Mission (DRM). An Interim report was released in June 2011, with a final report due later in 2012. The predicted performance of the Interim DRM Observatory will be described, including optical quality, observing efficiency, and sensitivity for representative observing scenarios. Observing constraints and other limitations on performance will also be presented, with an emphasis on potential Guest Observer programs. Finally, a brief status update will be provided on open trade studies of interest to the scientific community. The final DRM may differ from the Interim DRM presented here. However, the underlying requirements of the scientific programs are not expected to change, hence the capabilities of the IDRM are likely to be maintained even if the implementation changes in significant ways.

Constraints on global temperature target overshoot

NASA Astrophysics Data System (ADS)

MacMartin, D. G.; Ricke, K.; Millar, R.

2016-12-01

The climate science and policy communities are beginning to assess the feasibility and potential benefits of limiting global warming to 1.5°C or 2°C. Understanding the dependence of the magnitude and duration of possible temporary exceedance (i.e., "overshoot") of these targets on sustainable energy decarbonization futures and carbon dioxide (CO2) removal rates will be an important contribution of the scientific community to this policy discussion. Drawing upon results from the mitigation literature and the IPCC Working Group 3 (WG3) scenario database, we examine the global mean temperature implications of differing independent pathways for the decarbonization of global energy supply and the implementation of negative emissions technologies. We find that within the range of decarbonization and negative emissions futures considered by WG3, the most ambitious rates of both decarbonization and deployment of negative emissions technologies are required to avoid overshoot of 1.5°C. The magnitude of temperature overshoot is more sensitive to the rate of decarbonization, but limiting the duration of overshoot to less than two centuries will require ambitious deployment of both decarbonization and negative emissions technology. The dependencies of temperature overshoots properties upon currently untested negative emissions technologies suggests that it will be important to assess how climate impacts depend on the magnitude and duration of overshoot, not just long term residual warming. As a new round of research proceeds with a 1.5°C threshold in mind, it will be important to understand the drivers behind various global temperature linked impacts and how these are influenced by both the duration and magnitude of a temporary overshoot of the target. This understanding will allow policy makers to better link climate policy goals to specific technological needs. Figure: Magnitude and duration of 1.5°C temperature target overshoot for "likely" range of climate response

Adaptive waveform optimization design for target detection in cognitive radar

NASA Astrophysics Data System (ADS)

Zhang, Xiaowen; Wang, Kaizhi; Liu, Xingzhao

2017-01-01

The problem of adaptive waveform design for target detection in cognitive radar (CR) is investigated. This problem is analyzed in signal-dependent interference, as well as additive channel noise for extended target with unknown target impulse response (TIR). In order to estimate the TIR accurately, the Kalman filter is used in target tracking. In each Kalman filtering iteration, a flexible online waveform spectrum optimization design taking both detection and range resolution into account is modeled in Fourier domain. Unlike existing CR waveform, the proposed waveform can be simultaneously updated according to the environment information fed back by receiver and radar performance demands. Moreover, the influence of waveform spectral phase to radar performance is analyzed. Simulation results demonstrate that CR with the proposed waveform performs better than a traditional radar system with a fixed waveform and offers more flexibility and suitability. In addition, waveform spectral phase will not influence tracking, detection, and range resolution performance but will greatly influence waveform forming speed and peak-to-average power ratio.

Conceptual design considerations and neutronics of lithium fall laser fusion target chambers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Meier, W.R.; Thomson, W.B.

1978-05-31

Atomics International and Lawrence Livermore Laboratory are involved in the conceptual design of a laser fusion power plant incorporating the lithium fall target chamber. In this paper we discuss some of the more important design considerations for the target chamber and evaluate its nuclear performance. Sizing and configuration of the fall, hydraulic effects, and mechanical design considerations are addressed. The nuclear aspects examined include tritium breeding, energy deposition, and radiation damage.

Advances in target design for heavy ion fusion

NASA Astrophysics Data System (ADS)

Callahan, D. A.; Tabak, M.; Bennett, G. R.; Cuneo, M. E.; Vesey, R. A.; Nikroo, A.; Czechowicz, D.; Steinman, D.

2005-12-01

Over the past few years, the emphasis in heavy ion target design has moved from the distributed radiator target to the 'hybrid' target because the hybrid target allows a larger beam focal spot than the distributed radiator (~5 mm radius rather than ~2 mm radius). The larger spot relaxes some of the requirements on the driver, but introduces some new target physics issues. Most notable is the use of shine shields and shims in the hohlraum to achieve symmetry rather than achieving symmetry by beam placement. The shim is a thin layer of material placed on or near the capsule surface to block a small amount of excess radiation. While we have been developing this technique for the heavy ion hybrid target, the technique can also be used in any indirect drive target. We have begun testing the concept of a shim to improve symmetry using a double-ended z-pinch hohlraum on the Sandia Z-machine. Experiments using shimmed thin wall capsules have shown that we can reverse the sign of a P2 asymmetry and significantly reduce the size of a P4 asymmetry. These initial experiments demonstrate the concept of a shim as another method for controlling early time asymmetries in ICF capsules.

Designing an Active Target Test Projection Chamber

NASA Astrophysics Data System (ADS)

Koci, James; Tan Ahn Collaboration, Dr.; Nicolas Dixneuf Collaboration

2015-10-01

The development of instrumentation in nuclear physics is crucial for advancing our ability to measure the properties of exotic nuclei. One limitation of the use of exotic nuclei in experiment is their very low production intensities. Recently, detectors, called active-target dectectors, have been developed to address this issue. Active-target detectors use a gas medium to image charged-particle tracks that are emitted in nuclear reactions. Last semester, I designed a vacuum chamber to be used in developing Micro-Pattern Gas detectors that will upgrade the capabilities of an active-target detector called the Prototype AT-TPC. With the exterior of the chamber complete, I have now been using an electric field modeling program, Garfield, developed by CERN to design a field cage to be placed within the vacuum chamber. The field cage will be a box-like apparatus consisting of two parallel metal plates connected with a resistor chain and attached to wires wrapped between them. The cage will provide a uniform electric field within the chamber to drift electrons from nuclear reactions down to the detector in the bottom of the chamber. These signals are then amplified by a proportional counter, and the data is sent to a computer. For the long term, we would like to incorporate a Micro-Pattern Gas Detectors in the interior of the chamber and eventually use the AT-TPC to examine various nuclei. Dr. Ahn is my advising professor.

UAVs Task and Motion Planning in the Presence of Obstacles and Prioritized Targets

PubMed Central

Gottlieb, Yoav; Shima, Tal

2015-01-01

The intertwined task assignment and motion planning problem of assigning a team of fixed-winged unmanned aerial vehicles to a set of prioritized targets in an environment with obstacles is addressed. It is assumed that the targets’ locations and initial priorities are determined using a network of unattended ground sensors used to detect potential threats at restricted zones. The targets are characterized by a time-varying level of importance, and timing constraints must be fulfilled before a vehicle is allowed to visit a specific target. It is assumed that the vehicles are carrying body-fixed sensors and, thus, are required to approach a designated target while flying straight and level. The fixed-winged aerial vehicles are modeled as Dubins vehicles, i.e., having a constant speed and a minimum turning radius constraint. The investigated integrated problem of task assignment and motion planning is posed in the form of a decision tree, and two search algorithms are proposed: an exhaustive algorithm that improves over run time and provides the minimum cost solution, encoded in the tree, and a greedy algorithm that provides a quick feasible solution. To satisfy the target’s visitation timing constraint, a path elongation motion planning algorithm amidst obstacles is provided. Using simulations, the performance of the algorithms is compared, evaluated and exemplified. PMID:26610522

Trajectory Design and Control for the Compton Gamma Ray Observatory Re-Entry

NASA Technical Reports Server (NTRS)

Hoge, Susan; Vaughn, Frank J., Jr.

2001-01-01

The Compton Gamma Ray Observatory (CGRO) controlled re-entry operation was successfully conducted in June of 2000. The surviving parts of the spacecraft landed in the Pacific Ocean within the nominal impact target zone. The design of the maneuvers to control the trajectory to accomplish this re-entry presented several challenges. These challenges included the timing and duration of the maneuvers, propellant management, post-maneuver state determination, collision avoidance with other spacecraft, accounting for the break-up of the spacecraft into several pieces with a wide range of ballistic coefficients, and ensuring that the impact footprint would remain within the desired impact target zone in the event of contingencies. This paper presents the initial re-entry trajectory design and traces the evolution of that design into the maneuver sequence used for the re-entry. The paper also discusses the spacecraft systems and operational constraints imposed on the trajectory design and the required modifications to the initial design based on those constraints. Data from the reentry operation are also presented.

Linear-constraint wavefront control for exoplanet coronagraphic imaging systems

NASA Astrophysics Data System (ADS)

Sun, He; Eldorado Riggs, A. J.; Kasdin, N. Jeremy; Vanderbei, Robert J.; Groff, Tyler Dean

2017-01-01

A coronagraph is a leading technology for achieving high-contrast imaging of exoplanets in a space telescope. It uses a system of several masks to modify the diffraction and achieve extremely high contrast in the image plane around target stars. However, coronagraphic imaging systems are very sensitive to optical aberrations, so wavefront correction using deformable mirrors (DMs) is necessary to avoid contrast degradation in the image plane. Electric field conjugation (EFC) and Stroke minimization (SM) are two primary high-contrast wavefront controllers explored in the past decade. EFC minimizes the average contrast in the search areas while regularizing the strength of the control inputs. Stroke minimization calculates the minimum DM commands under the constraint that a target average contrast is achieved. Recently in the High Contrast Imaging Lab at Princeton University (HCIL), a new linear-constraint wavefront controller based on stroke minimization was developed and demonstrated using numerical simulation. Instead of only constraining the average contrast over the entire search area, the new controller constrains the electric field of each single pixel using linear programming, which could led to significant increases in speed of the wavefront correction and also create more uniform dark holes. As a follow-up of this work, another linear-constraint controller modified from EFC is demonstrated theoretically and numerically and the lab verification of the linear-constraint controllers is reported. Based on the simulation and lab results, the pros and cons of linear-constraint controllers are carefully compared with EFC and stroke minimization.

Understanding spearfishing in a coral reef fishery: Fishers’ opportunities, constraints, and decision-making

PubMed Central

Pavlowich, Tyler; Kapuscinski, Anne R.

2017-01-01

Social and ecological systems come together during the act of fishing. However, we often lack a deep understanding of the fishing process, despite its importance for understanding and managing fisheries. A quantitative, mechanistic understanding of the opportunities fishers encounter, the constraints they face, and how they make decisions within the context of opportunities and constraints will enhance the design of fisheries management strategies to meet linked ecological and social objectives and will improve scientific capacity to predict impacts of different strategies. We examined the case of spearfishing in a Caribbean coral reef fishery. We mounted cameras on fishers’ spearguns to observe the fish they encountered, what limited their ability to catch fish, and how they made decisions about which fish to target. We observed spearfishers who dove with and without the assistance of compressed air, and compared the fishing process of each method using content analysis of videos and decision models of fishers’ targeting selections. Compressor divers encountered more fish, took less time to catch each fish, and had a higher rate of successful pursuits. We also analyzed differences among taxa in this multispecies fishery, because some taxa are known to be ecologically or economically more valuable than others. Parrotfish are ecologically indispensable for healthy coral reefs, and they were encountered and captured more frequently than any other taxon. Fishers made decisions about which fish to target based on a fish’s market value, proximity to the fisher, and taxon. The information uncovered on fishers’ opportunities, constraints, and decision making has implications for managing this fishery and others. Moreover, it demonstrates the value of pursuing an improved understanding of the fishing process from the perspective of the fishers. PMID:28750077

Introduction to spallation physics and spallation-target design

DOE Office of Scientific and Technical Information (OSTI.GOV)

Russell, G.J.; Pitcher, E.J.; Daemen, L.L.

1995-10-01

When coupled with the spallation process in appropriate target materials, high-power accelerators can be used to produce large numbers of neutrons, thus providing an alternate method to the use of nuclear reactors for this purpose. Spallation offers exciting new possibilities for generating intense neutron fluxes for a variety of applications, including: (a) spallation-neutron sources for materials science research; (b) accelerator-based production of tritium; (c) accelerator-based transmutation of waste; (d) accelerator-based destruction of plutonium; and (e) radioisotope production for medical and energy applications. Target design plays a key role in these applications, with neutron production/leakage being strongly dependent on the incidentmore » particle type and energy, and target material and geometry.« less

Human Immunity and the Design of Multi-Component, Single Target Vaccines

PubMed Central

Saul, Allan; Fay, Michael P.

2007-01-01

Background Inclusion of multiple immunogens to target a single organism is a strategy being pursued for many experimental vaccines, especially where it is difficult to generate a strongly protective response from a single immunogen. Although there are many human vaccines that contain multiple defined immunogens, in almost every case each component targets a different pathogen. As a consequence, there is little practical experience for deciding where the increased complexity of vaccines with multiple defined immunogens vaccines targeting single pathogens will be justifiable. Methodology/Principal Findings A mathematical model, with immunogenicity parameters derived from a database of human responses to established vaccines, was used to predict the increase in the efficacy and the proportion of the population protected resulting from addition of further immunogens. The gains depended on the relative protection and the range of responses in the population to each immunogen and also to the correlation of the responses between immunogens. In most scenarios modeled, the gain in overall efficacy obtained by adding more immunogens was comparable to gains obtained from a single immunogen through the use of better formulations or adjuvants. Multi-component single target vaccines were more effective at decreasing the proportion of poor responders than increasing the overall efficacy of the vaccine in a population. Conclusions/Significance Inclusion of limited number of antigens in a vaccine aimed at targeting a single organism will increase efficacy, but the gains are relatively modest and for a practical vaccine there are constraints that are likely to limit multi-component single target vaccines to a small number of key antigens. The model predicts that this type of vaccine will be most useful where the critical issue is the reduction in proportion of poor responders. PMID:17786221

Computational design of trimeric influenza-neutralizing proteins targeting the hemagglutinin receptor binding site

DOE Office of Scientific and Technical Information (OSTI.GOV)

Strauch, Eva-Maria; Bernard, Steffen M.; La, David

Many viral surface glycoproteins and cell surface receptors are homo-oligomers1, 2, 3, 4, and thus can potentially be targeted by geometrically matched homo-oligomers that engage all subunits simultaneously to attain high avidity and/or lock subunits together. The adaptive immune system cannot generally employ this strategy since the individual antibody binding sites are not arranged with appropriate geometry to simultaneously engage multiple sites in a single target homo-oligomer. We describe a general strategy for the computational design of homo-oligomeric protein assemblies with binding functionality precisely matched to homo-oligomeric target sites5, 6, 7, 8. In the first step, a small protein ismore » designed that binds a single site on the target. In the second step, the designed protein is assembled into a homo-oligomer such that the designed binding sites are aligned with the target sites. We use this approach to design high-avidity trimeric proteins that bind influenza A hemagglutinin (HA) at its conserved receptor binding site. The designed trimers can both capture and detect HA in a paper-based diagnostic format, neutralizes influenza in cell culture, and completely protects mice when given as a single dose 24 h before or after challenge with influenza.« less

DESAP 1: A structural design program with stress and displacement constraints. Volume 1: Theoretical and user's manual

NASA Technical Reports Server (NTRS)

Kiusalaas, J.; Reddy, G. B.

1977-01-01

A finite element program is presented for computer-automated, minimum weight design of elastic structures with constraints on stresses (including local instability criteria) and displacements. Volume 1 of the report contains the theoretical and user's manual of the program. Sample problems and the listing of the program are included in Volumes 2 and 3. The element subroutines are organized so as to facilitate additions and changes by the user. As a result, a relatively minor programming effort would be required to make DESAP 1 into a special purpose program to handle the user's specific design requirements and failure criteria.

Dynamic Constraint Satisfaction with Reasonable Global Constraints

NASA Technical Reports Server (NTRS)

Frank, Jeremy

2003-01-01

Previously studied theoretical frameworks for dynamic constraint satisfaction problems (DCSPs) employ a small set of primitive operators to modify a problem instance. They do not address the desire to model problems using sophisticated global constraints, and do not address efficiency questions related to incremental constraint enforcement. In this paper, we extend a DCSP framework to incorporate global constraints with flexible scope. A simple approach to incremental propagation after scope modification can be inefficient under some circumstances. We characterize the cases when this inefficiency can occur, and discuss two ways to alleviate this problem: adding rejection variables to the scope of flexible constraints, and adding new features to constraints that permit increased control over incremental propagation.

Structure Constraints in a Constraint-Based Planner

NASA Technical Reports Server (NTRS)

Pang, Wan-Lin; Golden, Keith

2004-01-01

In this paper we report our work on a new constraint domain, where variables can take structured values. Earth-science data processing (ESDP) is a planning domain that requires the ability to represent and reason about complex constraints over structured data, such as satellite images. This paper reports on a constraint-based planner for ESDP and similar domains. We discuss our approach for translating a planning problem into a constraint satisfaction problem (CSP) and for representing and reasoning about structured objects and constraints over structures.

Target-cancer cell specific activatable fluorescence imaging Probes: Rational Design and in vivo Applications

PubMed Central

Kobayashi, Hisataka; Choyke, Peter L.

2010-01-01

CONSPECTUS Conventional imaging methods, such as angiography, computed tomography, magnetic resonance imaging and radionuclide imaging, rely on contrast agents (iodine, gadolinium, radioisotopes) that are “always on”. While these agents have proven clinically useful, they are not sufficiently sensitive because of the inadequate target to background ratio. A unique aspect of optical imaging is that fluorescence probes can be designed to be activatable, i.e. only “turned on” under certain conditions. These probes can be designed to emit signal only after binding a target tissue, greatly increasing sensitivity and specificity in the detection of disease. There are two basic types of activatable fluorescence probes; 1) conventional enzymatically activatable probes, which exist in the quenched state until activated by enzymatic cleavage mostly outside of the cells, and 2) newly designed target-cell specific activatable probes, which are quenched until activated in targeted cells by endolysosomal processing that results when the probe binds specific cell-surface receptors and is subsequently internalized. Herein, we present a review of the rational design and in vivo applications of target-cell specific activatable probes. Designing these probes based on their photo-chemical (e.g. activation strategy), pharmacological (e.g. biodistribution), and biological (e.g. target specificity) properties has recently allowed the rational design and synthesis of target-cell specific activatable fluorescence imaging probes, which can be conjugated to a wide variety of targeting molecules. Several different photo-chemical mechanisms have been utilized, each of which offers a unique capability for probe design. These include: self-quenching, homo- and hetero-fluorescence resonance energy transfer (FRET), H-dimer formation and photon-induced electron transfer (PeT). In addition, the repertoire is further expanded by the option for reversibility or irreversibility of the signal

Methodology and Results of the Near-Earth Object (NEO) Human Space Flight (HSF) Accessible Targets Study (NHATS)

NASA Technical Reports Server (NTRS)

Barbee, Brent W.; Mink, Ronald G.; Adamo, Daniel R.; Alberding, Cassandra M.

2011-01-01

Near-Earth Asteroids (NEAs) have been identified by the Administration as potential destinations for human explorers during the mid-2020s. Planning such ambitious missions requires selecting potentially accessible targets from the growing known population of 8,008 NEAs. NASA is therefore conducting the Near-Earth Object (NEO) Human Space Flight (HSF) Accessible Targets Study (NHATS), in which the trajectory opportunities to all known NEAs are being systematically evaluated with respect to a set of defined constraints. While the NHATS algorithms have identified hundreds of NEAs which satisfy purposely inclusive trajectory constraints, only a handful of them offer truly attractive mission opportunities in the time frame of greatest interest. In this paper we will describe the structure of the NHATS algorithms and the constraints utilized in the study, present current study results, and discuss various mission design considerations for future human space flight missions to NEAs.

Computational design of nanoparticle drug delivery systems for selective targeting

NASA Astrophysics Data System (ADS)

Duncan, Gregg A.; Bevan, Michael A.

2015-09-01

Ligand-functionalized nanoparticles capable of selectively binding to diseased versus healthy cell populations are attractive for improved efficacy of nanoparticle-based drug and gene therapies. However, nanoparticles functionalized with high affinity targeting ligands may lead to undesired off-target binding to healthy cells. In this work, Monte Carlo simulations were used to quantitatively determine net surface interactions, binding valency, and selectivity between targeted nanoparticles and cell surfaces. Dissociation constant, KD, and target membrane protein density, ρR, are explored over a range representative of healthy and cancerous cell surfaces. Our findings show highly selective binding to diseased cell surfaces can be achieved with multiple, weaker affinity targeting ligands that can be further optimized by varying the targeting ligand density, ρL. Using the approach developed in this work, nanomedicines can be optimally designed for exclusively targeting diseased cells and tissues.Ligand-functionalized nanoparticles capable of selectively binding to diseased versus healthy cell populations are attractive for improved efficacy of nanoparticle-based drug and gene therapies. However, nanoparticles functionalized with high affinity targeting ligands may lead to undesired off-target binding to healthy cells. In this work, Monte Carlo simulations were used to quantitatively determine net surface interactions, binding valency, and selectivity between targeted nanoparticles and cell surfaces. Dissociation constant, KD, and target membrane protein density, ρR, are explored over a range representative of healthy and cancerous cell surfaces. Our findings show highly selective binding to diseased cell surfaces can be achieved with multiple, weaker affinity targeting ligands that can be further optimized by varying the targeting ligand density, ρL. Using the approach developed in this work, nanomedicines can be optimally designed for exclusively targeting

Design of the polar neutron-imaging aperture for use at the National Ignition Facility

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fatherley, V. E., E-mail: vef@lanl.gov; Martinez, J. I.; Merrill, F. E.

2016-11-15

The installation of a neutron imaging diagnostic with a polar view at the National Ignition Facility (NIF) required design of a new aperture, an extended pinhole array (PHA). This PHA is different from the pinhole array for the existing equatorial system due to significant changes in the alignment and recording systems. The complex set of component requirements, as well as significant space constraints in its intended location, makes the design of this aperture challenging. In addition, lessons learned from development of prior apertures mandate careful aperture metrology prior to first use. This paper discusses the PHA requirements, constraints, and themore » final design. The PHA design is complex due to size constraints, machining precision, assembly tolerances, and design requirements. When fully assembled, the aperture is a 15 mm × 15 mm × 200 mm tungsten and gold assembly. The PHA body is made from 2 layers of tungsten and 11 layers of gold. The gold layers include 4 layers containing penumbral openings, 4 layers containing pinholes and 3 spacer layers. In total, there are 64 individual, triangular pinholes with a field of view (FOV) of 200 μm and 6 penumbral apertures. Each pinhole is pointed to a slightly different location in the target plane, making the effective FOV of this PHA a 700 μm square in the target plane. The large FOV of the PHA reduces the alignment requirements both for the PHA and the target, allowing for alignment with a laser tracking system at NIF.« less

Computational design of high efficiency release targets for use at ISOL facilities

NASA Astrophysics Data System (ADS)

Liu, Y.; Alton, G. D.; Middleton, J. W.

1999-06-01

This report describes efforts made at the Oak Ridge National Laboratory to design high-efficiency-release targets that simultaneously incorporate the short diffusion lengths, high permeabilities, controllable temperatures, and heat removal properties required for the generation of useful radioactive ion beam (RIB) intensities for nuclear physics and astrophysics research using the isotope separation on-line (ISOL) technique. Short diffusion lengths are achieved either by using thin fibrous target materials or by coating thin layers of selected target material onto low-density carbon fibers such as reticulated vitreous carbon fiber (RVCF) or carbon-bonded-carbon-fiber (CBCF) to form highly permeable composite target matrices. Computational studies which simulate the generation and removal of primary beam deposited heat from target materials have been conducted to optimize the design of target/heat-sink systems for generating RIBs. The results derived from diffusion release-rate simulation studies for selected targets and thermal analyses of temperature distributions within a prototype target/heat-sink system subjected to primary ion beam irradiation will be presented in this report.

incaRNAfbinv: a web server for the fragment-based design of RNA sequences

PubMed Central

Drory Retwitzer, Matan; Reinharz, Vladimir; Ponty, Yann; Waldispühl, Jérôme; Barash, Danny

2016-01-01

Abstract In recent years, new methods for computational RNA design have been developed and applied to various problems in synthetic biology and nanotechnology. Lately, there is considerable interest in incorporating essential biological information when solving the inverse RNA folding problem. Correspondingly, RNAfbinv aims at including biologically meaningful constraints and is the only program to-date that performs a fragment-based design of RNA sequences. In doing so it allows the design of sequences that do not necessarily exactly fold into the target, as long as the overall coarse-grained tree graph shape is preserved. Augmented by the weighted sampling algorithm of incaRNAtion, our web server called incaRNAfbinv implements the method devised in RNAfbinv and offers an interactive environment for the inverse folding of RNA using a fragment-based design approach. It takes as input: a target RNA secondary structure; optional sequence and motif constraints; optional target minimum free energy, neutrality and GC content. In addition to the design of synthetic regulatory sequences, it can be used as a pre-processing step for the detection of novel natural occurring RNAs. The two complementary methodologies RNAfbinv and incaRNAtion are merged together and fully implemented in our web server incaRNAfbinv, available at http://www.cs.bgu.ac.il/incaRNAfbinv. PMID:27185893

From bricolage to BioBricks™: Synthetic biology and rational design.

PubMed

Lewens, Tim

2013-12-01

Synthetic biology is often described as a project that applies rational design methods to the organic world. Although humans have influenced organic lineages in many ways, it is nonetheless reasonable to place synthetic biology towards one end of a continuum between purely 'blind' processes of organic modification at one extreme, and wholly rational, design-led processes at the other. An example from evolutionary electronics illustrates some of the constraints imposed by the rational design methodology itself. These constraints reinforce the limitations of the synthetic biology ideal, limitations that are often freely acknowledged by synthetic biology's own practitioners. The synthetic biology methodology reflects a series of constraints imposed on finite human designers who wish, as far as is practicable, to communicate with each other and to intervene in nature in reasonably targeted and well-understood ways. This is better understood as indicative of an underlying awareness of human limitations, rather than as expressive of an objectionable impulse to mastery over nature. Copyright © 2013 Elsevier Ltd. All rights reserved.

An iterative and targeted sampling design informed by habitat suitability models for detecting focal plant species over extensive areas.

PubMed

Wang, Ophelia; Zachmann, Luke J; Sesnie, Steven E; Olsson, Aaryn D; Dickson, Brett G

2014-01-01

Prioritizing areas for management of non-native invasive plants is critical, as invasive plants can negatively impact plant community structure. Extensive and multi-jurisdictional inventories are essential to prioritize actions aimed at mitigating the impact of invasions and changes in disturbance regimes. However, previous work devoted little effort to devising sampling methods sufficient to assess the scope of multi-jurisdictional invasion over extensive areas. Here we describe a large-scale sampling design that used species occurrence data, habitat suitability models, and iterative and targeted sampling efforts to sample five species and satisfy two key management objectives: 1) detecting non-native invasive plants across previously unsampled gradients, and 2) characterizing the distribution of non-native invasive plants at landscape to regional scales. Habitat suitability models of five species were based on occurrence records and predictor variables derived from topography, precipitation, and remotely sensed data. We stratified and established field sampling locations according to predicted habitat suitability and phenological, substrate, and logistical constraints. Across previously unvisited areas, we detected at least one of our focal species on 77% of plots. In turn, we used detections from 2011 to improve habitat suitability models and sampling efforts in 2012, as well as additional spatial constraints to increase detections. These modifications resulted in a 96% detection rate at plots. The range of habitat suitability values that identified highly and less suitable habitats and their environmental conditions corresponded to field detections with mixed levels of agreement. Our study demonstrated that an iterative and targeted sampling framework can address sampling bias, reduce time costs, and increase detections. Other studies can extend the sampling framework to develop methods in other ecosystems to provide detection data. The sampling methods

An Iterative and Targeted Sampling Design Informed by Habitat Suitability Models for Detecting Focal Plant Species over Extensive Areas

PubMed Central

Wang, Ophelia; Zachmann, Luke J.; Sesnie, Steven E.; Olsson, Aaryn D.; Dickson, Brett G.

2014-01-01

Prioritizing areas for management of non-native invasive plants is critical, as invasive plants can negatively impact plant community structure. Extensive and multi-jurisdictional inventories are essential to prioritize actions aimed at mitigating the impact of invasions and changes in disturbance regimes. However, previous work devoted little effort to devising sampling methods sufficient to assess the scope of multi-jurisdictional invasion over extensive areas. Here we describe a large-scale sampling design that used species occurrence data, habitat suitability models, and iterative and targeted sampling efforts to sample five species and satisfy two key management objectives: 1) detecting non-native invasive plants across previously unsampled gradients, and 2) characterizing the distribution of non-native invasive plants at landscape to regional scales. Habitat suitability models of five species were based on occurrence records and predictor variables derived from topography, precipitation, and remotely sensed data. We stratified and established field sampling locations according to predicted habitat suitability and phenological, substrate, and logistical constraints. Across previously unvisited areas, we detected at least one of our focal species on 77% of plots. In turn, we used detections from 2011 to improve habitat suitability models and sampling efforts in 2012, as well as additional spatial constraints to increase detections. These modifications resulted in a 96% detection rate at plots. The range of habitat suitability values that identified highly and less suitable habitats and their environmental conditions corresponded to field detections with mixed levels of agreement. Our study demonstrated that an iterative and targeted sampling framework can address sampling bias, reduce time costs, and increase detections. Other studies can extend the sampling framework to develop methods in other ecosystems to provide detection data. The sampling methods

Learning Kinematic Constraints in Laparoscopic Surgery

PubMed Central

Huang, Felix C.; Mussa-Ivaldi, Ferdinando A.; Pugh, Carla M.; Patton, James L.

2012-01-01

To better understand how kinematic variables impact learning in surgical training, we devised an interactive environment for simulated laparoscopic maneuvers, using either 1) mechanical constraints typical of a surgical “box-trainer” or 2) virtual constraints in which free hand movements control virtual tool motion. During training, the virtual tool responded to the absolute position in space (Position-Based) or the orientation (Orientation-Based) of a hand-held sensor. Volunteers were further assigned to different sequences of target distances (Near-Far-Near or Far-Near-Far). Training with the Orientation-Based constraint enabled much lower path error and shorter movement times during training, which suggests that tool motion that simply mirrors joint motion is easier to learn. When evaluated in physically constrained (physical box-trainer) conditions, each group exhibited improved performance from training. However, Position-Based training enabled greater reductions in movement error relative to Orientation-Based (mean difference: 14.0 percent; CI: 0.7, 28.6). Furthermore, the Near-Far-Near schedule allowed a greater decrease in task time relative to the Far-Near-Far sequence (mean −13:5 percent, CI: −19:5, −7:5). Training that focused on shallow tool insertion (near targets) might promote more efficient movement strategies by emphasizing the curvature of tool motion. In addition, our findings suggest that an understanding of absolute tool position is critical to coping with mechanical interactions between the tool and trocar. PMID:23293709

Constraint-Based Scheduling System

NASA Technical Reports Server (NTRS)

Zweben, Monte; Eskey, Megan; Stock, Todd; Taylor, Will; Kanefsky, Bob; Drascher, Ellen; Deale, Michael; Daun, Brian; Davis, Gene

1995-01-01

Report describes continuing development of software for constraint-based scheduling system implemented eventually on massively parallel computer. Based on machine learning as means of improving scheduling. Designed to learn when to change search strategy by analyzing search progress and learning general conditions under which resource bottleneck occurs.

Wide-Spectrum Microscope with a Long Working Distance Aspherical Objective Based on Obscuration Constraint

PubMed Central

Wang, Weibo; Wang, Chao; Liu, Jian; Tan, Jiubin

2016-01-01

We present an approach for an initial configuration design based on obscuration constraint and on-axis Taylor series expansion to realize the design of long working distance microscope (numerical aperture (NA) = 0.13 and working distance (WD) = 525 mm) with a low obscuration aspherical Schwarzschild objective in wide-spectrum imaging (λ = 400–900 nm). Experiments of the testing on the resolution target and inspection on United States Air Force (USAF) resolution chart and a line charge-coupled device (CCD) (pixel size of 14 μm × 56 μm) with different wavelength light sources (λ = 480 nm, 550 nm, 660 nm, 850 nm) were implemented to verify the validity of the proposed method. PMID:27834874

Nutrient cycling Microbial Ecosystems: Assembly, Function and Targeted Design

DTIC Science & Technology

2017-05-05

different chemical transformations, converting potentially harmful chemicals via a series of intermediates, to harmless waste products. This shuttling of...Report: Nutrient-cycling Microbial Ecosystems: Assembly, Function and Targeted Design The views, opinions and/or findings contained in this report...are those of the author(s) and should not contrued as an official Department of the Army position, policy or decision, unless so designated by other

Design and Fabrication of Opacity Targets for the National Ignition Facility

DOE PAGES

Cardenas, Tana; Schmidt, Derek William; Dodd, Evan S.; ...

2017-12-22

Accurate models for opacity of partially ionized atoms are important for modeling and understanding stellar interiors and other high-energy-density phenomena such as inertial confinement fusion. Lawrence Livermore National Laboratory is leading a multilaboratory effort to conduct experiments on the National Ignition Facility (NIF) to try to reproduce recent opacity tests at the Sandia National Laboratory Z-facility. Since 2015, the NIF effort has evolved several hohlraum designs that consist of multiple pieces joined together. The target also has three components attached to the main stalk over a long distance with high tolerances that have resulted in several design iterations. The targetmore » has made use of rapid prototyped features to attach a capsule and collimator under the hohlraum while avoiding interference with the beams. Furthermore, this paper discusses the evolution of the hohlraum and overall target design and the challenges involved with fabricating and assembling these targets.« less

Design and Fabrication of Opacity Targets for the National Ignition Facility

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cardenas, Tana; Schmidt, Derek William; Dodd, Evan S.

Accurate models for opacity of partially ionized atoms are important for modeling and understanding stellar interiors and other high-energy-density phenomena such as inertial confinement fusion. Lawrence Livermore National Laboratory is leading a multilaboratory effort to conduct experiments on the National Ignition Facility (NIF) to try to reproduce recent opacity tests at the Sandia National Laboratory Z-facility. Since 2015, the NIF effort has evolved several hohlraum designs that consist of multiple pieces joined together. The target also has three components attached to the main stalk over a long distance with high tolerances that have resulted in several design iterations. The targetmore » has made use of rapid prototyped features to attach a capsule and collimator under the hohlraum while avoiding interference with the beams. Furthermore, this paper discusses the evolution of the hohlraum and overall target design and the challenges involved with fabricating and assembling these targets.« less

Design of the hairpin ribozyme for targeting specific RNA sequences.

PubMed

Hampel, A; DeYoung, M B; Galasinski, S; Siwkowski, A

1997-01-01

The following steps should be taken when designing the hairpin ribozyme to cleave a specific target sequence: 1. Select a target sequence containing BN*GUC where B is C, G, or U. 2. Select the target sequence in areas least likely to have extensive interfering structure. 3. Design the conventional hairpin ribozyme as shown in Fig. 1, such that it can form a 4 bp helix 2 and helix 1 lengths up to 10 bp. 4. Synthesize this ribozyme from single-stranded DNA templates with a double-stranded T7 promoter. 5. Prepare a series of short substrates capable of forming a range of helix 1 lengths of 5-10 bp. 6. Identify these by direct RNA sequencing. 7. Assay the extent of cleavage of each substrate to identify the optimal length of helix 1. 8. Prepare the hairpin tetraloop ribozyme to determine if catalytic efficiency can be improved.

A Framework for Dynamic Constraint Reasoning Using Procedural Constraints

NASA Technical Reports Server (NTRS)

Jonsson, Ari K.; Frank, Jeremy D.

1999-01-01

Many complex real-world decision and control problems contain an underlying constraint reasoning problem. This is particularly evident in a recently developed approach to planning, where almost all planning decisions are represented by constrained variables. This translates a significant part of the planning problem into a constraint network whose consistency determines the validity of the plan candidate. Since higher-level choices about control actions can add or remove variables and constraints, the underlying constraint network is invariably highly dynamic. Arbitrary domain-dependent constraints may be added to the constraint network and the constraint reasoning mechanism must be able to handle such constraints effectively. Additionally, real problems often require handling constraints over continuous variables. These requirements present a number of significant challenges for a constraint reasoning mechanism. In this paper, we introduce a general framework for handling dynamic constraint networks with real-valued variables, by using procedures to represent and effectively reason about general constraints. The framework is based on a sound theoretical foundation, and can be proven to be sound and complete under well-defined conditions. Furthermore, the framework provides hybrid reasoning capabilities, as alternative solution methods like mathematical programming can be incorporated into the framework, in the form of procedures.

Effects of task constraints on reaching kinematics by healthy adults.

PubMed

Wu, Ching-Yi; Lin, Keh-Chung; Lin, Kwan-Hwa; Chang, Chein-Wei; Chen, Chia-Ling

2005-06-01

Understanding the control of movement requires an awareness of how tasks constrain movements. The present study investigated the effects of two types of task constraints--spatial accuracy (effector size) and target location--on reaching kinematics. 15 right-handed healthy young adults (7 men, 8 women) whose mean age was 23.6 yr. (SD=3.9 yr.) performed the ringing task under six conditions, formed by the crossing of effector size (larger vs smaller size) and target location (left, right, or a central position). Significant main effects of effector size and target location were found for peak velocity and movement time. There was a significant interaction for the percentage of time to peak velocity. The findings suggested that task constraints may modulate movement performance in specific ways. Effects of effector size might be a consequence of feedforward and feedback control, and location effects might be influenced by both biomechanical and neurological factors.

Application of two procedures for dual-point design of transonic airfoils

NASA Technical Reports Server (NTRS)

Mineck, Raymond E.; Campbell, Richard L.; Allison, Dennis O.

1994-01-01

Two dual-point design procedures were developed to reduce the objective function of a baseline airfoil at two design points. The first procedure to develop a redesigned airfoil used a weighted average of the shapes of two intermediate airfoils redesigned at each of the two design points. The second procedure used a weighted average of two pressure distributions obtained from an intermediate airfoil redesigned at each of the two design points. Each procedure was used to design a new airfoil with reduced wave drag at the cruise condition without increasing the wave drag or pitching moment at the climb condition. Two cycles of the airfoil shape-averaging procedure successfully designed a new airfoil that reduced the objective function and satisfied the constraints. One cycle of the target (desired) pressure-averaging procedure was used to design two new airfoils that reduced the objective function and came close to satisfying the constraints.

Possible-Word Constraints in Cantonese Speech Segmentation

ERIC Educational Resources Information Center

Yip, Michael C. W.

2004-01-01

A Cantonese syllable-spotting experiment was conducted to examine whether the Possible-Word Constraint (PWC), proposed by Norris, McQueen, Cutler, and Butterfield (1997), can apply in Cantonese speech segmentation. In the experiment, listeners were asked to spot out the target Cantonese syllable from a series of nonsense sound strings. Results…

Experiential knowledge of expert coaches can help identify informational constraints on performance of dynamic interceptive actions.

PubMed

Greenwood, Daniel; Davids, Keith; Renshaw, Ian

2014-01-01

Coordination of dynamic interceptive movements is predicated on cyclical relations between an individual's actions and information sources from the performance environment. To identify dynamic informational constraints, which are interwoven with individual and task constraints, coaches' experiential knowledge provides a complementary source to support empirical understanding of performance in sport. In this study, 15 expert coaches from 3 sports (track and field, gymnastics and cricket) participated in a semi-structured interview process to identify potential informational constraints which they perceived to regulate action during run-up performance. Expert coaches' experiential knowledge revealed multiple information sources which may constrain performance adaptations in such locomotor pointing tasks. In addition to the locomotor pointing target, coaches' knowledge highlighted two other key informational constraints: vertical reference points located near the locomotor pointing target and a check mark located prior to the locomotor pointing target. This study highlights opportunities for broadening the understanding of perception and action coupling processes, and the identified information sources warrant further empirical investigation as potential constraints on athletic performance. Integration of experiential knowledge of expert coaches with theoretically driven empirical knowledge represents a promising avenue to drive future applied science research and pedagogical practice.

Choosing a software design method for real-time Ada applications: JSD process inversion as a means to tailor a design specification to the performance requirements and target machine

NASA Technical Reports Server (NTRS)

Withey, James V.

1986-01-01

The validity of real-time software is determined by its ability to execute on a computer within the time constraints of the physical system it is modeling. In many applications the time constraints are so critical that the details of process scheduling are elevated to the requirements analysis phase of the software development cycle. It is not uncommon to find specifications for a real-time cyclic executive program included to assumed in such requirements. It was found that prelininary designs structured around this implementation abscure the data flow of the real world system that is modeled and that it is consequently difficult and costly to maintain, update and reuse the resulting software. A cyclic executive is a software component that schedules and implicitly synchronizes the real-time software through periodic and repetitive subroutine calls. Therefore a design method is sought that allows the deferral of process scheduling to the later stages of design. The appropriate scheduling paradigm must be chosen given the performance constraints, the largest environment and the software's lifecycle. The concept of process inversion is explored with respect to the cyclic executive.

Optimum design using VICONOPT, a buckling and strength constraint program for prismatic assemblies of anisotropic plates

NASA Technical Reports Server (NTRS)

Butler, R.; Williams, F. W.

1992-01-01

A computer program for obtaining the optimum (least mass) dimensions of the kind of prismatic assemblies of laminated, composite plates which occur in advanced aerospace construction is described. Rigorous buckling analysis (derived from exact member theory) and a tailored design procedure are used to produce designs which satisfy buckling and material strength constraints and configurational requirements. Analysis is two to three orders of magnitude quicker than FEM, keeps track of all the governing modes of failure and is efficiently adapted to give sensitivities and to maintain feasibility. Tailoring encourages convergence in fewer sizing cycles than competing programs and permits start designs which are a long way from feasible and/or optimum. Comparisons with its predecessor, PASCO, show that the program is more likely to produce an optimum, will do so more quickly in some cases, and remains accurate for a wider range of problems.

Pharmacophore based design of some multi-targeted compounds targeted against pathways of diabetic complications.

PubMed

Chadha, Navriti; Silakari, Om

2017-09-01

Diabetic complications is a complex metabolic disorder developed primarily due to prolonged hyperglycemia in the body. The complexity of the disease state as well as the unifying pathophysiology discussed in the literature reports exhibited that the use of multi-targeted agents with multiple complementary biological activities may offer promising therapy for the intervention of the disease over the single-target drugs. In the present study, novel thiazolidine-2,4-dione analogues were designed as multi-targeted agents implicated against the molecular pathways involved in diabetic complications using knowledge based as well as in-silico approaches such as pharmacophore mapping, molecular docking etc. The hit molecules were duly synthesized and biochemical estimation of these molecules against aldose reductase (ALR2), protein kinase Cβ (PKCβ) and poly (ADP-ribose) polymerase 1 (PARP-1) led to identification of compound 2 that showed good potency against PARP-1 and ALR2 enzymes. These positive results support the progress of a low cost multi-targeted agent with putative roles in diabetic complications. Copyright © 2017 Elsevier Inc. All rights reserved.

Fluence map optimization (FMO) with dose-volume constraints in IMRT using the geometric distance sorting method.

PubMed

Lan, Yihua; Li, Cunhua; Ren, Haozheng; Zhang, Yong; Min, Zhifang

2012-10-21

A new heuristic algorithm based on the so-called geometric distance sorting technique is proposed for solving the fluence map optimization with dose-volume constraints which is one of the most essential tasks for inverse planning in IMRT. The framework of the proposed method is basically an iterative process which begins with a simple linear constrained quadratic optimization model without considering any dose-volume constraints, and then the dose constraints for the voxels violating the dose-volume constraints are gradually added into the quadratic optimization model step by step until all the dose-volume constraints are satisfied. In each iteration step, an interior point method is adopted to solve each new linear constrained quadratic programming. For choosing the proper candidate voxels for the current dose constraint adding, a so-called geometric distance defined in the transformed standard quadratic form of the fluence map optimization model was used to guide the selection of the voxels. The new geometric distance sorting technique can mostly reduce the unexpected increase of the objective function value caused inevitably by the constraint adding. It can be regarded as an upgrading to the traditional dose sorting technique. The geometry explanation for the proposed method is also given and a proposition is proved to support our heuristic idea. In addition, a smart constraint adding/deleting strategy is designed to ensure a stable iteration convergence. The new algorithm is tested on four cases including head-neck, a prostate, a lung and an oropharyngeal, and compared with the algorithm based on the traditional dose sorting technique. Experimental results showed that the proposed method is more suitable for guiding the selection of new constraints than the traditional dose sorting method, especially for the cases whose target regions are in non-convex shapes. It is a more efficient optimization technique to some extent for choosing constraints than the dose

GLRS-R 2-colour retroreflector target design and predicted performance

NASA Astrophysics Data System (ADS)

Lund, Glenn

The retroreflector ground target design for the GLRS-R spaceborne dual wavelength laser ranging system is described. The passive design flows down from the requirements of high station autonomy, high global field of view, little or no multiple pulse returns, and adequate optical cross section for most ranging geometries. The solution makes use of five hollow cube corner retroreflectors of which one points to the zenith and the remaining four are inclined from the vertical at uniform azimuthal spacings. The need for large retroreflectors is expected to generate narrow diffraction lobes. A good compromise solution is found by spoiling just one of the retroereflector dihedral angles from 90 deg, thus generating two symmetrically oriented diffraction lobes in the return beam. The required spoil angles are found to have little dependance on ground target latitude. Various link budget analyses are presented. They show the influence of such factors as point ahead optimization, turbulence, ranging angle, atmospheric visibility, and ground target thermal deformations.

New designs of LMJ targets for early ignition experiments

NASA Astrophysics Data System (ADS)

C-Clérouin, C.; Bonnefille, M.; Dattolo, E.; Fremerye, P.; Galmiche, D.; Gauthier, P.; Giorla, J.; Laffite, S.; Liberatore, S.; Loiseau, P.; Malinie, G.; Masse, L.; Poggi, F.; Seytor, P.

2008-05-01

The LMJ experimental plans include the attempt of ignition and burn of an ICF capsule with 40 laser quads, delivering up to 1.4MJ and 380TW. New targets needing reduced laser energy with only a small decrease in robustness are then designed for this purpose. A first strategy is to use scaled-down cylindrical hohlraums and capsules, taking advantage of our better understanding of the problem, set on theoretical modelling, simulations and experiments. Another strategy is to work specifically on the coupling efficiency parameter, i.e. the ratio of the energy absorbed by the capsule to the laser energy, which is with parametric instabilities a crucial drawback of indirect drive. An alternative design is proposed, made up of the nominal 60 quads capsule, named A1040, in a rugby-shaped hohlraum. Robustness evaluations of these different targets are in progress.

Primer-BLAST: A tool to design target-specific primers for polymerase chain reaction

PubMed Central

2012-01-01

Background Choosing appropriate primers is probably the single most important factor affecting the polymerase chain reaction (PCR). Specific amplification of the intended target requires that primers do not have matches to other targets in certain orientations and within certain distances that allow undesired amplification. The process of designing specific primers typically involves two stages. First, the primers flanking regions of interest are generated either manually or using software tools; then they are searched against an appropriate nucleotide sequence database using tools such as BLAST to examine the potential targets. However, the latter is not an easy process as one needs to examine many details between primers and targets, such as the number and the positions of matched bases, the primer orientations and distance between forward and reverse primers. The complexity of such analysis usually makes this a time-consuming and very difficult task for users, especially when the primers have a large number of hits. Furthermore, although the BLAST program has been widely used for primer target detection, it is in fact not an ideal tool for this purpose as BLAST is a local alignment algorithm and does not necessarily return complete match information over the entire primer range. Results We present a new software tool called Primer-BLAST to alleviate the difficulty in designing target-specific primers. This tool combines BLAST with a global alignment algorithm to ensure a full primer-target alignment and is sensitive enough to detect targets that have a significant number of mismatches to primers. Primer-BLAST allows users to design new target-specific primers in one step as well as to check the specificity of pre-existing primers. Primer-BLAST also supports placing primers based on exon/intron locations and excluding single nucleotide polymorphism (SNP) sites in primers. Conclusions We describe a robust and fully implemented general purpose primer design tool

Designing under Constraints: Cell Phone Case Design Challenge

ERIC Educational Resources Information Center

Sutton, Kevin; Grubbs, Michael E.; Ernst, Jeremy

2014-01-01

Engineering design has been suggested as a viable instructional approach for Technology Education (TE) to intentionally provide students the opportunity to apply multidisciplinary concepts to solve ill-defined design challenges (Wells & Ernst, 2012; Sanders & Wells, 2010; Wicklein, 2006). Currently, the context for design challenges in TE…

Effect of Tip-Speed Constraints on the Optimized Design of a Wind Turbine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dykes, K.; Resor, B.; Platt, A.

This study investigates the effect of tip-velocity constraints on system levelized cost of energy (LCOE). The results indicate that a change in maximum tip speed from 80 to 100~m/s could produce a 32% decrease in gearbox weight (a 33% reduction in cost) which would result in an overall reduction of 1%-9% in system LCOE depending on the design approach. Three 100~m/s design cases were considered including a low tip-speed ratio/high-solidity rotor design, a high tip-speed ratio/ low-solidity rotor design, and finally a flexible blade design in which a high tip-speed ratio was used along with removing the tip deflection constraintmore » on the rotor design. In all three cases, the significant reduction in gearbox weight caused by the higher tip-speed and lower overall gear ratio was counterbalanced by increased weights for the rotor and/or other drivetrain components and the tower. As a result, the increased costs of either the rotor or drivetrain components offset the overall reduction in turbine costs from down-sizing the gearbox. Other system costs were not significantly affected, whereas energy production was slightly reduced in the 100~m/s case low tip-speed ratio case and increased in the high tip-speed ratio case. This resulted in system cost of energy reductions moving from the 80~m/s design to the 100~m/s designs of 1.2% for the low tip-speed ratio, 4.6% for the high tip-speed ratio, and 9.5% for the final flexible case (the latter result is optimistic because the impact of deflection of the flexible blade on power production was not modeled). Overall, the results demonstrate that there is a trade-off in system design between the maximum tip velocity and the overall wind plant cost of energy, and there are many trade-offs within the overall system in designing a turbine for a high maximum tip velocity.« less

Constraints on the evolution of a doublesex target gene arising from doublesex’s pleiotropic deployment

PubMed Central

Luo, Shengzhan D.; Baker, Bruce S.

2015-01-01

“Regulatory evolution,” that is, changes in a gene’s expression pattern through changes at its regulatory sequence, rather than changes at the coding sequence of the gene or changes of the upstream transcription factors, has been increasingly recognized as a pervasive evolution mechanism. Many somatic sexually dimorphic features of Drosophila melanogaster are the results of gene expression regulated by the doublesex (dsx) gene, which encodes sex-specific transcription factors (DSXF in females and DSXM in males). Rapid changes in such sexually dimorphic features are likely a result of changes at the regulatory sequence of the target genes. We focused on the Flavin-containing monooxygenase-2 (Fmo-2) gene, a likely direct dsx target, to elucidate how sexually dimorphic expression and its evolution are brought about. We found that dsx is deployed to regulate the Fmo-2 transcription both in the midgut and in fat body cells of the spermatheca (a female-specific tissue), through a canonical DSX-binding site in the Fmo-2 regulatory sequence. In the melanogaster group, Fmo-2 transcription in the midgut has evolved rapidly, in contrast to the conserved spermathecal transcription. We identified two cis-regulatory modules (CRM-p and CRM-d) that direct sexually monomorphic or dimorphic Fmo-2 transcription, respectively, in the midguts of these species. Changes of Fmo-2 transcription in the midgut from sexually dimorphic to sexually monomorphic in some species are caused by the loss of CRM-d function, but not the loss of the canonical DSX-binding site. Thus, conferring transcriptional regulation on a CRM level allows the regulation to evolve rapidly in one tissue while evading evolutionary constraints posed by other tissues. PMID:25675536

Constraint reasoning in deep biomedical models.

PubMed

Cruz, Jorge; Barahona, Pedro

2005-05-01

Deep biomedical models are often expressed by means of differential equations. Despite their expressive power, they are difficult to reason about and make decisions, given their non-linearity and the important effects that the uncertainty on data may cause. The objective of this work is to propose a constraint reasoning framework to support safe decisions based on deep biomedical models. The methods used in our approach include the generic constraint propagation techniques for reducing the bounds of uncertainty of the numerical variables complemented with new constraint reasoning techniques that we developed to handle differential equations. The results of our approach are illustrated in biomedical models for the diagnosis of diabetes, tuning of drug design and epidemiology where it was a valuable decision-supporting tool notwithstanding the uncertainty on data. The main conclusion that follows from the results is that, in biomedical decision support, constraint reasoning may be a worthwhile alternative to traditional simulation methods, especially when safe decisions are required.

A multiplex primer design algorithm for target amplification of continuous genomic regions.

PubMed

Ozturk, Ahmet Rasit; Can, Tolga

2017-06-19

Targeted Next Generation Sequencing (NGS) assays are cost-efficient and reliable alternatives to Sanger sequencing. For sequencing of very large set of genes, the target enrichment approach is suitable. However, for smaller genomic regions, the target amplification method is more efficient than both the target enrichment method and Sanger sequencing. The major difficulty of the target amplification method is the preparation of amplicons, regarding required time, equipment, and labor. Multiplex PCR (MPCR) is a good solution for the mentioned problems. We propose a novel method to design MPCR primers for a continuous genomic region, following the best practices of clinically reliable PCR design processes. On an experimental setup with 48 different combinations of factors, we have shown that multiple parameters might effect finding the first feasible solution. Increasing the length of the initial primer candidate selection sequence gives better results whereas waiting for a longer time to find the first feasible solution does not have a significant impact. We generated MPCR primer designs for the HBB whole gene, MEFV coding regions, and human exons between 2000 bp to 2100 bp-long. Our benchmarking experiments show that the proposed MPCR approach is able produce reliable NGS assay primers for a given sequence in a reasonable amount of time.

Statistical Techniques to Explore the Quality of Constraints in Constraint-Based Modeling Environments

ERIC Educational Resources Information Center

Gálvez, Jaime; Conejo, Ricardo; Guzmán, Eduardo

2013-01-01

One of the most popular student modeling approaches is Constraint-Based Modeling (CBM). It is an efficient approach that can be easily applied inside an Intelligent Tutoring System (ITS). Even with these characteristics, building new ITSs requires carefully designing the domain model to be taught because different sources of errors could affect…

Targeted proteins for diabetes drug design

NASA Astrophysics Data System (ADS)

Doan Trang Nguyen, Ngoc; Thi Le, Ly

2012-03-01

Type 2 diabetes mellitus is a common metabolism disorder characterized by high glucose in the bloodstream, especially in the case of insulin resistance and relative insulin deficiency. Nowadays, it is very common in middle-aged people and involves such dangerous symptoms as increasing risk of stroke, obesity and heart failure. In Vietnam, besides the common treatment of insulin injection, some herbal medication is used but no unified optimum remedy for the disease yet exists and there is no production of antidiabetic drugs in the domestic market yet. In the development of nanomedicine at the present time, drug design is considered as an innovative tool for researchers to study the mechanisms of diseases at the molecular level. The aim of this article is to review some common protein targets involved in type 2 diabetes, offering a new idea for designing new drug candidates to produce antidiabetic drugs against type 2 diabetes for Vietnamese people.

Structural topology optimization with fuzzy constraint

NASA Astrophysics Data System (ADS)

Rosko, Peter

2011-12-01

The paper deals with the structural topology optimization with fuzzy constraint. The optimal topology of structure is defined as a material distribution problem. The objective is the weight of the structure. The multifrequency dynamic loading is considered. The optimal topology design of the structure has to eliminate the danger of the resonance vibration. The uncertainty of the loading is defined with help of fuzzy loading. Special fuzzy constraint is created from exciting frequencies. Presented study is applicable in engineering and civil engineering. Example demonstrates the presented theory.

Designing large-scale conservation corridors for pattern and process.

PubMed

Rouget, Mathieu; Cowling, Richard M; Lombard, Amanda T; Knight, Andrew T; Kerley, Graham I H

2006-04-01

A major challenge for conservation assessments is to identify priority areas that incorporate biological patterns and processes. Because large-scale processes are mostly oriented along environmental gradients, we propose to accommodate them by designing regional-scale corridors to capture these gradients. Based on systematic conservation planning principles such as representation and persistence, we identified large tracts of untransformed land (i.e., conservation corridors) for conservation that would achieve biodiversity targets for pattern and process in the Subtropical Thicket Biome of South Africa. We combined least-cost path analysis with a target-driven algorithm to identify the best option for capturing key environmental gradients while considering biodiversity targets and conservation opportunities and constraints. We identified seven conservation corridors on the basis of subtropical thicket representation, habitat transformation and degradation, wildlife suitability, irreplaceability of vegetation types, protected area networks, and future land-use pressures. These conservation corridors covered 21.1% of the planning region (ranging from 600 to 5200 km2) and successfully achieved targets for biological processes and to a lesser extent for vegetation types. The corridors we identified are intended to promote the persistence of ecological processes (gradients and fixed processes) and fulfill half of the biodiversity pattern target. We compared the conservation corridors with a simplified corridor design consisting of a fixed-width buffer along major rivers. Conservation corridors outperformed river buffers in seven out of eight criteria. Our corridor design can provide a tool for quantifying trade-offs between various criteria (biodiversity pattern and process, implementation constraints and opportunities). A land-use management model was developed to facilitate implementation of conservation actions within these corridors.

Eliciting explanations: Constraints on when self-explanation aids learning.

PubMed

Rittle-Johnson, Bethany; Loehr, Abbey M

2017-10-01

Generating explanations for oneself in an attempt to make sense of new information (i.e., self-explanation) is often a powerful learning technique. Despite its general effectiveness, in a growing number of studies, prompting for self-explanation improved some aspects of learning, but reduced learning of other aspects. Drawing on this recent research, as well as on research comparing self-explanation under different conditions, we propose four constraints on the effectiveness of self-explanation. First, self-explanation promotes attention to particular types of information, so it is better suited to promote particular learning outcomes in particular types of domains, such as transfer in domains guided by general principles or heuristics. Second, self-explaining a variety of types of information can improve learning, but explaining one's own solution methods or choices may reduce learning under certain conditions. Third, explanation prompts focus effort on particular aspects of the to-be-learned material, potentially drawing effort away from other important information. Explanation prompts must be carefully designed to align with target learning outcomes. Fourth, prompted self-explanation often promotes learning better than unguided studying, but alternative instructional techniques may be more effective under some conditions. Attention to these constraints should optimize the effectiveness of self-explanation as an instructional technique in future research and practice.

Ligand design for riboswitches, an emerging target class for novel antibiotics.

PubMed

Rekand, Illimar Hugo; Brenk, Ruth

2017-09-01

Riboswitches are cis-acting gene regulatory elements and constitute potential targets for new antibiotics. Recent studies in this field have started to explore these targets for drug discovery. New ligands found by fragment screening, design of analogs of the natural ligands or serendipitously by phenotypic screening have shown antibacterial effects in cell assays against a range of bacteria strains and in animal models. In this review, we highlight the most advanced drug design work of riboswitch ligands and discuss the challenges in the field with respect to the development of antibiotics with a new mechanism of action.

Target-cancer-cell-specific activatable fluorescence imaging probes: rational design and in vivo applications.

PubMed

Kobayashi, Hisataka; Choyke, Peter L

2011-02-15

Conventional imaging methods, such as angiography, computed tomography (CT), magnetic resonance imaging (MRI), and radionuclide imaging, rely on contrast agents (iodine, gadolinium, and radioisotopes, for example) that are "always on." Although these indicators have proven clinically useful, their sensitivity is lacking because of inadequate target-to-background signal ratio. A unique aspect of optical imaging is that fluorescence probes can be designed to be activatable, that is, only "turned on" under certain conditions. These probes are engineered to emit signal only after binding a target tissue; this design greatly increases sensitivity and specificity in the detection of disease. Current research focuses on two basic types of activatable fluorescence probes. The first developed were conventional enzymatically activatable probes. These fluorescent molecules exist in the quenched state until activated by enzymatic cleavage, which occurs mostly outside of the cells. However, more recently, researchers have begun designing target-cell-specific activatable probes. These fluorophores exist in the quenched state until activated within targeted cells by endolysosomal processing, which results when the probe binds specific receptors on the cell surface and is subsequently internalized. In this Account, we present a review of the rational design and in vivo applications of target-cell-specific activatable probes. In engineering these probes, researchers have asserted control over a variety of factors, including photochemistry, pharmacological profile, and biological properties. Their progress has recently allowed the rational design and synthesis of target-cell-specific activatable fluorescence imaging probes, which can be conjugated to a wide variety of targeting molecules. Several different photochemical mechanisms have been utilized, each of which offers a unique capability for probe design. These include self-quenching, homo- and hetero-fluorescence resonance

The constraints satisfaction problem approach in the design of an architectural functional layout

NASA Astrophysics Data System (ADS)

Zawidzki, Machi; Tateyama, Kazuyoshi; Nishikawa, Ikuko

2011-09-01

A design support system with a new strategy for finding the optimal functional configurations of rooms for architectural layouts is presented. A set of configurations satisfying given constraints is generated and ranked according to multiple objectives. The method can be applied to problems in architectural practice, urban or graphic design-wherever allocation of related geometrical elements of known shape is optimized. Although the methodology is shown using simplified examples-a single story residential building with two apartments each having two rooms-the results resemble realistic functional layouts. One example of a practical size problem of a layout of three apartments with a total of 20 rooms is demonstrated, where the generated solution can be used as a base for a realistic architectural blueprint. The discretization of design space is discussed, followed by application of a backtrack search algorithm used for generating a set of potentially 'good' room configurations. Next the solutions are classified by a machine learning method (FFN) as 'proper' or 'improper' according to the internal communication criteria. Examples of interactive ranking of the 'proper' configurations according to multiple criteria and choosing 'the best' ones are presented. The proposed framework is general and universal-the criteria, parameters and weights can be individually defined by a user and the search algorithm can be adjusted to a specific problem.

Designing Multi-target Compound Libraries with Gaussian Process Models.

PubMed

Bieler, Michael; Reutlinger, Michael; Rodrigues, Tiago; Schneider, Petra; Kriegl, Jan M; Schneider, Gisbert

2016-05-01

We present the application of machine learning models to selecting G protein-coupled receptor (GPCR)-focused compound libraries. The library design process was realized by ant colony optimization. A proprietary Boehringer-Ingelheim reference set consisting of 3519 compounds tested in dose-response assays at 11 GPCR targets served as training data for machine learning and activity prediction. We compared the usability of the proprietary data with a public data set from ChEMBL. Gaussian process models were trained to prioritize compounds from a virtual combinatorial library. We obtained meaningful models for three of the targets (5-HT2c , MCH, A1), which were experimentally confirmed for 12 of 15 selected and synthesized or purchased compounds. Overall, the models trained on the public data predicted the observed assay results more accurately. The results of this study motivate the use of Gaussian process regression on public data for virtual screening and target-focused compound library design. © 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Rational design of chemical genetic probes of RNA function and lead therapeutics targeting repeating transcripts.

PubMed

Disney, Matthew D

2013-12-01

RNA is an important yet vastly underexploited target for small molecule chemical probes or lead therapeutics. Small molecules have been used successfully to modulate the function of the bacterial ribosome, viral RNAs and riboswitches. These RNAs are either highly expressed or can be targeted using substrate mimicry, a mainstay in the design of enzyme inhibitors. However, most cellular RNAs are neither highly expressed nor have a lead small molecule inhibitor, a significant challenge for drug discovery efforts. Herein, I describe the design of small molecules targeting expanded repeating transcripts that cause myotonic muscular dystrophy (DM). These test cases illustrate the challenges of designing small molecules that target RNA and the advantages of targeting repeating transcripts. Lastly, I discuss how small molecules might be more advantageous than oligonucleotides for targeting RNA. Copyright © 2013 Elsevier Ltd. All rights reserved.

A "Reverse-Schur" Approach to Optimization With Linear PDE Constraints: Application to Biomolecule Analysis and Design.

PubMed

Bardhan, Jaydeep P; Altman, Michael D; Tidor, B; White, Jacob K

2009-01-01

We present a partial-differential-equation (PDE)-constrained approach for optimizing a molecule's electrostatic interactions with a target molecule. The approach, which we call reverse-Schur co-optimization, can be more than two orders of magnitude faster than the traditional approach to electrostatic optimization. The efficiency of the co-optimization approach may enhance the value of electrostatic optimization for ligand-design efforts-in such projects, it is often desirable to screen many candidate ligands for their viability, and the optimization of electrostatic interactions can improve ligand binding affinity and specificity. The theoretical basis for electrostatic optimization derives from linear-response theory, most commonly continuum models, and simple assumptions about molecular binding processes. Although the theory has been used successfully to study a wide variety of molecular binding events, its implications have not yet been fully explored, in part due to the computational expense associated with the optimization. The co-optimization algorithm achieves improved performance by solving the optimization and electrostatic simulation problems simultaneously, and is applicable to both unconstrained and constrained optimization problems. Reverse-Schur co-optimization resembles other well-known techniques for solving optimization problems with PDE constraints. Model problems as well as realistic examples validate the reverse-Schur method, and demonstrate that our technique and alternative PDE-constrained methods scale very favorably compared to the standard approach. Regularization, which ordinarily requires an explicit representation of the objective function, can be included using an approximate Hessian calculated using the new BIBEE/P (boundary-integral-based electrostatics estimation by preconditioning) method.

System engineering techniques for establishing balanced design and performance guidelines for the advanced telerobotic testbed

NASA Technical Reports Server (NTRS)

Zimmerman, W. F.; Matijevic, J. R.

1987-01-01

Novel system engineering techniques have been developed and applied to establishing structured design and performance objectives for the Telerobotics Testbed that reduce technical risk while still allowing the testbed to demonstrate an advancement in state-of-the-art robotic technologies. To estblish the appropriate tradeoff structure and balance of technology performance against technical risk, an analytical data base was developed which drew on: (1) automation/robot-technology availability projections, (2) typical or potential application mission task sets, (3) performance simulations, (4) project schedule constraints, and (5) project funding constraints. Design tradeoffs and configuration/performance iterations were conducted by comparing feasible technology/task set configurations against schedule/budget constraints as well as original program target technology objectives. The final system configuration, task set, and technology set reflected a balanced advancement in state-of-the-art robotic technologies, while meeting programmatic objectives and schedule/cost constraints.

Decision making with epistemic uncertainty under safety constraints: An application to seismic design

USGS Publications Warehouse

Veneziano, D.; Agarwal, A.; Karaca, E.

2009-01-01

The problem of accounting for epistemic uncertainty in risk management decisions is conceptually straightforward, but is riddled with practical difficulties. Simple approximations are often used whereby future variations in epistemic uncertainty are ignored or worst-case scenarios are postulated. These strategies tend to produce sub-optimal decisions. We develop a general framework based on Bayesian decision theory and exemplify it for the case of seismic design of buildings. When temporal fluctuations of the epistemic uncertainties and regulatory safety constraints are included, the optimal level of seismic protection exceeds the normative level at the time of construction. Optimal Bayesian decisions do not depend on the aleatory or epistemic nature of the uncertainties, but only on the total (epistemic plus aleatory) uncertainty and how that total uncertainty varies randomly during the lifetime of the project. ?? 2009 Elsevier Ltd. All rights reserved.

State-of-the-art in design rules for drug delivery platforms: lessons learned from FDA-approved nanomedicines.

PubMed

Dawidczyk, Charlene M; Kim, Chloe; Park, Jea Ho; Russell, Luisa M; Lee, Kwan Hyi; Pomper, Martin G; Searson, Peter C

2014-08-10

The ability to efficiently deliver a drug to a tumor site is dependent on a wide range of physiologically imposed design constraints. Nanotechnology provides the possibility of creating delivery vehicles where these design constraints can be decoupled, allowing new approaches for reducing the unwanted side effects of systemic delivery, increasing targeting efficiency and efficacy. Here we review the design strategies of the two FDA-approved antibody-drug conjugates (Brentuximab vedotin and Trastuzumab emtansine) and the four FDA-approved nanoparticle-based drug delivery platforms (Doxil, DaunoXome, Marqibo, and Abraxane) in the context of the challenges associated with systemic targeted delivery of a drug to a solid tumor. The lessons learned from these nanomedicines provide an important insight into the key challenges associated with the development of new platforms for systemic delivery of anti-cancer drugs. Copyright © 2014 Elsevier B.V. All rights reserved.

Mock Target Window OTR and IR Design and Testing

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wass, Alexander Joseph

In order to fully verify temperature measurements made on the target window using infrared (IR) optical non-contact methods, actual comparative measurements are made with a real beam distribution as the heat source using Argonne National Laboratory’s (ANL) 35 MeV electron accelerator. Using Monte Carlo N-Particle (MCNP) simulations and thermal Finite Element Analysis (FEA), a cooled mock target window with thermocouple implants is designed to be used in such a test to achieve window temperatures up to 700°C. An uncoated and blackcoated mock window is designed to enhance the IR temperature measurements and verify optical transmitted radiation (OTR) imagery. This allowsmore » us to fully verify and characterize our temperature accuracy with our current IR camera method and any future method we may wish to explore using actual production conditions. This test also provides us with valuable conclusions/concerns regarding the calibration method we developed using our IR test stand at TA-53 in MPF-14.« less

Balancing Flexible Constraints and Measurement Precision in Computerized Adaptive Testing

ERIC Educational Resources Information Center

Moyer, Eric L.; Galindo, Jennifer L.; Dodd, Barbara G.

2012-01-01

Managing test specifications--both multiple nonstatistical constraints and flexibly defined constraints--has become an important part of designing item selection procedures for computerized adaptive tests (CATs) in achievement testing. This study compared the effectiveness of three procedures: constrained CAT, flexible modified constrained CAT,…

Designing Targeted Educational Voucher Schemes for the Poor in Developing Countries

ERIC Educational Resources Information Center

Shafiq, M. Najeeb

2009-01-01

Targeted educational voucher schemes [TEVS] are often proposed for poor children in developing countries. This article explores the design of an effective TEVS using three policy instruments: regulation, support services, and finance. The regulation design addresses the rules that must be adhered to by participating households, children, and…

Full-Carpet Design of a Low-Boom Demonstrator Concept

NASA Technical Reports Server (NTRS)

Ordaz, Irian; Wintzer, Mathias; Rallabhandi, Sriram K.

2015-01-01

The Cart3D adjoint-based design framework is used to mitigate the undesirable o -track sonic boom properties of a demonstrator concept designed for low-boom directly under the flight path. First, the requirements of a Cart3D design mesh are determined using a high-fidelity mesh adapted to minimize the discretization error of the CFD analysis. Low-boom equivalent area targets are then generated at the under-track and one off-track azimuthal position for the baseline configuration. The under-track target is generated using a trim- feasible low-boom target generation process, ensuring that the final design is not only low-boom, but also trimmed at the specified flight condition. The o -track equivalent area target is generated by minimizing the A-weighted loudness using an efficient adjoint-based approach. The configuration outer mold line is then parameterized and optimized to match the off-body pressure distributions prescribed by the low-boom targets. The numerical optimizer uses design gradients which are calculated using the Cart3D adjoint- based design capability. Optimization constraints are placed on the geometry to satisfy structural feasibility. The low-boom properties of the final design are verified using the adaptive meshing approach. This analysis quantifies the error associated with the CFD mesh that is used for design. Finally, an alternate mesh construction and target positioning approach offering greater computational efficiency is demonstrated and verified.

Multi-Objective Trajectory Optimization of a Hypersonic Reconnaissance Vehicle with Temperature Constraints

NASA Astrophysics Data System (ADS)

Masternak, Tadeusz J.

This research determines temperature-constrained optimal trajectories for a scramjet-based hypersonic reconnaissance vehicle by developing an optimal control formulation and solving it using a variable order Gauss-Radau quadrature collocation method with a Non-Linear Programming (NLP) solver. The vehicle is assumed to be an air-breathing reconnaissance aircraft that has specified takeoff/landing locations, airborne refueling constraints, specified no-fly zones, and specified targets for sensor data collections. A three degree of freedom scramjet aircraft model is adapted from previous work and includes flight dynamics, aerodynamics, and thermal constraints. Vehicle control is accomplished by controlling angle of attack, roll angle, and propellant mass flow rate. This model is incorporated into an optimal control formulation that includes constraints on both the vehicle and mission parameters, such as avoidance of no-fly zones and coverage of high-value targets. To solve the optimal control formulation, a MATLAB-based package called General Pseudospectral Optimal Control Software (GPOPS-II) is used, which transcribes continuous time optimal control problems into an NLP problem. In addition, since a mission profile can have varying vehicle dynamics and en-route imposed constraints, the optimal control problem formulation can be broken up into several "phases" with differing dynamics and/or varying initial/final constraints. Optimal trajectories are developed using several different performance costs in the optimal control formulation: minimum time, minimum time with control penalties, and maximum range. The resulting analysis demonstrates that optimal trajectories that meet specified mission parameters and constraints can be quickly determined and used for larger-scale operational and campaign planning and execution.

Design of an ignition target for the laser megajoule, mitigating parametric instabilities

NASA Astrophysics Data System (ADS)

Laffite, S.; Loiseau, P.

2010-10-01

Laser plasma interaction (LPI) is a critical issue in ignition target design. Based on both scaling laws and two-dimensional calculations, this article describes how we can constrain a laser megajoule (LMJ) [J. Ebrardt and J. M. Chaput, J. Phys.: Conf. Ser. 112, 032005 (2008)] target design by mitigating LPI. An ignition indirect drive target has been designed for the 2/3 LMJ step. It requires 0.9 MJ and 260 TW of laser energy and power, to achieve a temperature of 300 eV in a rugby-shaped Hohlraum and give a yield of about 20 MJ. The study focuses on the analysis of linear gain for stimulated Raman and Brillouin scatterings. Enlarging the focal spot is an obvious way to reduce linear gains. We show that this reduction is nonlinear with the focal spot size. For relatively small focal spot area, linear gains are significantly reduced by enlarging the focal spot. However, there is no benefit in too large focal spots because of necessary larger laser entrance holes, which require more laser energy. Furthermore, this leads to the existence, for a given design, of a minimum value for linear gains for which we cannot go below.

MRPrimer: a MapReduce-based method for the thorough design of valid and ranked primers for PCR

PubMed Central

Kim, Hyerin; Kang, NaNa; Chon, Kang-Wook; Kim, Seonho; Lee, NaHye; Koo, JaeHyung; Kim, Min-Soo

2015-01-01

Primer design is a fundamental technique that is widely used for polymerase chain reaction (PCR). Although many methods have been proposed for primer design, they require a great deal of manual effort to generate feasible and valid primers, including homology tests on off-target sequences using BLAST-like tools. That approach is inconvenient for many target sequences of quantitative PCR (qPCR) due to considering the same stringent and allele-invariant constraints. To address this issue, we propose an entirely new method called MRPrimer that can design all feasible and valid primer pairs existing in a DNA database at once, while simultaneously checking a multitude of filtering constraints and validating primer specificity. Furthermore, MRPrimer suggests the best primer pair for each target sequence, based on a ranking method. Through qPCR analysis using 343 primer pairs and the corresponding sequencing and comparative analyses, we showed that the primer pairs designed by MRPrimer are very stable and effective for qPCR. In addition, MRPrimer is computationally efficient and scalable and therefore useful for quickly constructing an entire collection of feasible and valid primers for frequently updated databases like RefSeq. Furthermore, we suggest that MRPrimer can be utilized conveniently for experiments requiring primer design, especially real-time qPCR. PMID:26109350

Acceleration constraints in modeling and control of nonholonomic systems

NASA Astrophysics Data System (ADS)

Bajodah, Abdulrahman H.

2003-10-01

Acceleration constraints are used to enhance modeling techniques for dynamical systems. In particular, Kane's equations of motion subjected to bilateral constraints, unilateral constraints, and servo-constraints are modified by utilizing acceleration constraints for the purpose of simplifying the equations and increasing their applicability. The tangential properties of Kane's method provide relationships between the holonomic and the nonholonomic partial velocities, and hence allow one to describe nonholonomic generalized active and inertia forces in terms of their holonomic counterparts, i.e., those which correspond to the system without constraints. Therefore, based on the modeling process objectives, the holonomic and the nonholonomic vector entities in Kane's approach are used interchangeably to model holonomic and nonholonomic systems. When the holonomic partial velocities are used to model nonholonomic systems, the resulting models are full-order (also called nonminimal or unreduced) and separated in accelerations. As a consequence, they are readily integrable and can be used for generic system analysis. Other related topics are constraint forces, numerical stability of the nonminimal equations of motion, and numerical constraint stabilization. Two types of unilateral constraints considered are impulsive and friction constraints. Impulsive constraints are modeled by means of a continuous-in-velocities and impulse-momentum approaches. In controlled motion, the acceleration form of constraints is utilized with the Moore-Penrose generalized inverse of the corresponding constraint matrix to solve for the inverse dynamics of servo-constraints, and for the redundancy resolution of overactuated manipulators. If control variables are involved in the algebraic constraint equations, then these tools are used to modify the controlled equations of motion in order to facilitate control system design. An illustrative example of spacecraft stabilization is presented.

CFD Analysis and Design of Detailed Target Configurations for an Accelerator-Driven Subcritical System

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kraus, Adam; Merzari, Elia; Sofu, Tanju

2016-08-01

High-fidelity analysis has been utilized in the design of beam target options for an accelerator driven subcritical system. Designs featuring stacks of plates with square cross section have been investigated for both tungsten and uranium target materials. The presented work includes the first thermal-hydraulic simulations of the full, detailed target geometry. The innovative target cooling manifold design features many regions with complex flow features, including 90 bends and merging jets, which necessitate three-dimensional fluid simulations. These were performed using the commercial computational fluid dynamics code STAR-CCM+. Conjugate heat transfer was modeled between the plates, cladding, manifold structure, and fluid. Steady-statemore » simulations were performed but lacked good residual convergence. Unsteady simulations were then performed, which converged well and demonstrated that flow instability existed in the lower portion of the manifold. It was established that the flow instability had little effect on the peak plate temperatures, which were well below the melting point. The estimated plate surface temperatures and target region pressure were shown to provide sufficient margin to subcooled boiling for standard operating conditions. This demonstrated the safety of both potential target configurations during normal operation.« less

Influence of Hatha yoga on physical activity constraints, physical fitness, and body image of breast cancer survivors: a pilot study.

PubMed

Van Puymbroeck, Marieke; Schmid, Arlene; Shinew, Kimberly J; Hsieh, Pei-Chun

2011-01-01

Breast cancer survivors often experience changes in their perception of their bodies following surgical treatment. These changes in body image may increase self-consciousness and perceptions of physical activity constraints and reduce participation in physical activity. While the number of studies examining different types of yoga targeting women with breast cancer has increased, studies thus far have not studied the influence that Hatha yoga has on body image and physical activity constraints. The objective of this study was to explore the changes that occur in breast cancer survivors in terms of body image, perceived constraints, and physical fitness following an 8-week Hatha yoga intervention. This study used a nonrandomized two-group pilot study, comparing an 8-week Hatha yoga intervention with a light exercise group, both designed for women who were at least nine months post-treatment for breast cancer. Both quantitative and qualitative data were collected in the areas of body image, physical activity constraints, and physical fitness. Findings indicated that quantitatively, yoga participants experienced reductions in physical activity constraints and improvements in lower- and upper-body strength and flexibility, while control participants experienced improvements in abdominal strength and lower-body strength. Qualitative findings support changes in body image, physical activity constraints, and physical fitness for the participants in the yoga group. In conclusion, Hatha yoga may reduce constraints to physical activity and improve fitness in breast cancer survivors. More research is needed to explore the relationship between Hatha yoga and improvements in body image.

Conformational stability as a design target to control protein aggregation.

PubMed

Costanzo, Joseph A; O'Brien, Christopher J; Tiller, Kathryn; Tamargo, Erin; Robinson, Anne Skaja; Roberts, Christopher J; Fernandez, Erik J

2014-05-01

Non-native protein aggregation is a prevalent problem occurring in many biotechnological manufacturing processes and can compromise the biological activity of the target molecule or induce an undesired immune response. Additionally, some non-native aggregation mechanisms lead to amyloid fibril formation, which can be associated with debilitating diseases. For natively folded proteins, partial or complete unfolding is often required to populate aggregation-prone conformational states, and therefore one proposed strategy to mitigate aggregation is to increase the free energy for unfolding (ΔGunf) prior to aggregation. A computational design approach was tested using human γD crystallin (γD-crys) as a model multi-domain protein. Two mutational strategies were tested for their ability to reduce/increase aggregation rates by increasing/decreasing ΔGunf: stabilizing the less stable domain and stabilizing the domain-domain interface. The computational protein design algorithm, RosettaDesign, was implemented to identify point variants. The results showed that although the predicted free energies were only weakly correlated with the experimental ΔGunf values, increased/decreased aggregation rates for γD-crys correlated reasonably well with decreases/increases in experimental ΔGunf, illustrating improved conformational stability as a possible design target to mitigate aggregation. However, the results also illustrate that conformational stability is not the sole design factor controlling aggregation rates of natively folded proteins.

Design of optimal groundwater remediation systems under flexible environmental-standard constraints.

PubMed

Fan, Xing; He, Li; Lu, Hong-Wei; Li, Jing

2015-01-01

In developing optimal groundwater remediation strategies, limited effort has been exerted to solve the uncertainty in environmental quality standards. When such uncertainty is not considered, either over optimistic or over pessimistic optimization strategies may be developed, probably leading to the formulation of rigid remediation strategies. This study advances a mathematical programming modeling approach for optimizing groundwater remediation design. This approach not only prevents the formulation of over optimistic and over pessimistic optimization strategies but also provides a satisfaction level that indicates the degree to which the environmental quality standard is satisfied. Therefore the approach may be expected to be significantly more acknowledged by the decision maker than those who do not consider standard uncertainty. The proposed approach is applied to a petroleum-contaminated site in western Canada. Results from the case study show that (1) the peak benzene concentrations can always satisfy the environmental standard under the optimal strategy, (2) the pumping rates of all wells decrease under a relaxed standard or long-term remediation approach, (3) the pumping rates are less affected by environmental quality constraints under short-term remediation, and (4) increased flexible environmental standards have a reduced effect on the optimal remediation strategy.

Modifier constraint in alkali borophosphate glasses using topological constraint theory

NASA Astrophysics Data System (ADS)

Li, Xiang; Zeng, Huidan; Jiang, Qi; Zhao, Donghui; Chen, Guorong; Wang, Zhaofeng; Sun, Luyi; Chen, Jianding

2016-12-01

In recent years, composition-dependent properties of glasses have been successfully predicted using the topological constraint theory. The constraints of the glass network are derived from two main parts: network formers and network modifiers. The constraints of the network formers can be calculated on the basis of the topological structure of the glass. However, the latter cannot be accurately calculated in this way, because of the existing of ionic bonds. In this paper, the constraints of the modifier ions in phosphate glasses were thoroughly investigated using the topological constraint theory. The results show that the constraints of the modifier ions are gradually increased with the addition of alkali oxides. Furthermore, an improved topological constraint theory for borophosphate glasses is proposed by taking the composition-dependent constraints of the network modifiers into consideration. The proposed theory is subsequently evaluated by analyzing the composition dependence of the glass transition temperature in alkali borophosphate glasses. This method is supposed to be extended to other similar glass systems containing alkali ions.

Design specification for the European Spallation Source neutron generating target element

NASA Astrophysics Data System (ADS)

Aguilar, A.; Sordo, F.; Mora, T.; Mena, L.; Mancisidor, M.; Aguilar, J.; Bakedano, G.; Herranz, I.; Luna, P.; Magan, M.; Vivanco, R.; Jimenez-Villacorta, F.; Sjogreen, K.; Oden, U.; Perlado, J. M.; Martinez, J. L.; Bermejo, F. J.

2017-06-01

The paper addresses some of the most relevant issues concerning the thermal hydraulics and radiation damage of the neutron generation target to be built at the European Spallation Source as recently approved after a critical design review. The target unit consists of a set of Tungsten blocks placed inside a wheel of 2.5 m diameter which rotates at some 0.5 Hz in order to distribute the heat generated from incoming protons which reach the target in the radial direction. The spallation material elements are composed of an array of Tungsten pieces which rest on a rotating steel support (the cassette) and are distributed in a cross-flow configuration. The thermal, mechanical and radiation effects resulting from the impact of a 2 GeV proton pulse are analysed in detail as well as an evaluation of the inventory of spallation products. The current design is found to conform to specifications and found to be robust enough to deal with several accident scenarios.

Design of two-channel filter bank using nature inspired optimization based fractional derivative constraints.

PubMed

Kuldeep, B; Singh, V K; Kumar, A; Singh, G K

2015-01-01

In this article, a novel approach for 2-channel linear phase quadrature mirror filter (QMF) bank design based on a hybrid of gradient based optimization and optimization of fractional derivative constraints is introduced. For the purpose of this work, recently proposed nature inspired optimization techniques such as cuckoo search (CS), modified cuckoo search (MCS) and wind driven optimization (WDO) are explored for the design of QMF bank. 2-Channel QMF is also designed with particle swarm optimization (PSO) and artificial bee colony (ABC) nature inspired optimization techniques. The design problem is formulated in frequency domain as sum of L2 norm of error in passband, stopband and transition band at quadrature frequency. The contribution of this work is the novel hybrid combination of gradient based optimization (Lagrange multiplier method) and nature inspired optimization (CS, MCS, WDO, PSO and ABC) and its usage for optimizing the design problem. Performance of the proposed method is evaluated by passband error (ϕp), stopband error (ϕs), transition band error (ϕt), peak reconstruction error (PRE), stopband attenuation (As) and computational time. The design examples illustrate the ingenuity of the proposed method. Results are also compared with the other existing algorithms, and it was found that the proposed method gives best result in terms of peak reconstruction error and transition band error while it is comparable in terms of passband and stopband error. Results show that the proposed method is successful for both lower and higher order 2-channel QMF bank design. A comparative study of various nature inspired optimization techniques is also presented, and the study singles out CS as a best QMF optimization technique. Copyright © 2014 ISA. Published by Elsevier Ltd. All rights reserved.

GLRS-R 2-colour retroreflector target design and predicted performance

NASA Technical Reports Server (NTRS)

Lund, Glenn

1993-01-01

This paper reports on the retroreflector ground-target design for the GLRS-R spaceborne dual-wavelength laser ranging system. The described passive design flows down from the requirements of high station autonomy, high global FOV (up to 60 degrees zenith angle), little or no multiple pulse returns, and adequate optical cross section for most ranging geometries. The proposed solution makes use of 5 hollow cube-corner retroreflectors of which one points to the zenith and the remaining four are inclined from the vertical at uniform azimuthal spacings. The need for fairly large (is approximately 10 cm) retroreflectors is expected (within turbulence limitations) to generate quite narrow diffraction lobes, thus placing non-trivial requirements on the vectorial accuracy of velocity aberration corrections. A good compromise solution is found by appropriately spoiling just one of the retroreflector dihedral angles from 90 degrees, thus generating two symmetrically oriented diffraction lobes in the return beam. The required spoil angles are found to have little dependence on ground target latitude. Various link budget analyses are presented, showing the influence of such factors as point-ahead optimization, turbulence, ranging angle, atmospheric visibility and ground target thermal deformations.

GLRS-R 2-colour retroreflector target design and predicted performance

NASA Astrophysics Data System (ADS)

Lund, Glenn

1993-06-01

This paper reports on the retroreflector ground-target design for the GLRS-R spaceborne dual-wavelength laser ranging system. The described passive design flows down from the requirements of high station autonomy, high global FOV (up to 60 degrees zenith angle), little or no multiple pulse returns, and adequate optical cross section for most ranging geometries. The proposed solution makes use of 5 hollow cube-corner retroreflectors of which one points to the zenith and the remaining four are inclined from the vertical at uniform azimuthal spacings. The need for fairly large (is approximately 10 cm) retroreflectors is expected (within turbulence limitations) to generate quite narrow diffraction lobes, thus placing non-trivial requirements on the vectorial accuracy of velocity aberration corrections. A good compromise solution is found by appropriately spoiling just one of the retroreflector dihedral angles from 90 degrees, thus generating two symmetrically oriented diffraction lobes in the return beam. The required spoil angles are found to have little dependence on ground target latitude. Various link budget analyses are presented, showing the influence of such factors as point-ahead optimization, turbulence, ranging angle, atmospheric visibility and ground target thermal deformations.

Design of nuclease-based target recycling signal amplification in aptasensors.

PubMed

Yan, Mengmeng; Bai, Wenhui; Zhu, Chao; Huang, Yafei; Yan, Jiao; Chen, Ailiang

2016-03-15

Compared with conventional antibody-based immunoassay methods, aptasensors based on nucleic acid aptamer have made at least two significant breakthroughs. One is that aptamers are more easily used for developing various simple and rapid homogeneous detection methods by "sample in signal out" without multi-step washing. The other is that aptamers are more easily employed for developing highly sensitive detection methods by using various nucleic acid-based signal amplification approaches. As many substances playing regulatory roles in physiology or pathology exist at an extremely low concentration and many chemical contaminants occur in trace amounts in food or environment, aptasensors for signal amplification contribute greatly to detection of such targets. Among the signal amplification approaches in highly sensitive aptasensors, the nuclease-based target recycling signal amplification has recently become a research focus because it shows easy design, simple operation, and rapid reaction and can be easily developed for homogenous assay. In this review, we summarized recent advances in the development of various nuclease-based target recycling signal amplification with the aim to provide a general guide for the design of aptamer-based ultrasensitive biosensing assays. Copyright © 2015 Elsevier B.V. All rights reserved.

Design challenges in nanoparticle-based platforms: Implications for targeted drug delivery systems

NASA Astrophysics Data System (ADS)

Mullen, Douglas Gurnett

Characterization and control of heterogeneous distributions of nanoparticle-ligand components are major design challenges for nanoparticle-based platforms. This dissertation begins with an examination of poly(amidoamine) (PAMAM) dendrimer-based targeted delivery platform. A folic acid targeted modular platform was developed to target human epithelial cancer cells. Although active targeting was observed in vitro, active targeting was not found in vivo using a mouse tumor model. A major flaw of this platform design was that it did not provide for characterization or control of the component distribution. Motivated by the problems experienced with the modular design, the actual composition of nanoparticle-ligand distributions were examined using a model dendrimer-ligand system. High Pressure Liquid Chromatography (HPLC) resolved the distribution of components in samples with mean ligand/dendrimer ratios ranging from 0.4 to 13. A peak fitting analysis enabled the quantification of the component distribution. Quantified distributions were found to be significantly more heterogeneous than commonly expected and standard analytical parameters, namely the mean ligand/nanoparticle ratio, failed to adequately represent the component heterogeneity. The distribution of components was also found to be sensitive to particle modifications that preceded the ligand conjugation. With the knowledge gained from this detailed distribution analysis, a new platform design was developed to provide a system with dramatically improved control over the number of components and with improved batch reproducibility. Using semi-preparative HPLC, individual dendrimer-ligand components were isolated. The isolated dendrimer with precise numbers of ligands were characterized by NMR and analytical HPLC. In total, nine different dendrimer-ligand components were obtained with degrees of purity ≥80%. This system has the potential to serve as a platform to which a precise number of functional molecules

Propulsive Maneuver Design for the 2007 Mars Phoenix Lander Mission

NASA Technical Reports Server (NTRS)

Raofi, Behzad; Bhat, Ramachandra S.; Helfrich, Cliff

2008-01-01

On May 25, 2008, the Mars Phoenix Lander (PHX) successfully landed in the northern planes of Mars in order to continue and complement NASA's "follow the water" theme as its predecessor Mars missions, such as Mars Odyssey (ODY) and Mars Exploration Rovers, have done in recent years. Instruments on the lander, through a robotic arm able to deliver soil samples to the deck, will perform in-situ and remote-sensing investigations to characterize the chemistry of materials at the local surface, subsurface, and atmosphere. Lander instruments will also identify the potential history of key indicator elements of significance to the biological potential of Mars, including potential organics within any accessible water ice. Precise trajectory control and targeting were necessary in order to achieve the accurate atmospheric entry conditions required for arriving at the desired landing site. The challenge for the trajectory control maneuver design was to meet or exceed these requirements in the presence of spacecraft limitations as well as other mission constraints. This paper describes the strategies used, including the specialized targeting specifically developed for PHX, in order to design and successfully execute the propulsive maneuvers that delivered the spacecraft to its targeted landing site while satisfying the planetary protection requirements in the presence of flight system constraints.

Dose-finding designs for trials of molecularly targeted agents and immunotherapies

PubMed Central

Chiuzan, Cody; Shtaynberger, Jonathan; Manji, Gulam A.; Duong, Jimmy K.; Schwartz, Gary K.; Ivanova, Anastasia; Lee, Shing M.

2017-01-01

Recently, there has been a surge of early phase trials of molecularly targeted agents (MTAs) and immunotherapies. These new therapies have different toxicity profiles compared to cytotoxic therapies. MTAs can benefit from new trial designs that allow inclusion of low-grade toxicities, late-onset toxicities, addition of an efficacy endpoint, and flexibility in the specification of a target toxicity probability. To study the degree of adoption of these methods, we conducted a Web of Science search of articles published between 2008 and 2014 that describe phase 1 oncology trials. Trials were categorized based on the dose-finding design used and the type of drug studied. Out of 1,712 dose-finding trials that met our criteria, 1,591 (92.9%) utilized a rule-based design, and 92 (5.4%; range 2.3% in 2009 to 9.7% in 2014) utilized a model-based or novel design. Over half of the trials tested an MTA or immunotherapy. Among the MTA and immunotherapy trials, 5.8% used model-based methods, compared to 3.9% and 8.3% of the chemotherapy or radiotherapy trials, respectively. While the percentage of trials using novel dose-finding designs has tripled since 2007, only 7.1% of trials use novel designs. PMID:28166468

Path following control of planar snake robots using virtual holonomic constraints: theory and experiments.

PubMed

Rezapour, Ehsan; Pettersen, Kristin Y; Liljebäck, Pål; Gravdahl, Jan T; Kelasidi, Eleni

This paper considers path following control of planar snake robots using virtual holonomic constraints. In order to present a model-based path following control design for the snake robot, we first derive the Euler-Lagrange equations of motion of the system. Subsequently, we define geometric relations among the generalized coordinates of the system, using the method of virtual holonomic constraints. These appropriately defined constraints shape the geometry of a constraint manifold for the system, which is a submanifold of the configuration space of the robot. Furthermore, we show that the constraint manifold can be made invariant by a suitable choice of feedback. In particular, we analytically design a smooth feedback control law to exponentially stabilize the constraint manifold. We show that enforcing the appropriately defined virtual holonomic constraints for the configuration variables implies that the robot converges to and follows a desired geometric path. Numerical simulations and experimental results are presented to validate the theoretical approach.

Rational Design of Cancer-Targeted Benzoselenadiazole by RGD Peptide Functionalization for Cancer Theranostics.

PubMed

Yang, Liye; Li, Wenying; Huang, Yanyu; Zhou, Yangliang; Chen, Tianfeng

2015-09-01

A cancer-targeted conjugate of the selenadiazole derivative BSeC (benzo[1,2,5] selenadiazole-5-carboxylic acid) with RGD peptide as targeting molecule and PEI (polyethylenimine) as a linker is rationally designed and synthesized in the present study. The results show that RGD-PEI-BSeC forms nanoparticles in aqueous solution with a core-shell nanostructure and high stability under physiological conditions. This rational design effectively enhances the selective cellular uptake and cellular retention of BSeC in human glioma cells, and increases its selectivity between cancer and normal cells. The nanoparticles enter the cells through receptor-mediated endocytosis via clathrin-mediated and nystatin-dependent lipid raft-mediated pathways. Internalized nanoparticles trigger glioma cell apoptosis by activation of ROS-mediated p53 phosphorylation. Therefore, this study provides a strategy for the rational design of selenium-containing cancer-targeted theranostics. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Tracking control of a marine surface vessel with full-state constraints

NASA Astrophysics Data System (ADS)

Yin, Zhao; He, Wei; Yang, Chenguang

2017-02-01

In this paper, a trajectory tracking control law is proposed for a class of marine surface vessels in the presence of full-state constraints and dynamics uncertainties. A barrier Lyapunov function (BLF) based control is employed to prevent states from violating the constraints. Neural networks are used to approximate the system uncertainties in the control design, and the control law is designed by using the Moore-Penrose inverse. The proposed control is able to compensate for the effects of full-state constraints. Meanwhile, the signals in the closed-loop system are guaranteed to be semiglobally uniformly bounded, with the asymptotic tracking being achieved. Finally, the performance of the proposed control has been tested and verified by simulation studies.

Design of photon converter and photoneutron target for High power electron accelerator based BNCT.

PubMed

Rahmani, Faezeh; Seifi, Samaneh; Anbaran, Hossein Tavakoli; Ghasemi, Farshad

2015-12-01

An electron accelerator, ILU-14, with current of 10 mA and 100 kW in power has been considered as one of the options for neutron source in Boron Neutron Capture Therapy (BNCT). The final design of neutron target has been obtained using MCNPX to optimize the neutron production. Tungsten in strip shape and D2O in cylindrical form have been proposed as the photon converter and the photoneutron target, respectively. In addition calculation of heat deposition in the photon target design has been considered to ensure mechanical stability of target. The results show that about 8.37×10(12) photoneutron/s with average energy of 615 keV can be produced by this neutron source design. In addition, using an appropriate beam shaping assembly an epithermal neutron flux of the order of 1.24×10(8) cm(-2) s(-1) can be obtained for BNCT applications. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Nature of Credit Constraints and Human Capital. NBER Working Paper No. 13912

ERIC Educational Resources Information Center

Lochner, Lance J.; Monge-Naranjo, Alexander

2008-01-01

This paper studies the nature and impact of credit constraints in the market for human capital. We derive endogenous constraints from the design of government student loan programs and from the limited repayment incentives in private lending markets. These constraints imply cross-sectional patterns for schooling, ability, and family income that…

A “Reverse-Schur” Approach to Optimization With Linear PDE Constraints: Application to Biomolecule Analysis and Design

PubMed Central

Bardhan, Jaydeep P.; Altman, Michael D.

2009-01-01

We present a partial-differential-equation (PDE)-constrained approach for optimizing a molecule’s electrostatic interactions with a target molecule. The approach, which we call reverse-Schur co-optimization, can be more than two orders of magnitude faster than the traditional approach to electrostatic optimization. The efficiency of the co-optimization approach may enhance the value of electrostatic optimization for ligand-design efforts–in such projects, it is often desirable to screen many candidate ligands for their viability, and the optimization of electrostatic interactions can improve ligand binding affinity and specificity. The theoretical basis for electrostatic optimization derives from linear-response theory, most commonly continuum models, and simple assumptions about molecular binding processes. Although the theory has been used successfully to study a wide variety of molecular binding events, its implications have not yet been fully explored, in part due to the computational expense associated with the optimization. The co-optimization algorithm achieves improved performance by solving the optimization and electrostatic simulation problems simultaneously, and is applicable to both unconstrained and constrained optimization problems. Reverse-Schur co-optimization resembles other well-known techniques for solving optimization problems with PDE constraints. Model problems as well as realistic examples validate the reverse-Schur method, and demonstrate that our technique and alternative PDE-constrained methods scale very favorably compared to the standard approach. Regularization, which ordinarily requires an explicit representation of the objective function, can be included using an approximate Hessian calculated using the new BIBEE/P (boundary-integral-based electrostatics estimation by preconditioning) method. PMID:23055839

Point design targets, specifications, and requirements for the 2010 NIF ignition campaign

NASA Astrophysics Data System (ADS)

Haan, Steven

2010-11-01

A set of point design targets has been specified for the initial ignition campaign on the National Ignition Facility [G. Miller, E. Moses, and C. Wuest, Opt. Eng. 443, 2841 (2004)]. The targets use an ablator of either Be(Cu) or CH(Ge). They are imploded in a U or Au hohlraum at peak radiation temperature 270 to 300eV. Considerations determining the point design include laser-plasma interactions, hydro stability, laser operations, and target fabrication. Simulations were used to evaluate choices, to define requirements, and to estimate sensitivity to uncertainties. Designs were updated to account for 2009 experimental results. We describe a formalism to evaluate the margin for ignition, in a parameter the Ignition Threshold Factor (ITF). Uncertainty and shot-to-shot variability can be evaluated, as well as sensitivity to systematic uncertainties. The formalism is used to estimate the probability of ignition for each target. In collaboration with J Lindl, D Callahan, D Clark, J Salmonson, B Hammel, L Atherton, R Cook, J Edwards, S Glenzer, A Hamza, S Hatchett, D Hinkel, D Ho, O Jones, O Landen, B MacGowan, M Marinak, E Moses, D Munro, S Pollaine, B Spears, P Springer, L Suter, C Thomas, R Town, S Weber, D Wilson, G Kyrala, M Herrmann, R Olson, R Vesey, A Nikroo, H Huang, and K Moreno.

Adaptable setups for magnetic drug targeting in human muscular arteries: Design and implementation

NASA Astrophysics Data System (ADS)

Hajiaghajani, Amirhossein; Hashemi, Soheil; Abdolali, Ali

2017-09-01

Magnetic drug targeting has been used to steer magnetic therapeutic agents and has received much attention for capillaries and human brain arteries. In this paper, we focus on noninvasive targeting of nanoparticles in muscular arteries, in where the vessel diameter and blood flow are much challengingly higher than brain capillaries. We aim to design a low intensity magnetic field which avoids potential side effects on blood cells while steers particles with high targeting rate. The setup design procedure is considerably flexible to be used in a wide variety of large vessels. Using particle tracing, a new method is proposed to connect the geometry of the vessel under the action of targeting to the required magnetic force. Specifications of the coil which is placed outside the body are derived based on this required force. Mutual effects of coil dimensions on the produced magnetic force are elaborated and summarized in a design flowchart to be used for arbitrary muscular vessel sizes. The performance of the optimized coil is validated by in vitro experiments and it is shown that particles are steered with the average efficiency of 80.2% for various conditions.

Thermodynamically optimal whole-genome tiling microarray design and validation.

PubMed

Cho, Hyejin; Chou, Hui-Hsien

2016-06-13

Microarray is an efficient apparatus to interrogate the whole transcriptome of species. Microarray can be designed according to annotated gene sets, but the resulted microarrays cannot be used to identify novel transcripts and this design method is not applicable to unannotated species. Alternatively, a whole-genome tiling microarray can be designed using only genomic sequences without gene annotations, and it can be used to detect novel RNA transcripts as well as known genes. The difficulty with tiling microarray design lies in the tradeoff between probe-specificity and coverage of the genome. Sequence comparison methods based on BLAST or similar software are commonly employed in microarray design, but they cannot precisely determine the subtle thermodynamic competition between probe targets and partially matched probe nontargets during hybridizations. Using the whole-genome thermodynamic analysis software PICKY to design tiling microarrays, we can achieve maximum whole-genome coverage allowable under the thermodynamic constraints of each target genome. The resulted tiling microarrays are thermodynamically optimal in the sense that all selected probes share the same melting temperature separation range between their targets and closest nontargets, and no additional probes can be added without violating the specificity of the microarray to the target genome. This new design method was used to create two whole-genome tiling microarrays for Escherichia coli MG1655 and Agrobacterium tumefaciens C58 and the experiment results validated the design.

Improving SALT productivity by using the theory of constraints

NASA Astrophysics Data System (ADS)

Coetzee, Johannes C.; Väisänen, Petri; O'Donoghue, Darragh E.; Kotze, Paul; Romero Colmenero, Encarni; Miszalski, Brent; Crawford, Steven M.; Kniazev, Alexei; Depagne, Éric; Rabe, Paul; Hettlage, Christian

2016-07-01

SALT, the Southern African Large Telescope, is a very cost effective 10 m class telescope. The operations cost per refereed science paper is currently approximately $70,000. To achieve this competitive advantage, specific design tradeoffs had to be made leading to technical constraints. On the other hand, the telescope has many advantages, such as being able to rapidly switch between different instruments and observing modes during the night. We provide details of the technical and operational constraints and how they were dealt with, by applying the theory of constraints, to substantially improve the observation throughput during the last semester.

Progress Toward Efficient Laminar Flow Analysis and Design

NASA Technical Reports Server (NTRS)

Campbell, Richard L.; Campbell, Matthew L.; Streit, Thomas

2011-01-01

A multi-fidelity system of computer codes for the analysis and design of vehicles having extensive areas of laminar flow is under development at the NASA Langley Research Center. The overall approach consists of the loose coupling of a flow solver, a transition prediction method and a design module using shell scripts, along with interface modules to prepare the input for each method. This approach allows the user to select the flow solver and transition prediction module, as well as run mode for each code, based on the fidelity most compatible with the problem and available resources. The design module can be any method that designs to a specified target pressure distribution. In addition to the interface modules, two new components have been developed: 1) an efficient, empirical transition prediction module (MATTC) that provides n-factor growth distributions without requiring boundary layer information; and 2) an automated target pressure generation code (ATPG) that develops a target pressure distribution that meets a variety of flow and geometry constraints. The ATPG code also includes empirical estimates of several drag components to allow the optimization of the target pressure distribution. The current system has been developed for the design of subsonic and transonic airfoils and wings, but may be extendable to other speed ranges and components. Several analysis and design examples are included to demonstrate the current capabilities of the system.

Antibody Drug Conjugates: Application of Quantitative Pharmacology in Modality Design and Target Selection.

PubMed

Sadekar, S; Figueroa, I; Tabrizi, M

2015-07-01

Antibody drug conjugates (ADCs) are a multi-component modality comprising of an antibody targeting a cell-specific antigen, a potent drug/payload, and a linker that can be processed within cellular compartments to release payload upon internalization. Numerous ADCs are being evaluated in both research and clinical settings within the academic and pharmaceutical industry due to their ability to selectively deliver potent payloads. Hence, there is a clear need to incorporate quantitative approaches during early stages of drug development for effective modality design and target selection. In this review, we describe a quantitative approach and framework for evaluation of the interplay between drug- and systems-dependent properties (i.e., target expression, density, localization, turnover, and affinity) in order to deliver a sufficient amount of a potent payload into the relevant target cells. As discussed, theoretical approaches with particular considerations given to various key properties for the target and modality suggest that delivery of the payload into particular effect cells to be more sensitive to antigen concentrations for targets with slow turnover rates as compared to those with faster internalization rates. Further assessments also suggest that increasing doses beyond the threshold of the target capacity (a function of target internalization and expression) may not impact the maximum amount of payload delivered to the intended effect cells. This article will explore the important application of quantitative sciences in selection of the target and design of ADC modalities.

Mechanistic and quantitative insight into cell surface targeted molecular imaging agent design.

PubMed

Zhang, Liang; Bhatnagar, Sumit; Deschenes, Emily; Thurber, Greg M

2016-05-05

Molecular imaging agent design involves simultaneously optimizing multiple probe properties. While several desired characteristics are straightforward, including high affinity and low non-specific background signal, in practice there are quantitative trade-offs between these properties. These include plasma clearance, where fast clearance lowers background signal but can reduce target uptake, and binding, where high affinity compounds sometimes suffer from lower stability or increased non-specific interactions. Further complicating probe development, many of the optimal parameters vary depending on both target tissue and imaging agent properties, making empirical approaches or previous experience difficult to translate. Here, we focus on low molecular weight compounds targeting extracellular receptors, which have some of the highest contrast values for imaging agents. We use a mechanistic approach to provide a quantitative framework for weighing trade-offs between molecules. Our results show that specific target uptake is well-described by quantitative simulations for a variety of targeting agents, whereas non-specific background signal is more difficult to predict. Two in vitro experimental methods for estimating background signal in vivo are compared - non-specific cellular uptake and plasma protein binding. Together, these data provide a quantitative method to guide probe design and focus animal work for more cost-effective and time-efficient development of molecular imaging agents.

Design and Preliminary Testing of the International Docking Adapter's Peripheral Docking Target

NASA Technical Reports Server (NTRS)

Foster, Christopher W.; Blaschak, Johnathan; Eldridge, Erin A.; Brazzel, Jack P.; Spehar, Peter T.

2015-01-01

The International Docking Adapter's Peripheral Docking Target (PDT) was designed to allow a docking spacecraft to judge its alignment relative to the docking system. The PDT was designed to be compatible with relative sensors using visible cameras, thermal imagers, or Light Detection and Ranging (LIDAR) technologies. The conceptual design team tested prototype designs and materials to determine the contrast requirements for the features. This paper will discuss the design of the PDT, the methodology and results of the tests, and the conclusions pertaining to PDT design that were drawn from testing.

Orion Exploration Mission Entry Interface Target Line

NASA Technical Reports Server (NTRS)

Rea, Jeremy R.

2016-01-01

The Orion Multi-Purpose Crew Vehicle is required to return to the continental United States at any time during the month. In addition, it is required to provide a survivable entry from a wide range of trans-lunar abort trajectories. The Entry Interface (EI) state must be targeted to ensure that all requirements are met for all possible return scenarios, even in the event of no communication with the Mission Control Center to provide an updated EI target. The challenge then is to functionalize an EI state constraint manifold that can be used in the on-board targeting algorithm, as well as the ground-based trajectory optimization programs. This paper presents the techniques used to define the EI constraint manifold and to functionalize it as a set of polynomials in several dimensions.

Constraint processing in our extensible language for cooperative imaging system

NASA Astrophysics Data System (ADS)

Aoki, Minoru; Murao, Yo; Enomoto, Hajime

1996-02-01

The extensible WELL (Window-based elaboration language) has been developed using the concept of common platform, where both client and server can communicate with each other with support from a communication manager. This extensible language is based on an object oriented design by introducing constraint processing. Any kind of services including imaging in the extensible language is controlled by the constraints. Interactive functions between client and server are extended by introducing agent functions including a request-respond relation. Necessary service integrations are satisfied with some cooperative processes using constraints. Constraints are treated similarly to data, because the system should have flexibilities in the execution of many kinds of services. The similar control process is defined by using intentional logic. There are two kinds of constraints, temporal and modal constraints. Rendering the constraints, the predicate format as the relation between attribute values can be a warrant for entities' validity as data. As an imaging example, a processing procedure of interaction between multiple objects is shown as an image application for the extensible system. This paper describes how the procedure proceeds in the system, and that how the constraints work for generating moving pictures.

Image-algebraic design of multispectral target recognition algorithms

NASA Astrophysics Data System (ADS)

Schmalz, Mark S.; Ritter, Gerhard X.

1994-06-01

In this paper, we discuss methods for multispectral ATR (Automated Target Recognition) of small targets that are sensed under suboptimal conditions, such as haze, smoke, and low light levels. In particular, we discuss our ongoing development of algorithms and software that effect intelligent object recognition by selecting ATR filter parameters according to ambient conditions. Our algorithms are expressed in terms of IA (image algebra), a concise, rigorous notation that unifies linear and nonlinear mathematics in the image processing domain. IA has been implemented on a variety of parallel computers, with preprocessors available for the Ada and FORTRAN languages. An image algebra C++ class library has recently been made available. Thus, our algorithms are both feasible implementationally and portable to numerous machines. Analyses emphasize the aspects of image algebra that aid the design of multispectral vision algorithms, such as parameterized templates that facilitate the flexible specification of ATR filters.

Improving memory after interruption: exploiting soft constraints and manipulating information access cost.

PubMed

Morgan, Phillip L; Patrick, John; Waldron, Samuel M; King, Sophia L; Patrick, Tanya

2009-12-01

Forgetting what one was doing prior to interruption is an everyday problem. The recent soft constraints hypothesis (Gray, Sims, Fu, & Schoelles, 2006) emphasizes the strategic adaptation of information processing strategy to the task environment. It predicts that increasing information access cost (IAC: the time, and physical and mental effort involved in accessing information) encourages a more memory-intensive strategy. Like interruptions, access costs are also intrinsic to most work environments, such as when opening documents and e-mails. Three experiments investigated whether increasing IAC during a simple copying task can be an effective method for reducing forgetting following interruption. IAC was designated Low (all information permanently visible), Medium (a mouse movement to uncover target information), or High (an additional few seconds to uncover such information). Experiment 1 found that recall improved across all three levels of IAC. Subsequent experiments found that High IAC facilitated resumption after interruption, particularly when interruption occurred on half of all trials (Experiment 2), and improved prospective memory following two different interrupting tasks, even when one involved the disruptive effect of using the same type of resource as the primary task (Experiment 3). The improvement of memory after interruption with increased IAC supports the prediction of the soft constraints hypothesis. The main disadvantage of a high access cost was a reduction in speed of task completion. The practicality of manipulating IAC as a design method for inducing a memory-intensive strategy to protect against forgetting is discussed. Copyright 2009 APA

MRPrimer: a MapReduce-based method for the thorough design of valid and ranked primers for PCR.

PubMed

Kim, Hyerin; Kang, NaNa; Chon, Kang-Wook; Kim, Seonho; Lee, NaHye; Koo, JaeHyung; Kim, Min-Soo

2015-11-16

Primer design is a fundamental technique that is widely used for polymerase chain reaction (PCR). Although many methods have been proposed for primer design, they require a great deal of manual effort to generate feasible and valid primers, including homology tests on off-target sequences using BLAST-like tools. That approach is inconvenient for many target sequences of quantitative PCR (qPCR) due to considering the same stringent and allele-invariant constraints. To address this issue, we propose an entirely new method called MRPrimer that can design all feasible and valid primer pairs existing in a DNA database at once, while simultaneously checking a multitude of filtering constraints and validating primer specificity. Furthermore, MRPrimer suggests the best primer pair for each target sequence, based on a ranking method. Through qPCR analysis using 343 primer pairs and the corresponding sequencing and comparative analyses, we showed that the primer pairs designed by MRPrimer are very stable and effective for qPCR. In addition, MRPrimer is computationally efficient and scalable and therefore useful for quickly constructing an entire collection of feasible and valid primers for frequently updated databases like RefSeq. Furthermore, we suggest that MRPrimer can be utilized conveniently for experiments requiring primer design, especially real-time qPCR. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Enhanced Polarimetric Radar Imaging Using Cross-Channel Coupling Constraints

DTIC Science & Technology

2014-06-19

4 2.2 Polarimetry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.2.1 Scattering Matrix...significant advances in polarimetry , the study of target aspects that can be determined by changing the transmitted and received wave polarization state...constraints. 1.2 Layout Chapter 2 presents relevant background information on polarimetry , SAR, and current image enhancement techniques. The Sinclair

Multi-scale image segmentation method with visual saliency constraints and its application

NASA Astrophysics Data System (ADS)

Chen, Yan; Yu, Jie; Sun, Kaimin

2018-03-01

Object-based image analysis method has many advantages over pixel-based methods, so it is one of the current research hotspots. It is very important to get the image objects by multi-scale image segmentation in order to carry out object-based image analysis. The current popular image segmentation methods mainly share the bottom-up segmentation principle, which is simple to realize and the object boundaries obtained are accurate. However, the macro statistical characteristics of the image areas are difficult to be taken into account, and fragmented segmentation (or over-segmentation) results are difficult to avoid. In addition, when it comes to information extraction, target recognition and other applications, image targets are not equally important, i.e., some specific targets or target groups with particular features worth more attention than the others. To avoid the problem of over-segmentation and highlight the targets of interest, this paper proposes a multi-scale image segmentation method with visually saliency graph constraints. Visual saliency theory and the typical feature extraction method are adopted to obtain the visual saliency information, especially the macroscopic information to be analyzed. The visual saliency information is used as a distribution map of homogeneity weight, where each pixel is given a weight. This weight acts as one of the merging constraints in the multi- scale image segmentation. As a result, pixels that macroscopically belong to the same object but are locally different can be more likely assigned to one same object. In addition, due to the constraint of visual saliency model, the constraint ability over local-macroscopic characteristics can be well controlled during the segmentation process based on different objects. These controls will improve the completeness of visually saliency areas in the segmentation results while diluting the controlling effect for non- saliency background areas. Experiments show that this method works

Trajectory Optimization of Electric Aircraft Subject to Subsystem Thermal Constraints

NASA Technical Reports Server (NTRS)

Falck, Robert D.; Chin, Jeffrey C.; Schnulo, Sydney L.; Burt, Jonathan M.; Gray, Justin S.

2017-01-01

Electric aircraft pose a unique design challenge in that they lack a simple way to reject waste heat from the power train. While conventional aircraft reject most of their excess heat in the exhaust stream, for electric aircraft this is not an option. To examine the implications of this challenge on electric aircraft design and performance, we developed a model of the electric subsystems for the NASA X-57 electric testbed aircraft. We then coupled this model with a model of simple 2D aircraft dynamics and used a Legendre-Gauss-Lobatto collocation optimal control approach to find optimal trajectories for the aircraft with and without thermal constraints. The results show that the X-57 heat rejection systems are well designed for maximum-range and maximum-efficiency flight, without the need to deviate from an optimal trajectory. Stressing the thermal constraints by reducing the cooling capacity or requiring faster flight has a minimal impact on performance, as the trajectory optimization technique is able to find flight paths which honor the thermal constraints with relatively minor deviations from the nominal optimal trajectory.

Design and construction of targeted AAVP vectors for mammalian cell transduction.

PubMed

Hajitou, Amin; Rangel, Roberto; Trepel, Martin; Soghomonyan, Suren; Gelovani, Juri G; Alauddin, Mian M; Pasqualini, Renata; Arap, Wadih

2007-01-01

Bacteriophage (phage) evolved as bacterial viruses, but can be adapted to transduce mammalian cells through ligand-directed targeting to a specific receptor. We have recently reported a new generation of hybrid prokaryotic-eukaryotic vectors, which are chimeras of genetic cis-elements of recombinant adeno-associated virus and phage (termed AAVP). This protocol describes the design and construction of ligand-directed AAVP vectors, production of AAVP particles and the methodology to transduce mammalian cells in vitro and to target tissues in vivo after systemic administration. Targeted AAVP particles are made in a two-step process. First, a ligand peptide of choice is displayed on the coat protein to generate a targeted backbone phage vector. Then, a recombinant AAV carrying a mammalian transgene cassette is inserted into an intergenomic region. High-titer suspensions (approximately 10(10)-10(11) transducing units per microl) can be produced within 3 days after vector construction. Transgene expression by targeted AAVP usually reaches maximum levels within 1 week.

An automated approach to magnetic divertor configuration design

NASA Astrophysics Data System (ADS)

Blommaert, M.; Dekeyser, W.; Baelmans, M.; Gauger, N. R.; Reiter, D.

2015-01-01

Automated methods based on optimization can greatly assist computational engineering design in many areas. In this paper an optimization approach to the magnetic design of a nuclear fusion reactor divertor is proposed and applied to a tokamak edge magnetic configuration in a first feasibility study. The approach is based on reduced models for magnetic field and plasma edge, which are integrated with a grid generator into one sensitivity code. The design objective chosen here for demonstrative purposes is to spread the divertor target heat load as much as possible over the entire target area. Constraints on the separatrix position are introduced to eliminate physically irrelevant magnetic field configurations during the optimization cycle. A gradient projection method is used to ensure stable cost function evaluations during optimization. The concept is applied to a configuration with typical Joint European Torus (JET) parameters and it automatically provides plausible configurations with reduced heat load.

Dynamical Constraints on Nontransiting Planets Orbiting TRAPPIST-1

NASA Astrophysics Data System (ADS)

Jontof-Hutter, Daniel; Truong, Vinh H.; Ford, Eric B.; Robertson, Paul; Terrien, Ryan C.

2018-06-01

We derive lower bounds on the orbital distance and inclination of a putative planet beyond the transiting seven planets of TRAPPIST-1, for a range of masses ranging from 0.08 M Jup to 3.5 M Jup. While the outer architecture of this system will ultimately be constrained by radial velocity measurements over time, we present dynamical constraints from the remarkably coplanar configuration of the seven transiting planets, which is sensitive to modestly inclined perturbers. We find that the observed configuration is unlikely if a Jovian-mass planet inclined by ≥3° to the transiting planet exists within 0.53 au, exceeding any constraints from transit timing variations (TTV) induced in the known planets from an undetected perturber. Our results will inform RV programs targeting TRAPPIST-1, and for near coplanar outer planets, tighter constraints are anticipated for radial velocity (RV) precisions of ≲140 m s‑1. At higher inclinations, putative planets are ruled out to greater orbital distances with orbital periods up to a few years.

Modifications to risk-targeted seismic design maps for subduction and near-fault hazards

USGS Publications Warehouse

Liel, Abbie B.; Luco, Nicolas; Raghunandan, Meera; Champion, C.; Haukaas, Terje

2015-01-01

ASCE 7-10 introduced new seismic design maps that define risk-targeted ground motions such that buildings designed according to these maps will have 1% chance of collapse in 50 years. These maps were developed by iterative risk calculation, wherein a generic building collapse fragility curve is convolved with the U.S. Geological Survey hazard curve until target risk criteria are met. Recent research shows that this current approach may be unconservative at locations where the tectonic environment is much different than that used to develop the generic fragility curve. This study illustrates how risk-targeted ground motions at selected sites would change if generic building fragility curve and hazard assessment were modified to account for seismic risk from subduction earthquakes and near-fault pulses. The paper also explores the difficulties in implementing these changes.

Constraint Optimization Literature Review

DTIC Science & Technology

2015-11-01

COPs. 15. SUBJECT TERMS high-performance computing, mobile ad hoc network, optimization, constraint, satisfaction 16. SECURITY CLASSIFICATION OF: 17...Optimization Problems 1 2.1 Constraint Satisfaction Problems 1 2.2 Constraint Optimization Problems 3 3. Constraint Optimization Algorithms 9 3.1...Constraint Satisfaction Algorithms 9 3.1.1 Brute-Force search 9 3.1.2 Constraint Propagation 10 3.1.3 Depth-First Search 13 3.1.4 Local Search 18

Divertor target shape optimization in realistic edge plasma geometry

NASA Astrophysics Data System (ADS)

Dekeyser, W.; Reiter, D.; Baelmans, M.

2014-07-01

Tokamak divertor design for next-step fusion reactors heavily relies on numerical simulations of the plasma edge. Currently, the design process is mainly done in a forward approach, where the designer is strongly guided by his experience and physical intuition in proposing divertor shapes, which are then thoroughly assessed by numerical computations. On the other hand, automated design methods based on optimization have proven very successful in the related field of aerodynamic design. By recasting design objectives and constraints into the framework of a mathematical optimization problem, efficient forward-adjoint based algorithms can be used to automatically compute the divertor shape which performs the best with respect to the selected edge plasma model and design criteria. In the past years, we have extended these methods to automated divertor target shape design, using somewhat simplified edge plasma models and geometries. In this paper, we build on and extend previous work to apply these shape optimization methods for the first time in more realistic, single null edge plasma and divertor geometry, as commonly used in current divertor design studies. In a case study with JET-like parameters, we show that the so-called one-shot method is very effective is solving divertor target design problems. Furthermore, by detailed shape sensitivity analysis we demonstrate that the development of the method already at the present state provides physically plausible trends, allowing to achieve a divertor design with an almost perfectly uniform power load for our particular choice of edge plasma model and design criteria.

COBRApy: COnstraints-Based Reconstruction and Analysis for Python.

PubMed

Ebrahim, Ali; Lerman, Joshua A; Palsson, Bernhard O; Hyduke, Daniel R

2013-08-08

COnstraint-Based Reconstruction and Analysis (COBRA) methods are widely used for genome-scale modeling of metabolic networks in both prokaryotes and eukaryotes. Due to the successes with metabolism, there is an increasing effort to apply COBRA methods to reconstruct and analyze integrated models of cellular processes. The COBRA Toolbox for MATLAB is a leading software package for genome-scale analysis of metabolism; however, it was not designed to elegantly capture the complexity inherent in integrated biological networks and lacks an integration framework for the multiomics data used in systems biology. The openCOBRA Project is a community effort to promote constraints-based research through the distribution of freely available software. Here, we describe COBRA for Python (COBRApy), a Python package that provides support for basic COBRA methods. COBRApy is designed in an object-oriented fashion that facilitates the representation of the complex biological processes of metabolism and gene expression. COBRApy does not require MATLAB to function; however, it includes an interface to the COBRA Toolbox for MATLAB to facilitate use of legacy codes. For improved performance, COBRApy includes parallel processing support for computationally intensive processes. COBRApy is an object-oriented framework designed to meet the computational challenges associated with the next generation of stoichiometric constraint-based models and high-density omics data sets. http://opencobra.sourceforge.net/

Target tracking and pointing for arrays of phase-locked lasers

NASA Astrophysics Data System (ADS)

Macasaet, Van P.; Hughes, Gary B.; Lubin, Philip; Madajian, Jonathan; Zhang, Qicheng; Griswold, Janelle; Kulkarni, Neeraj; Cohen, Alexander; Brashears, Travis

2016-09-01

Arrays of phase-locked lasers are envisioned for planetary defense and exploration systems. High-energy beams focused on a threatening asteroid evaporate surface material, creating a reactionary thrust that alters the asteroid's orbit. The same system could be used to probe an asteroid's composition, to search for unknown asteroids, and to propel interplanetary and interstellar spacecraft. Phased-array designs are capable of producing high beam intensity, and allow beam steering and beam profile manipulation. Modular designs allow ongoing addition of emitter elements to a growing array. This paper discusses pointing control for extensible laser arrays. Rough pointing is determined by spacecraft attitude control. Lateral movement of the laser emitter tips behind the optical elements provides intermediate pointing adjustment for individual array elements and beam steering. Precision beam steering and beam formation is accomplished by coordinated phase modulation across the array. Added cells are incorporated into the phase control scheme by precise alignment to local mechanical datums using fast, optical relative position sensors. Infrared target sensors are also positioned within the datum scheme, and provide information about the target vector relative to datum coordinates at each emitter. Multiple target sensors allow refined determination of the target normal plane, providing information to the phase controller for each emitter. As emitters and sensors are added, local position data allows accurate prediction of the relative global position of emitters across the array, providing additional constraints to the phase controllers. Mechanical design and associated phase control that is scalable for target distance and number of emitters is presented.

antaRNA: ant colony-based RNA sequence design.

PubMed

Kleinkauf, Robert; Mann, Martin; Backofen, Rolf

2015-10-01

RNA sequence design is studied at least as long as the classical folding problem. Although for the latter the functional fold of an RNA molecule is to be found ,: inverse folding tries to identify RNA sequences that fold into a function-specific target structure. In combination with RNA-based biotechnology and synthetic biology ,: reliable RNA sequence design becomes a crucial step to generate novel biochemical components. In this article ,: the computational tool antaRNA is presented. It is capable of compiling RNA sequences for a given structure that comply in addition with an adjustable full range objective GC-content distribution ,: specific sequence constraints and additional fuzzy structure constraints. antaRNA applies ant colony optimization meta-heuristics and its superior performance is shown on a biological datasets. http://www.bioinf.uni-freiburg.de/Software/antaRNA CONTACT: backofen@informatik.uni-freiburg.de Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press.

Constraint-Muse: A Soft-Constraint Based System for Music Therapy

NASA Astrophysics Data System (ADS)

Hölzl, Matthias; Denker, Grit; Meier, Max; Wirsing, Martin

Monoidal soft constraints are a versatile formalism for specifying and solving multi-criteria optimization problems with dynamically changing user preferences. We have developed a prototype tool for interactive music creation, called Constraint Muse, that uses monoidal soft constraints to ensure that a dynamically generated melody harmonizes with input from other sources. Constraint Muse provides an easy to use interface based on Nintendo Wii controllers and is intended to be used in music therapy for people with Parkinson’s disease and for children with high-functioning autism or Asperger’s syndrome.

Fuel Optimal, Finite Thrust Guidance Methods to Circumnavigate with Lighting Constraints

NASA Astrophysics Data System (ADS)

Prince, E. R.; Carr, R. W.; Cobb, R. G.

This paper details improvements made to the authors' most recent work to find fuel optimal, finite-thrust guidance to inject an inspector satellite into a prescribed natural motion circumnavigation (NMC) orbit about a resident space object (RSO) in geosynchronous orbit (GEO). Better initial guess methodologies are developed for the low-fidelity model nonlinear programming problem (NLP) solver to include using Clohessy- Wiltshire (CW) targeting, a modified particle swarm optimization (PSO), and MATLAB's genetic algorithm (GA). These initial guess solutions may then be fed into the NLP solver as an initial guess, where a different NLP solver, IPOPT, is used. Celestial lighting constraints are taken into account in addition to the sunlight constraint, ensuring that the resulting NMC also adheres to Moon and Earth lighting constraints. The guidance is initially calculated given a fixed final time, and then solutions are also calculated for fixed final times before and after the original fixed final time, allowing mission planners to choose the lowest-cost solution in the resulting range which satisfies all constraints. The developed algorithms provide computationally fast and highly reliable methods for determining fuel optimal guidance for NMC injections while also adhering to multiple lighting constraints.

Design and characterization of ebolavirus GP prehairpin intermediate mimics as drug targets

PubMed Central

Clinton, Tracy R; Weinstock, Matthew T; Jacobsen, Michael T; Szabo-Fresnais, Nicolas; Pandya, Maya J; Whitby, Frank G; Herbert, Andrew S; Prugar, Laura I; McKinnon, Rena; Hill, Christopher P; Welch, Brett D; Dye, John M; Eckert, Debra M; Kay, Michael S

2015-01-01

Ebolaviruses are highly lethal filoviruses that cause hemorrhagic fever in humans and nonhuman primates. With no approved treatments or preventatives, the development of an anti-ebolavirus therapy to protect against natural infections and potential weaponization is an urgent global health need. Here, we describe the design, biophysical characterization, and validation of peptide mimics of the ebolavirus N-trimer, a highly conserved region of the GP2 fusion protein, to be used as targets to develop broad-spectrum inhibitors of ebolavirus entry. The N-trimer region of GP2 is 90% identical across all ebolavirus species and forms a critical part of the prehairpin intermediate that is exposed during viral entry. Specifically, we fused designed coiled coils to the N-trimer to present it as a soluble trimeric coiled coil as it appears during membrane fusion. Circular dichroism, sedimentation equilibrium, and X-ray crystallography analyses reveal the helical, trimeric structure of the designed N-trimer mimic targets. Surface plasmon resonance studies validate that the N-trimer mimic binds its native ligand, the C-peptide region of GP2. The longest N-trimer mimic also inhibits virus entry, thereby confirming binding of the C-peptide region during viral entry and the presence of a vulnerable prehairpin intermediate. Using phage display as a model system, we validate the suitability of the N-trimer mimics as drug screening targets. Finally, we describe the foundational work to use the N-trimer mimics as targets in mirror-image phage display, which will be used to identify d-peptide inhibitors of ebolavirus entry. PMID:25287718

Design and characterization of ebolavirus GP prehairpin intermediate mimics as drug targets.

PubMed

Clinton, Tracy R; Weinstock, Matthew T; Jacobsen, Michael T; Szabo-Fresnais, Nicolas; Pandya, Maya J; Whitby, Frank G; Herbert, Andrew S; Prugar, Laura I; McKinnon, Rena; Hill, Christopher P; Welch, Brett D; Dye, John M; Eckert, Debra M; Kay, Michael S

2015-04-01

Ebolaviruses are highly lethal filoviruses that cause hemorrhagic fever in humans and nonhuman primates. With no approved treatments or preventatives, the development of an anti-ebolavirus therapy to protect against natural infections and potential weaponization is an urgent global health need. Here, we describe the design, biophysical characterization, and validation of peptide mimics of the ebolavirus N-trimer, a highly conserved region of the GP2 fusion protein, to be used as targets to develop broad-spectrum inhibitors of ebolavirus entry. The N-trimer region of GP2 is 90% identical across all ebolavirus species and forms a critical part of the prehairpin intermediate that is exposed during viral entry. Specifically, we fused designed coiled coils to the N-trimer to present it as a soluble trimeric coiled coil as it appears during membrane fusion. Circular dichroism, sedimentation equilibrium, and X-ray crystallography analyses reveal the helical, trimeric structure of the designed N-trimer mimic targets. Surface plasmon resonance studies validate that the N-trimer mimic binds its native ligand, the C-peptide region of GP2. The longest N-trimer mimic also inhibits virus entry, thereby confirming binding of the C-peptide region during viral entry and the presence of a vulnerable prehairpin intermediate. Using phage display as a model system, we validate the suitability of the N-trimer mimics as drug screening targets. Finally, we describe the foundational work to use the N-trimer mimics as targets in mirror-image phage display, which will be used to identify D-peptide inhibitors of ebolavirus entry. © 2014 The Protein Society.

PRO_LIGAND: an approach to de novo molecular design. 2. Design of novel molecules from molecular field analysis (MFA) models and pharmacophores.

PubMed

Waszkowycz, B; Clark, D E; Frenkel, D; Li, J; Murray, C W; Robson, B; Westhead, D R

1994-11-11

A computational approach for molecular design, PRO_LIGAND, has been developed within the PROMETHEUS molecular design and simulation system in order to provide a unified framework for the de novo generation of diverse molecules which are either similar or complementary to a specified target. In this instance, the target is a pharmacophore derived from a series of active structures either by a novel interpretation of molecular field analysis data or by a pharmacophore-mapping procedure based on clique detection. After a brief introduction to PRO_LIGAND, a detailed description is given of the two pharmacophore generation procedures and their abilities are demonstrated by the elucidation of pharmacophores for steroid binding and ACE inhibition, respectively. As a further indication of its efficacy in aiding the rational drug design process, PRO_LIGAND is then employed to build novel organic molecules to satisfy the physicochemical constraints implied by the pharmacophores.

Silver ions-mediated conformational switch: facile design of structure-controllable nucleic acid probes.

PubMed

Wang, Yongxiang; Li, Jishan; Wang, Hao; Jin, Jianyu; Liu, Jinhua; Wang, Kemin; Tan, Weihong; Yang, Ronghua

2010-08-01

Conformationally constraint nucleic acid probes were usually designed by forming an intramolecular duplex based on Watson-Crick hydrogen bonds. The disadvantages of these approaches are the inflexibility and instability in complex environment of the Watson-Crick-based duplex. We report that this hydrogen bonding pattern can be replaced by metal-ligation between specific metal ions and the natural bases. To demonstrate the feasibility of this principle, two linear oligonucleotides and silver ions were examined as models for DNA hybridization assay and adenosine triphosphate detection. The both nucleic acids contain target binding sequences in the middle and cytosine (C)-rich sequences at the lateral portions. The strong interaction between Ag(+) ions and cytosines forms stable C-Ag(+)-C structures, which promises the oligonucleotides to form conformationally constraint formations. In the presence of its target, interaction between the loop sequences and the target unfolds the C-Ag(+)-C structures, and the corresponding probes unfolding can be detected by a change in their fluorescence emission. We discuss the thermodynamic and kinetic opportunities that are provided by using Ag(+) ion complexes instead of traditional Watson-Crick-based duplex. In particular, the intrinsic feature of the metal-ligation motif facilitates the design of functional nucleic acids probes by independently varying the concentration of Ag(+) ions in the medium.

Solving Constraint-Satisfaction Problems In Prolog Language

NASA Technical Reports Server (NTRS)

Nachtsheim, Philip R.

1991-01-01

Technique for solution of constraint-satisfaction problems uses definite-clause grammars of Prolog computer language. Exploits fact that grammar-rule notation viewed as "state-change notation". Facilitates development of dynamic representation performing informed as well as blind searches. Applicable to design, scheduling, and planning problems.

Sequence-based design of bioactive small molecules that target precursor microRNAs.

PubMed

Velagapudi, Sai Pradeep; Gallo, Steven M; Disney, Matthew D

2014-04-01

Oligonucleotides are designed to target RNA using base pairing rules, but they can be hampered by poor cellular delivery and nonspecific stimulation of the immune system. Small molecules are preferred as lead drugs or probes but cannot be designed from sequence. Herein, we describe an approach termed Inforna that designs lead small molecules for RNA from solely sequence. Inforna was applied to all human microRNA hairpin precursors, and it identified bioactive small molecules that inhibit biogenesis by binding nuclease-processing sites (44% hit rate). Among 27 lead interactions, the most avid interaction is between a benzimidazole (1) and precursor microRNA-96. Compound 1 selectively inhibits biogenesis of microRNA-96, upregulating a protein target (FOXO1) and inducing apoptosis in cancer cells. Apoptosis is ablated when FOXO1 mRNA expression is knocked down by an siRNA, validating compound selectivity. Markedly, microRNA profiling shows that 1 only affects microRNA-96 biogenesis and is at least as selective as an oligonucleotide.

Sequence-based design of bioactive small molecules that target precursor microRNAs

PubMed Central

Velagapudi, Sai Pradeep; Gallo, Steven M.; Disney, Matthew D.

2014-01-01

Oligonucleotides are designed to target RNA using base pairing rules, however, they are hampered by poor cellular delivery and non-specific stimulation of the immune system. Small molecules are preferred as lead drugs or probes, but cannot be designed from sequence. Herein, we describe an approach termed Inforna that designs lead small molecules for RNA from solely sequence. Inforna was applied to all human microRNA precursors and identified bioactive small molecules that inhibit biogenesis by binding to nuclease processing sites (41% hit rate). Amongst 29 lead interactions, the most avid interaction is between a benzimidazole (1) and precursor microRNA-96. Compound 1 selectively inhibits biogenesis of microRNA-96, upregulating a protein target (FOXO1) and inducing apoptosis in cancer cells. Apoptosis is ablated when FOXO1 mRNA expression is knocked down by an siRNA, validating compound selectivity. Importantly, microRNA profiling shows that 1 only significantly effects microRNA-96 biogenesis and is more selective than an oligonucleotide. PMID:24509821

Automated divertor target design by adjoint shape sensitivity analysis and a one-shot method

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dekeyser, W., E-mail: Wouter.Dekeyser@kuleuven.be; Reiter, D.; Baelmans, M.

As magnetic confinement fusion progresses towards the development of first reactor-scale devices, computational tokamak divertor design is a topic of high priority. Presently, edge plasma codes are used in a forward approach, where magnetic field and divertor geometry are manually adjusted to meet design requirements. Due to the complex edge plasma flows and large number of design variables, this method is computationally very demanding. On the other hand, efficient optimization-based design strategies have been developed in computational aerodynamics and fluid mechanics. Such an optimization approach to divertor target shape design is elaborated in the present paper. A general formulation ofmore » the design problems is given, and conditions characterizing the optimal designs are formulated. Using a continuous adjoint framework, design sensitivities can be computed at a cost of only two edge plasma simulations, independent of the number of design variables. Furthermore, by using a one-shot method the entire optimization problem can be solved at an equivalent cost of only a few forward simulations. The methodology is applied to target shape design for uniform power load, in simplified edge plasma geometry.« less

Multiple Target Laser Designator (MTLD)

DTIC Science & Technology

2007-03-01

Optimized Liquid Crystal Scanning Element Optimize the Nonimaging Predictive Algorithm for Target Ranging, Tracking, and Position Estimation...commercial potential. 3.0 PROGRESS THIS QUARTER 3.1 Optimization of Nonimaging Holographic Antenna for Target Tracking and Position Estimation (Task 6) In

Alternative Constraint Handling Technique for Four-Bar Linkage Path Generation

NASA Astrophysics Data System (ADS)

Sleesongsom, S.; Bureerat, S.

2018-03-01

This paper proposes an extension of a new concept for path generation from our previous work by adding a new constraint handling technique. The propose technique was initially designed for problems without prescribed timing by avoiding the timing constraint, while remain constraints are solving with a new constraint handling technique. The technique is one kind of penalty technique. The comparative study is optimisation of path generation problems are solved using self-adaptive population size teaching-learning based optimization (SAP-TLBO) and original TLBO. In this study, two traditional path generation test problem are used to test the proposed technique. The results show that the new technique can be applied with the path generation problem without prescribed timing and gives better results than the previous technique. Furthermore, SAP-TLBO outperforms the original one.

Modeling Multibody Stage Separation Dynamics Using Constraint Force Equation Methodology

NASA Technical Reports Server (NTRS)

Tartabini, Paul V.; Roithmayr, Carlos M.; Toniolo, Matthew D.; Karlgaard, Christopher D.; Pamadi, Bandu N.

2011-01-01

This paper discusses the application of the constraint force equation methodology and its implementation for multibody separation problems using three specially designed test cases. The first test case involves two rigid bodies connected by a fixed joint, the second case involves two rigid bodies connected with a universal joint, and the third test case is that of Mach 7 separation of the X-43A vehicle. For the first two cases, the solutions obtained using the constraint force equation method compare well with those obtained using industry- standard benchmark codes. For the X-43A case, the constraint force equation solutions show reasonable agreement with the flight-test data. Use of the constraint force equation method facilitates the analysis of stage separation in end-to-end simulations of launch vehicle trajectories

Synchronization controller design of two coupling permanent magnet synchronous motors system with nonlinear constraints.

PubMed

Deng, Zhenhua; Shang, Jing; Nian, Xiaohong

2015-11-01

In this paper, two coupling permanent magnet synchronous motors system with nonlinear constraints is studied. First of all, the mathematical model of the system is established according to the engineering practices, in which the dynamic model of motor and the nonlinear coupling effect between two motors are considered. In order to keep the two motors synchronization, a synchronization controller based on load observer is designed via cross-coupling idea and interval matrix. Moreover, speed, position and current signals of two motor all are taken as self-feedback signal as well as cross-feedback signal in the proposed controller, which is conducive to improving the dynamical performance and the synchronization performance of the system. The proposed control strategy is verified by simulation via Matlab/Simulink program. The simulation results show that the proposed control method has a better control performance, especially synchronization performance, than that of the conventional PI controller. Copyright © 2015 ISA. Published by Elsevier Ltd. All rights reserved.

Recent Developments in the VISRAD 3-D Target Design and Radiation Simulation Code

NASA Astrophysics Data System (ADS)

Macfarlane, Joseph; Golovkin, Igor; Sebald, James

2017-10-01

The 3-D view factor code VISRAD is widely used in designing HEDP experiments at major laser and pulsed-power facilities, including NIF, OMEGA, OMEGA-EP, ORION, Z, and LMJ. It simulates target designs by generating a 3-D grid of surface elements, utilizing a variety of 3-D primitives and surface removal algorithms, and can be used to compute the radiation flux throughout the surface element grid by computing element-to-element view factors and solving power balance equations. Target set-up and beam pointing are facilitated by allowing users to specify positions and angular orientations using a variety of coordinates systems (e.g., that of any laser beam, target component, or diagnostic port). Analytic modeling for laser beam spatial profiles for OMEGA DPPs and NIF CPPs is used to compute laser intensity profiles throughout the grid of surface elements. VISRAD includes a variety of user-friendly graphics for setting up targets and displaying results, can readily display views from any point in space, and can be used to generate image sequences for animations. We will discuss recent improvements to conveniently assess beam capture on target and beam clearance of diagnostic components, as well as plans for future developments.

Target design optimization for an electron accelerator driven subcritical facility with circular and square beam profiles.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gohar, M. Y. A; Sofu, T.; Zhong, Z.

2008-10-30

A subcritical facility driven by an electron accelerator is planned at the Kharkov Institute of Physics and Technology (KIPT) in Ukraine for medical isotope production, materials research, training, and education. The conceptual design of the facility is being pursued through collaborations between ANL and KIPT. As part of the design effort, the high-fidelity analyses of various target options are performed with formulations to reflect the realistic configuration and the three dimensional geometry of each design. This report summarizes the results of target design optimization studies for electron beams with two different beam profiles. The target design optimization is performed viamore » the sequential neutronic, thermal-hydraulic, and structural analyses for a comprehensive assessment of each configuration. First, a target CAD model is developed with proper emphasis on manufacturability to provide a basis for separate but consistent models for subsequent neutronic, thermal-hydraulic, and structural analyses. The optimizations are pursued for maximizing the neutron yield, streamlining the flow field to avoid hotspots, and minimizing the thermal stresses to increase the durability. In addition to general geometric modifications, the inlet/outlet channel configurations, target plate partitioning schemes, flow manipulations and rates, electron beam diameter/width options, and cladding material choices are included in the design optimizations. The electron beam interactions with the target assembly and the neutronic response of the subcritical facility are evaluated using the MCNPX code. the results for the electron beam energy deposition, neutron generation, and utilization in the subcritical pile are then used to characterize the axisymmetric heat generation profiles in the target assembly with explicit simulations of the beam tube, the coolant, the clad, and the target materials. Both tungsten and uranium are considered as target materials. Neutron spectra from

A Discussion of Issues in Integrity Constraint Monitoring

NASA Technical Reports Server (NTRS)

Fernandez, Francisco G.; Gates, Ann Q.; Cooke, Daniel E.

1998-01-01

In the development of large-scale software systems, analysts, designers, and programmers identify properties of data objects in the system. The ability to check those assertions during runtime is desirable as a means of verifying the integrity of the program. Typically, programmers ensure the satisfaction of such properties through the use of some form of manually embedded assertion check. The disadvantage to this approach is that these assertions become entangled within the program code. The goal of the research is to develop an integrity constraint monitoring mechanism whereby a repository of software system properties (called integrity constraints) are automatically inserted into the program by the mechanism to check for incorrect program behaviors. Such a mechanism would overcome many of the deficiencies of manually embedded assertion checks. This paper gives an overview of the preliminary work performed toward this goal. The manual instrumentation of constraint checking on a series of test programs is discussed, This review then is used as the basis for a discussion of issues to be considered in developing an automated integrity constraint monitor.

Risk-targeted versus current seismic design maps for the conterminous United States

USGS Publications Warehouse

Luco, Nicolas; Ellingwood, Bruce R.; Hamburger, Ronald O.; Hooper, John D.; Kimball, Jeffrey K.; Kircher, Charles A.

2007-01-01

The probabilistic portions of the seismic design maps in the NEHRP Provisions (FEMA, 2003/2000/1997), and in the International Building Code (ICC, 2006/2003/2000) and ASCE Standard 7-05 (ASCE, 2005a), provide ground motion values from the USGS that have a 2% probability of being exceeded in 50 years. Under the assumption that the capacity against collapse of structures designed for these "uniformhazard" ground motions is equal to, without uncertainty, the corresponding mapped value at the location of the structure, the probability of its collapse in 50 years is also uniform. This is not the case however, when it is recognized that there is, in fact, uncertainty in the structural capacity. In that case, siteto-site variability in the shape of ground motion hazard curves results in a lack of uniformity. This paper explains the basis for proposed adjustments to the uniform-hazard portions of the seismic design maps currently in the NEHRP Provisions that result in uniform estimated collapse probability. For seismic design of nuclear facilities, analogous but specialized adjustments have recently been defined in ASCE Standard 43-05 (ASCE, 2005b). In support of the 2009 update of the NEHRP Provisions currently being conducted by the Building Seismic Safety Council (BSSC), herein we provide examples of the adjusted ground motions for a selected target collapse probability (or target risk). Relative to the probabilistic MCE ground motions currently in the NEHRP Provisions, the risk-targeted ground motions for design are smaller (by as much as about 30%) in the New Madrid Seismic Zone, near Charleston, South Carolina, and in the coastal region of Oregon, with relatively little (<15%) change almost everywhere else in the conterminous U.S.

Infrared and Visible Image Fusion Based on Different Constraints in the Non-Subsampled Shearlet Transform Domain.

PubMed

Huang, Yan; Bi, Duyan; Wu, Dongpeng

2018-04-11

There are many artificial parameters when fuse infrared and visible images, to overcome the lack of detail in the fusion image because of the artifacts, a novel fusion algorithm for infrared and visible images that is based on different constraints in non-subsampled shearlet transform (NSST) domain is proposed. There are high bands and low bands of images that are decomposed by the NSST. After analyzing the characters of the bands, fusing the high level bands by the gradient constraint, the fused image can obtain more details; fusing the low bands by the constraint of saliency in the images, the targets are more salient. Before the inverse NSST, the Nash equilibrium is used to update the coefficient. The fused images and the quantitative results demonstrate that our method is more effective in reserving details and highlighting the targets when compared with other state-of-the-art methods.

Infrared and Visible Image Fusion Based on Different Constraints in the Non-Subsampled Shearlet Transform Domain

PubMed Central

Huang, Yan; Bi, Duyan; Wu, Dongpeng

2018-01-01

There are many artificial parameters when fuse infrared and visible images, to overcome the lack of detail in the fusion image because of the artifacts, a novel fusion algorithm for infrared and visible images that is based on different constraints in non-subsampled shearlet transform (NSST) domain is proposed. There are high bands and low bands of images that are decomposed by the NSST. After analyzing the characters of the bands, fusing the high level bands by the gradient constraint, the fused image can obtain more details; fusing the low bands by the constraint of saliency in the images, the targets are more salient. Before the inverse NSST, the Nash equilibrium is used to update the coefficient. The fused images and the quantitative results demonstrate that our method is more effective in reserving details and highlighting the targets when compared with other state-of-the-art methods. PMID:29641505

A Meta-Analysis of the Relationship between Social Constraints and Distress in Cancer Patients

PubMed Central

Adams, Rebecca N.; Winger, Joseph G.; Mosher, Catherine E.

2014-01-01

Social constraints on cancer-related disclosure have been associated with increased distress among cancer patients. The goals of this meta-analysis were: (1) to quantify the average strength of the relationships between social constraints and general and cancer-specific distress in cancer patients; and (2) to examine potential moderators of these relationships. A literature search was conducted using electronic databases, and 30 studies met inclusion criteria. Moderate, significant relationships were found between social constraints and both general distress (r=0.37; 95% CI: 0.31-0.43) and cancer-specific distress (r=0.37; 95% CI: 0.31-0.44). The relationship between social constraints and cancer-specific distress was stronger for studies of patients who, on average, had been diagnosed more recently. Relationships between social constraints and both general and cancer-specific distress did not vary by age or gender. Findings suggest that social constraints may be important to target in interventions to reduce distress in cancer patients, especially those who have been recently diagnosed. PMID:25262383

Design study of 10 kW direct fission target for RISP project

NASA Astrophysics Data System (ADS)

Tshoo, K.; Jang, D. Y.; Woo, H. J.; Kang, B. H.; Kim, G. D.; Hwang, W.; Kim, Y. K.

2014-03-01

We are developing Isotope Separation On-Line (ISOL) target system, which consists of 1.3 mm-thick uranium-carbide multi-disks and cylindrical tantalum heater, to be installed in new facility for Rare Isotope Science Project in Korea. The intense neutron-rich nuclei are produced via the fission process using the uranium carbide targets with a 70 MeV proton beam. The fission rate was estimated to be ˜1.5 × 1013/sec for 10 kW proton beam. The target system has been designed to be operated at a temperature of ˜2000 °C so as to improve the release effciency.

Inverse Design of Low-Boom Supersonic Concepts Using Reversed Equivalent-Area Targets

NASA Technical Reports Server (NTRS)

Li, Wu; Rallabhand, Sriam

2011-01-01

A promising path for developing a low-boom configuration is a multifidelity approach that (1) starts from a low-fidelity low-boom design, (2) refines the low-fidelity design with computational fluid dynamics (CFD) equivalent-area (Ae) analysis, and (3) improves the design with sonic-boom analysis by using CFD off-body pressure distributions. The focus of this paper is on the third step of this approach, in which the design is improved with sonic-boom analysis through the use of CFD calculations. A new inverse design process for off-body pressure tailoring is formulated and demonstrated with a low-boom supersonic configuration that was developed by using the mixed-fidelity design method with CFD Ae analysis. The new inverse design process uses the reverse propagation of the pressure distribution (dp/p) from a mid-field location to a near-field location, converts the near-field dp/p into an equivalent-area distribution, generates a low-boom target for the reversed equivalent area (Ae,r) of the configuration, and modifies the configuration to minimize the differences between the configuration s Ae,r and the low-boom target. The new inverse design process is used to modify a supersonic demonstrator concept for a cruise Mach number of 1.6 and a cruise weight of 30,000 lb. The modified configuration has a fully shaped ground signature that has a perceived loudness (PLdB) value of 78.5, while the original configuration has a partially shaped aft signature with a PLdB of 82.3.

Modified constraint-induced movement therapy for clients with chronic stroke: interrupted time series (ITS) design.

PubMed

Park, JuHyung; Lee, NaYun; Cho, YongHo; Yang, YeongAe

2015-03-01

[Purpose] The purpose of this study was to investigate the impact that modified constraint-induced movement therapy has on upper extremity function and the daily life of chronic stroke patients. [Subjects and Methods] Modified constraint-induced movement therapy was conduct for 2 stroke patients with hemiplegia. It was performed 5 days a week for 2 weeks, and the participants performed their daily living activities wearing mittens for 6 hours a day, including the 2 hours of the therapy program. The assessment was conducted 5 times in 3 weeks before and after intervention. The upper extremity function was measured using the box and block test and a dynamometer, and performance daily of living activities was assessed using the modified Barthel index. The results were analyzed using a scatterplot and linear regression. [Results] All the upper extremity functions of the participants all improved after the modified constraint-induced movement therapy. Performance of daily living activities by participant 1 showed no change, but the results of participant 2 had improved after the intervention. [Conclusion] Through the results of this research, it was identified that modified constraint-induced movement therapy is effective at improving the upper extremity functions and the performance of daily living activities of chronic stroke patients.

Geometry and Material Constraint Effects on Creep Crack Growth Behavior in Welded Joints

NASA Astrophysics Data System (ADS)

Li, Y.; Wang, G. Z.; Xuan, F. Z.; Tu, S. T.

2017-02-01

In this work, the geometry and material constraint effects on creep crack growth (CCG) and behavior in welded joints were investigated. The CCG paths and rates of two kinds of specimen geometry (C(T) and M(T)) with initial cracks located at soft HAZ (heat-affected zone with lower creep strength) and different material mismatches were simulated. The effect of constraint on creep crack initiation (CCI) time was discussed. The results show that there exists interaction between geometry and material constraints in terms of their effects on CCG rate and CCI time of welded joints. Under the condition of low geometry constraint, the effect of material constraint on CCG rate and CCI time becomes more obvious. Higher material constraint can promote CCG due to the formation of higher stress triaxiality around crack tip. Higher geometry constraint can increase CCG rate and reduce CCI time of welded joints. Both geometry and material constraints should be considered in creep life assessment and design for high-temperature welded components.

Allowable carbon emissions lowered by multiple climate targets.

PubMed

Steinacher, Marco; Joos, Fortunat; Stocker, Thomas F

2013-07-11

Climate targets are designed to inform policies that would limit the magnitude and impacts of climate change caused by anthropogenic emissions of greenhouse gases and other substances. The target that is currently recognized by most world governments places a limit of two degrees Celsius on the global mean warming since preindustrial times. This would require large sustained reductions in carbon dioxide emissions during the twenty-first century and beyond. Such a global temperature target, however, is not sufficient to control many other quantities, such as transient sea level rise, ocean acidification and net primary production on land. Here, using an Earth system model of intermediate complexity (EMIC) in an observation-informed Bayesian approach, we show that allowable carbon emissions are substantially reduced when multiple climate targets are set. We take into account uncertainties in physical and carbon cycle model parameters, radiative efficiencies, climate sensitivity and carbon cycle feedbacks along with a large set of observational constraints. Within this framework, we explore a broad range of economically feasible greenhouse gas scenarios from the integrated assessment community to determine the likelihood of meeting a combination of specific global and regional targets under various assumptions. For any given likelihood of meeting a set of such targets, the allowable cumulative emissions are greatly reduced from those inferred from the temperature target alone. Therefore, temperature targets alone are unable to comprehensively limit the risks from anthropogenic emissions.

TRACON Aircraft Arrival Planning and Optimization Through Spatial Constraint Satisfaction

NASA Technical Reports Server (NTRS)

Bergh, Christopher P.; Krzeczowski, Kenneth J.; Davis, Thomas J.; Denery, Dallas G. (Technical Monitor)

1995-01-01

A new aircraft arrival planning and optimization algorithm has been incorporated into the Final Approach Spacing Tool (FAST) in the Center-TRACON Automation System (CTAS) developed at NASA-Ames Research Center. FAST simulations have been conducted over three years involving full-proficiency, level five air traffic controllers from around the United States. From these simulations an algorithm, called Spatial Constraint Satisfaction, has been designed, coded, undergone testing, and soon will begin field evaluation at the Dallas-Fort Worth and Denver International airport facilities. The purpose of this new design is an attempt to show that the generation of efficient and conflict free aircraft arrival plans at the runway does not guarantee an operationally acceptable arrival plan upstream from the runway -information encompassing the entire arrival airspace must be used in order to create an acceptable aircraft arrival plan. This new design includes functions available previously but additionally includes necessary representations of controller preferences and workload, operationally required amounts of extra separation, and integrates aircraft conflict resolution. As a result, the Spatial Constraint Satisfaction algorithm produces an optimized aircraft arrival plan that is more acceptable in terms of arrival procedures and air traffic controller workload. This paper discusses the current Air Traffic Control arrival planning procedures, previous work in this field, the design of the Spatial Constraint Satisfaction algorithm, and the results of recent evaluations of the algorithm.

Constraint monitoring in TOSCA

NASA Technical Reports Server (NTRS)

Beck, Howard

1992-01-01

The Job-Shop Scheduling Problem (JSSP) deals with the allocation of resources over time to factory operations. Allocations are subject to various constraints (e.g., production precedence relationships, factory capacity constraints, and limits on the allowable number of machine setups) which must be satisfied for a schedule to be valid. The identification of constraint violations and the monitoring of constraint threats plays a vital role in schedule generation in terms of the following: (1) directing the scheduling process; and (2) informing scheduling decisions. This paper describes a general mechanism for identifying constraint violations and monitoring threats to the satisfaction of constraints throughout schedule generation.

Mean-Reverting Portfolio With Budget Constraint

NASA Astrophysics Data System (ADS)

Zhao, Ziping; Palomar, Daniel P.

2018-05-01

This paper considers the mean-reverting portfolio design problem arising from statistical arbitrage in the financial markets. We first propose a general problem formulation aimed at finding a portfolio of underlying component assets by optimizing a mean-reversion criterion characterizing the mean-reversion strength, taking into consideration the variance of the portfolio and an investment budget constraint. Then several specific problems are considered based on the general formulation, and efficient algorithms are proposed. Numerical results on both synthetic and market data show that our proposed mean-reverting portfolio design methods can generate consistent profits and outperform the traditional design methods and the benchmark methods in the literature.

Standing wave design and optimization of a simulated moving bed chromatography for separation of xylobiose and xylose under the constraints on product concentration and pressure drop.

PubMed

Lee, Chung-Gi; Choi, Jae-Hwan; Park, Chanhun; Wang, Nien-Hwa Linda; Mun, Sungyong

2017-12-08

The feasibility of a simulated moving bed (SMB) technology for the continuous separation of high-purity xylobiose (X2) from the output of a β-xylosidase X1→X2 reaction has recently been confirmed. To ensure high economical efficiency of the X2 production method based on the use of xylose (X1) as a starting material, it is essential to accomplish the comprehensive optimization of the X2-separation SMB process in such a way that its X2 productivity can be maximized while maintaining the X2 product concentration from the SMB as high as possible in consideration of a subsequent lyophilization step. To address this issue, a suitable SMB optimization tool for the aforementioned task was prepared based on standing wave design theory. The prepared tool was then used to optimize the SMB operation parameters, column configuration, total column number, adsorbent particle size, and X2 yield while meeting the constraints on X2 purity, X2 product concentration, and pressure drop. The results showed that the use of a larger particle size caused the productivity to be limited by the constraint on X2 product concentration, and a maximum productivity was attained by choosing the particle size such that the effect of the X2-concentration limiting factor could be balanced with that of pressure-drop limiting factor. If the target level of X2 product concentration was elevated, higher productivity could be achieved by decreasing particle size, raising the level of X2 yield, and increasing the column number in the zones containing the front and rear of X2 solute band. Copyright © 2017 Elsevier B.V. All rights reserved.

Target design for materials processing very far from equilibrium

NASA Astrophysics Data System (ADS)

Barnard, John J.; Schenkel, Thomas

2016-10-01

Local heating and electronic excitations can trigger phase transitions or novel material states that can be stabilized by rapid quenching. An example on the few nanometer scale are phase transitions induced by the passage of swift heavy ions in solids where nitrogen-vacancy color centers form locally in diamonds when ions heat the diamond matrix to warm dense matter conditions at 0.5 eV. We optimize mask geometries for target materials such as silicon and diamond to induce phase transitions by intense ion pulses (e. g. from NDCX-II or from laser-plasma acceleration). The goal is to rapidly heat a solid target volumetrically and to trigger a phase transition or local lattice reconstruction followed by rapid cooling. The stabilized phase can then be studied ex situ. We performed HYDRA simulations that calculate peak temperatures for a series of excitation conditions and cooling rates of crystal targets with micro-structured masks. A simple analytical model, that includes ion heating and radial, diffusive cooling, was developed that agrees closely with the HYDRA simulations. The model gives scaling laws that can guide the design of targets over a wide range of parameters including those for NDCX-II and the proposed BELLA-i. This work was performed under the auspices of the U.S. DOE under contracts DE-AC52-07NA27344 (LLNL), DE-AC02-05CH11231 (LBNL) and was supported by the US DOE Office of Science, Fusion Energy Sciences. LLNL-ABS-697271.

Soft computing model for optimized siRNA design by identifying off target possibilities using artificial neural network model.

PubMed

Murali, Reena; John, Philips George; Peter S, David

2015-05-15

The ability of small interfering RNA (siRNA) to do posttranscriptional gene regulation by knocking down targeted genes is an important research topic in functional genomics, biomedical research and in cancer therapeutics. Many tools had been developed to design exogenous siRNA with high experimental inhibition. Even though considerable amount of work has been done in designing exogenous siRNA, design of effective siRNA sequences is still a challenging work because the target mRNAs must be selected such that their corresponding siRNAs are likely to be efficient against that target and unlikely to accidentally silence other transcripts due to sequence similarity. In some cases, siRNAs may tolerate mismatches with the target mRNA, but knockdown of genes other than the intended target could make serious consequences. Hence to design siRNAs, two important concepts must be considered: the ability in knocking down target genes and the off target possibility on any nontarget genes. So before doing gene silencing by siRNAs, it is essential to analyze their off target effects in addition to their inhibition efficacy against a particular target. Only a few methods have been developed by considering both efficacy and off target possibility of siRNA against a gene. In this paper we present a new design of neural network model with whole stacking energy (ΔG) that enables to identify the efficacy and off target effect of siRNAs against target genes. The tool lists all siRNAs against a particular target with their inhibition efficacy and number of matches or sequence similarity with other genes in the database. We could achieve an excellent performance of Pearson Correlation Coefficient (R=0. 74) and Area Under Curve (AUC=0.906) when the threshold of whole stacking energy is ≥-34.6 kcal/mol. To the best of the author's knowledge, this is one of the best score while considering the "combined efficacy and off target possibility" of siRNA for silencing a gene. The proposed model

A Real-Time Brain-Machine Interface Combining Motor Target and Trajectory Intent Using an Optimal Feedback Control Design

PubMed Central

Shanechi, Maryam M.; Williams, Ziv M.; Wornell, Gregory W.; Hu, Rollin C.; Powers, Marissa; Brown, Emery N.

2013-01-01

Real-time brain-machine interfaces (BMI) have focused on either estimating the continuous movement trajectory or target intent. However, natural movement often incorporates both. Additionally, BMIs can be modeled as a feedback control system in which the subject modulates the neural activity to move the prosthetic device towards a desired target while receiving real-time sensory feedback of the state of the movement. We develop a novel real-time BMI using an optimal feedback control design that jointly estimates the movement target and trajectory of monkeys in two stages. First, the target is decoded from neural spiking activity before movement initiation. Second, the trajectory is decoded by combining the decoded target with the peri-movement spiking activity using an optimal feedback control design. This design exploits a recursive Bayesian decoder that uses an optimal feedback control model of the sensorimotor system to take into account the intended target location and the sensory feedback in its trajectory estimation from spiking activity. The real-time BMI processes the spiking activity directly using point process modeling. We implement the BMI in experiments consisting of an instructed-delay center-out task in which monkeys are presented with a target location on the screen during a delay period and then have to move a cursor to it without touching the incorrect targets. We show that the two-stage BMI performs more accurately than either stage alone. Correct target prediction can compensate for inaccurate trajectory estimation and vice versa. The optimal feedback control design also results in trajectories that are smoother and have lower estimation error. The two-stage decoder also performs better than linear regression approaches in offline cross-validation analyses. Our results demonstrate the advantage of a BMI design that jointly estimates the target and trajectory of movement and more closely mimics the sensorimotor control system. PMID:23593130

The Effects of Constraints and Mastery on Mental and Physical Health: Conceptual and Methodological Considerations

PubMed Central

Infurna, Frank J.; Mayer, Axel

2015-01-01

Perceived control and health are closely interrelated in adulthood and old age. However, less is known regarding the differential implications of two facets of perceived control, constraints and mastery, for mental and physical health. Furthermore, a limitation of previous research testing the pathways linking perceived control to mental and physical health is that mediation was tested with cross-sectional designs and not in a longitudinal mediation design that accounts for temporal ordering and prior confounds. Using data from the Health and Retirement Study (HRS; n = 7,612, M age = 68, SD = 10.66; 59% women) we examined the effect of constraints and mastery on 4-year changes in mental and physical health and whether physical activity mediated such effects in a longitudinal mediation design. Using confirmatory factor analysis, we modeled the two-factor structure of perceived control that consisted of constraints and mastery. In our longitudinal mediation model, where we accounted for possible confounders (e.g., age, gender, education, neuroticism, conscientiousness, memory, and health conditions), constraints showed a stronger total effect on mental and physical health, than mastery, such that more constraints were associated with 4-year declines in mental and physical health. Physical activity did not mediate the effect of constraints and mastery on mental and physical health (indirect effect). In order to demonstrate the importance of a longitudinal mediation model that accounts for confounders, we also estimated the mediated effect using two models commonly used in the literature: cross-sectional mediation model and longitudinal mediation model without accounting for confounders. These mediation models indicated a spurious indirect effect that cannot be causally interpreted. Our results showcase that constraints and mastery have differential implications for mental and physical health, as well as how a longitudinal mediation design can illustrate (or not

The effects of constraints and mastery on mental and physical health: Conceptual and methodological considerations.

PubMed

Infurna, Frank J; Mayer, Axel

2015-06-01

Perceived control and health are closely interrelated in adulthood and old age. However, less is known regarding the differential implications of 2 facets of perceived control, constraints and mastery, for mental and physical health. Furthermore, a limitation of previous research testing the pathways linking perceived control to mental and physical health is that mediation was tested with cross-sectional designs and not in a longitudinal mediation design that accounts for temporal ordering and prior confounds. Using data from the Health and Retirement Study (HRS; n = 7,612, M age = 68, SD = 10.66; 59% women) we examined the effect of constraints and mastery on 4-year changes in mental and physical health and whether physical activity mediated such effects in a longitudinal mediation design. Using confirmatory factor analysis, we modeled the 2-factor structure of perceived control that consisted of constraints and mastery. In our longitudinal mediation model, where we accounted for possible confounders (e.g., age, gender, education, neuroticism, conscientiousness, memory, and health conditions), constraints showed a stronger total effect on mental and physical health, than mastery, such that more constraints were associated with 4-year declines in mental and physical health. Physical activity did not mediate the effect of constraints and mastery on mental and physical health (indirect effect). To demonstrate the importance of a longitudinal mediation model that accounts for confounders, we also estimated the mediated effect using 2 models commonly used in the literature: cross-sectional mediation model and longitudinal mediation model without accounting for confounders. These mediation models indicated a spurious indirect effect that cannot be causally interpreted. Our results showcase that constraints and mastery have differential implications for mental and physical health, as well as how a longitudinal mediation design can illustrate (or not) pathways in

Maximizing in vivo target clearance by design of pH-dependent target binding antibodies with altered affinity to FcRn.

PubMed

Yang, Danlin; Giragossian, Craig; Castellano, Steven; Lasaro, Marcio; Xiao, Haiguang; Saraf, Himanshu; Hess Kenny, Cynthia; Rybina, Irina; Huang, Zhong-Fu; Ahlberg, Jennifer; Bigwarfe, Tammy; Myzithras, Maria; Waltz, Erica; Roberts, Simon; Kroe-Barrett, Rachel; Singh, Sanjaya

2017-10-01

Antibodies with pH-dependent binding to both target antigens and neonatal Fc receptor (FcRn) provide an alternative tool to conventional neutralizing antibodies, particularly for therapies where reduction in antigen level is challenging due to high target burden. However, the requirements for optimal binding kinetic framework and extent of pH dependence for these antibodies to maximize target clearance from circulation are not well understood. We have identified a series of naturally-occurring high affinity antibodies with pH-dependent target binding properties. By in vivo studies in cynomolgus monkeys, we show that pH-dependent binding to the target alone is not sufficient for effective target removal from circulation, but requires Fc mutations that increase antibody binding to FcRn. Affinity-enhanced pH-dependent FcRn binding that is double-digit nM at pH 7.4 and single-digit nM at pH 6 achieved maximal target reduction when combined with similar target binding affinities in reverse pH directions. Sustained target clearance below the baseline level was achieved 3 weeks after single-dose administration at 1.5 mg/kg. Using the experimentally derived mechanistic model, we demonstrate the essential kinetic interplay between target turnover and antibody pH-dependent binding during the FcRn recycling, and identify the key components for achieving maximal target clearance. These results bridge the demand for improved patient dosing convenience with the "know-how" of therapeutic modality by design.

Model-Dependent Constraint on Quark Total Angular Momentum Based on the Transverse Target-spin Asymmetry Measured in Deeply Virtual Compton Scattering at HERMES

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nowak, Wolf-Dieter

Results are reported on the transverse target-spin asymmetry (TTSA) associated with deeply virtual Compton scattering on the proton. The data have been accumulated in the years 2002-2004 by the HERMES experiment at DESY, in which the HERA 27.6 GeV e+ beam scattered on a transversely polarized hydrogen target. Two azimuthal amplitudes of the TTSA appearing to LO in 1/Q and {alpha}s, A{sub UT}{sup sin({phi}-{phi}{sub S})cos{phi}} and A{sub UT}{sup cos({phi} -{phi}{sub S})sin{phi}}, are given as a function of -t,xB,Q2 in the kinematic range |t| < 0.7 GeV2, 0.03 < xB < 0.35 and 1 < Q2 < 10 GeV2. The firstmore » amplitude is found to be sensitive to the generalized parton distribution (GPD) E of the proton, which can be parameterized in a GPD model through quark total angular momentum Jq(q = u, d). Within the context of this model, a constraint in the (Ju,Jd) plane is obtained from HERMES TTSA data.« less

Genome-wide Target Enrichment-aided Chip Design: a 66 K SNP Chip for Cashmere Goat.

PubMed

Qiao, Xian; Su, Rui; Wang, Yang; Wang, Ruijun; Yang, Ting; Li, Xiaokai; Chen, Wei; He, Shiyang; Jiang, Yu; Xu, Qiwu; Wan, Wenting; Zhang, Yaolei; Zhang, Wenguang; Chen, Jiang; Liu, Bin; Liu, Xin; Fan, Yixing; Chen, Duoyuan; Jiang, Huaizhi; Fang, Dongming; Liu, Zhihong; Wang, Xiaowen; Zhang, Yanjun; Mao, Danqing; Wang, Zhiying; Di, Ran; Zhao, Qianjun; Zhong, Tao; Yang, Huanming; Wang, Jian; Wang, Wen; Dong, Yang; Chen, Xiaoli; Xu, Xun; Li, Jinquan

2017-08-17

Compared with the commercially available single nucleotide polymorphism (SNP) chip based on the Bead Chip technology, the solution hybrid selection (SHS)-based target enrichment SNP chip is not only design-flexible, but also cost-effective for genotype sequencing. In this study, we propose to design an animal SNP chip using the SHS-based target enrichment strategy for the first time. As an update to the international collaboration on goat research, a 66 K SNP chip for cashmere goat was created from the whole-genome sequencing data of 73 individuals. Verification of this 66 K SNP chip with the whole-genome sequencing data of 436 cashmere goats showed that the SNP call rates was between 95.3% and 99.8%. The average sequencing depth for target SNPs were 40X. The capture regions were shown to be 200 bp that flank target SNPs. This chip was further tested in a genome-wide association analysis of cashmere fineness (fiber diameter). Several top hit loci were found marginally associated with signaling pathways involved in hair growth. These results demonstrate that the 66 K SNP chip is a useful tool in the genomic analyses of cashmere goats. The successful chip design shows that the SHS-based target enrichment strategy could be applied to SNP chip design in other species.

New method to design stellarator coils without the winding surface

NASA Astrophysics Data System (ADS)

Zhu, Caoxiang; Hudson, Stuart R.; Song, Yuntao; Wan, Yuanxi

2018-01-01

Finding an easy-to-build coils set has been a critical issue for stellarator design for decades. Conventional approaches assume a toroidal ‘winding’ surface, but a poorly chosen winding surface can unnecessarily constrain the coil optimization algorithm, This article presents a new method to design coils for stellarators. Each discrete coil is represented as an arbitrary, closed, one-dimensional curve embedded in three-dimensional space. A target function to be minimized that includes both physical requirements and engineering constraints is constructed. The derivatives of the target function with respect to the parameters describing the coil geometries and currents are calculated analytically. A numerical code, named flexible optimized coils using space curves (FOCUS), has been developed. Applications to a simple stellarator configuration, W7-X and LHD vacuum fields are presented.

Designing Targeted Educational Voucher Schemes for the Poor in Developing Countries

ERIC Educational Resources Information Center

Shafiq, M. Najeeb

2010-01-01

A targeted educational voucher scheme (TEVS) is often proposed for the poor in developing countries. Essentially, TEVS involves issuing vouchers to poor households, thus enabling them to pay tuition and fees for their children's schooling at participating non-public schools. However, little is known about TEVS' design in developing countries. This…

The choice of the energy embedding law in the design of heavy ionic fusion cylindrical targets

NASA Astrophysics Data System (ADS)

Dolgoleva, GV; Zykova, A. I.

2017-10-01

The paper considers the numerical design of heavy ion fusion (FIHIF) targets, which is one of the branches of controlled thermonuclear fusion (CTF). One of the important tasks in the targets design for controlled thermonuclear fusion is the energy embedding selection whereby it is possible to obtain “burning” (the presence of thermonuclear reactions) of the working DT region. The work is devoted to the rapid ignition of FIHIF targets by means of an additional short-term energy contribution to the DT substance already compressed by massively more longer by energy embedding. This problem has been fairly well studied for laser targets, but this problem is new for heavy ion fusion targets. Maximum momentum increasing is very technically difficult and expensive on modern FIHIF installations. The work shows that the additional energy embedding (“igniting” impulse) reduces the requirements to the maximum impulse. The purpose of this work is to research the ignition impulse effect on the FIHIF target parameters.

An integrated control scheme for space robot after capturing non-cooperative target

NASA Astrophysics Data System (ADS)

Wang, Mingming; Luo, Jianjun; Yuan, Jianping; Walter, Ulrich

2018-06-01

How to identify the mass properties and eliminate the unknown angular momentum of space robotic system after capturing a non-cooperative target is of great challenge. This paper focuses on designing an integrated control framework which includes detumbling strategy, coordination control and parameter identification. Firstly, inverted and forward chain approaches are synthesized for space robot to obtain dynamic equation in operational space. Secondly, a detumbling strategy is introduced using elementary functions with normalized time, while the imposed end-effector constraints are considered. Next, a coordination control scheme for stabilizing both base and end-effector based on impedance control is implemented with the target's parameter uncertainty. With the measurements of the forces and torques exerted on the target, its mass properties are estimated during the detumbling process accordingly. Simulation results are presented using a 7 degree-of-freedom kinematically redundant space manipulator, which verifies the performance and effectiveness of the proposed method.

The Last Meter: Blind Visual Guidance to a Target.

PubMed

Manduchi, Roberto; Coughlan, James M

2014-01-01

Smartphone apps can use object recognition software to provide information to blind or low vision users about objects in the visual environment. A crucial challenge for these users is aiming the camera properly to take a well-framed picture of the desired target object. We investigate the effects of two fundamental constraints of object recognition - frame rate and camera field of view - on a blind person's ability to use an object recognition smartphone app. The app was used by 18 blind participants to find visual targets beyond arm's reach and approach them to within 30 cm. While we expected that a faster frame rate or wider camera field of view should always improve search performance, our experimental results show that in many cases increasing the field of view does not help, and may even hurt, performance. These results have important implications for the design of object recognition systems for blind users.

Multi-Constraint Multi-Variable Optimization of Source-Driven Nuclear Systems

NASA Astrophysics Data System (ADS)

Watkins, Edward Francis

1995-01-01

A novel approach to the search for optimal designs of source-driven nuclear systems is investigated. Such systems include radiation shields, fusion reactor blankets and various neutron spectrum-shaping assemblies. The novel approach involves the replacement of the steepest-descents optimization algorithm incorporated in the code SWAN by a significantly more general and efficient sequential quadratic programming optimization algorithm provided by the code NPSOL. The resulting SWAN/NPSOL code system can be applied to more general, multi-variable, multi-constraint shield optimization problems. The constraints it accounts for may include simple bounds on variables, linear constraints, and smooth nonlinear constraints. It may also be applied to unconstrained, bound-constrained and linearly constrained optimization. The shield optimization capabilities of the SWAN/NPSOL code system is tested and verified in a variety of optimization problems: dose minimization at constant cost, cost minimization at constant dose, and multiple-nonlinear constraint optimization. The replacement of the optimization part of SWAN with NPSOL is found feasible and leads to a very substantial improvement in the complexity of optimization problems which can be efficiently handled.

A Rapid Python-Based Methodology for Target-Focused Combinatorial Library Design.

PubMed

Li, Shiliang; Song, Yuwei; Liu, Xiaofeng; Li, Honglin

2016-01-01

The chemical space is so vast that only a small portion of it has been examined. As a complementary approach to systematically probe the chemical space, virtual combinatorial library design has extended enormous impacts on generating novel and diverse structures for drug discovery. Despite the favorable contributions, high attrition rates in drug development that mainly resulted from lack of efficacy and side effects make it increasingly challenging to discover good chemical starting points. In most cases, focused libraries, which are restricted to particular regions of the chemical space, are deftly exploited to maximize hit rate and improve efficiency at the beginning of the drug discovery and drug development pipeline. This paper presented a valid methodology for fast target-focused combinatorial library design in both reaction-based and production-based ways with the library creating rates of approximately 70,000 molecules per second. Simple, quick and convenient operating procedures are the specific features of the method. SHAFTS, a hybrid 3D similarity calculation software, was embedded to help refine the size of the libraries and improve hit rates. Two target-focused (p38-focused and COX2-focused) libraries were constructed efficiently in this study. This rapid library enumeration method is portable and applicable to any other targets for good chemical starting points identification collaborated with either structure-based or ligand-based virtual screening.

Numerical difficulties associated with using equality constraints to achieve multi-level decomposition in structural optimization

NASA Technical Reports Server (NTRS)

Thareja, R.; Haftka, R. T.

1986-01-01

There has been recent interest in multidisciplinary multilevel optimization applied to large engineering systems. The usual approach is to divide the system into a hierarchy of subsystems with ever increasing detail in the analysis focus. Equality constraints are usually placed on various design quantities at every successive level to ensure consistency between levels. In many previous applications these equality constraints were eliminated by reducing the number of design variables. In complex systems this may not be possible and these equality constraints may have to be retained in the optimization process. In this paper the impact of such a retention is examined for a simple portal frame problem. It is shown that the equality constraints introduce numerical difficulties, and that the numerical solution becomes very sensitive to optimization parameters for a wide range of optimization algorithms.

Possible-word constraints in Cantonese speech segmentation.

PubMed

Yip, Michael C

2004-03-01

A Cantonese syllable-spotting experiment was conducted to examine whether the Possible-Word Constraint (PWC), proposed by Norris, McQueen, Cutler, and Butterfield (1997), can apply in Cantonese speech segmentation. In the experiment, listeners were asked to spot out the target Cantonese syllable from a series of nonsense sound strings. Results suggested that listeners found it more difficult to spot out the target syllable [kDm1] in the nonsense sound strings that attached with a single consonant [tkDm1] than in the nonsense sound strings that attached either with a vowel [a:kDm1] or a pseudo-syllable [khow1kDm1]. Finally, the current set of results further supported that the PWC appears to be a language-universal mechanism in segmenting continuous speech.

Design and validation of an open-source library of dynamic reference frames for research and education in optical tracking.

PubMed

Brown, Alisa; Uneri, Ali; Silva, Tharindu De; Manbachi, Amir; Siewerdsen, Jeffrey H

2018-04-01

Dynamic reference frames (DRFs) are a common component of modern surgical tracking systems; however, the limited number of commercially available DRFs poses a constraint in developing systems, especially for research and education. This work presents the design and validation of a large, open-source library of DRFs compatible with passive, single-face tracking systems, such as Polaris stereoscopic infrared trackers (NDI, Waterloo, Ontario). An algorithm was developed to create new DRF designs consistent with intra- and intertool design constraints and convert to computer-aided design (CAD) files suitable for three-dimensional printing. A library of 10 such groups, each with 6 to 10 DRFs, was produced and tracking performance was validated in comparison to a standard commercially available reference, including pivot calibration, fiducial registration error (FRE), and target registration error (TRE). Pivot tests showed calibration error [Formula: see text], indistinguishable from the reference. FRE was [Formula: see text], and TRE in a CT head phantom was [Formula: see text], both equivalent to the reference. The library of DRFs offers a useful resource for surgical navigation research and could be extended to other tracking systems and alternative design constraints.

Design of targeted libraries against the human Chk1 kinase using PGVL Hub.

PubMed

Peng, Zhengwei; Hu, Qiyue

2011-01-01

PGVL Hub is a Pfizer internal desktop tool for chemical library and singleton design. In this chapter, we give a short introduction to PGVL Hub, the core workflow it supports, and the rich design capabilities it provides. By re-creating two legacy targeted libraries against the human checkpoint kinase 1 (Chk1) as a showcase, we illustrate how PGVL Hub could be used to help library designers carry out the steps in library design and realize design objectives such as SAR expansion and improvement in both kinase selectivity and compound aqueous solubility. Finally we share several tips about library design and usage of PGVL Hub.

Modern prodrug design for targeted oral drug delivery.

PubMed

Dahan, Arik; Zimmermann, Ellen M; Ben-Shabat, Shimon

2014-10-14

The molecular information that became available over the past two decades significantly influenced the field of drug design and delivery at large, and the prodrug approach in particular. While the traditional prodrug approach was aimed at altering various physiochemical parameters, e.g., lipophilicity and charge state, the modern approach to prodrug design considers molecular/cellular factors, e.g., membrane influx/efflux transporters and cellular protein expression and distribution. This novel targeted-prodrug approach is aimed to exploit carrier-mediated transport for enhanced intestinal permeability, as well as specific enzymes to promote activation of the prodrug and liberation of the free parent drug. The purpose of this article is to provide a concise overview of this modern prodrug approach, with useful successful examples for its utilization. In the past the prodrug approach used to be viewed as a last option strategy, after all other possible solutions were exhausted; nowadays this is no longer the case, and in fact, the prodrug approach should be considered already in the very earliest development stages. Indeed, the prodrug approach becomes more and more popular and successful. A mechanistic prodrug design that aims to allow intestinal permeability by specific transporters, as well as activation by specific enzymes, may greatly improve the prodrug efficiency, and allow for novel oral treatment options.

Robust Design Optimization via Failure Domain Bounding

NASA Technical Reports Server (NTRS)

Crespo, Luis G.; Kenny, Sean P.; Giesy, Daniel P.

2007-01-01

This paper extends and applies the strategies recently developed by the authors for handling constraints under uncertainty to robust design optimization. For the scope of this paper, robust optimization is a methodology aimed at problems for which some parameters are uncertain and are only known to belong to some uncertainty set. This set can be described by either a deterministic or a probabilistic model. In the methodology developed herein, optimization-based strategies are used to bound the constraint violation region using hyper-spheres and hyper-rectangles. By comparing the resulting bounding sets with any given uncertainty model, it can be determined whether the constraints are satisfied for all members of the uncertainty model (i.e., constraints are feasible) or not (i.e., constraints are infeasible). If constraints are infeasible and a probabilistic uncertainty model is available, upper bounds to the probability of constraint violation can be efficiently calculated. The tools developed enable approximating not only the set of designs that make the constraints feasible but also, when required, the set of designs for which the probability of constraint violation is below a prescribed admissible value. When constraint feasibility is possible, several design criteria can be used to shape the uncertainty model of performance metrics of interest. Worst-case, least-second-moment, and reliability-based design criteria are considered herein. Since the problem formulation is generic and the tools derived only require standard optimization algorithms for their implementation, these strategies are easily applicable to a broad range of engineering problems.

The Software Design for the Wide-Field Infrared Explorer Attitude Control System

NASA Technical Reports Server (NTRS)

Anderson, Mark O.; Barnes, Kenneth C.; Melhorn, Charles M.; Phillips, Tom

1998-01-01

The Wide-Field Infrared Explorer (WIRE), currently scheduled for launch in September 1998, is the fifth of five spacecraft in the NASA/Goddard Small Explorer (SMEX) series. This paper presents the design of WIRE's Attitude Control System flight software (ACS FSW). WIRE is a momentum-biased, three-axis stabilized stellar pointer which provides high-accuracy pointing and autonomous acquisition for eight to ten stellar targets per orbit. WIRE's short mission life and limited cryogen supply motivate requirements for Sun and Earth avoidance constraints which are designed to prevent catastrophic instrument damage and to minimize the heat load on the cryostat. The FSW implements autonomous fault detection and handling (FDH) to enforce these instrument constraints and to perform several other checks which insure the safety of the spacecraft. The ACS FSW implements modules for sensor data processing, attitude determination, attitude control, guide star acquisition, actuator command generation, command/telemetry processing, and FDH. These software components are integrated with a hierarchical control mode managing module that dictates which software components are currently active. The lowest mode in the hierarchy is the 'safest' one, in the sense that it utilizes a minimal complement of sensors and actuators to keep the spacecraft in a stable configuration (power and pointing constraints are maintained). As higher modes in the hierarchy are achieved, the various software functions are activated by the mode manager, and an increasing level of attitude control accuracy is provided. If FDH detects a constraint violation or other anomaly, it triggers a safing transition to a lower control mode. The WIRE ACS FSW satisfies all target acquisition and pointing accuracy requirements, enforces all pointing constraints, provides the ground with a simple means for reconfiguring the system via table load, and meets all the demands of its real-time embedded environment (16 MHz Intel

A compendium of chameleon constraints

DOE Office of Scientific and Technical Information (OSTI.GOV)

Burrage, Clare; Sakstein, Jeremy, E-mail: clare.burrage@nottingham.ac.uk, E-mail: jeremy.sakstein@port.ac.uk

2016-11-01

The chameleon model is a scalar field theory with a screening mechanism that explains how a cosmologically relevant light scalar can avoid the constraints of intra-solar-system searches for fifth-forces. The chameleon is a popular dark energy candidate and also arises in f ( R ) theories of gravity. Whilst the chameleon is designed to avoid historical searches for fifth-forces it is not unobservable and much effort has gone into identifying the best observables and experiments to detect it. These results are not always presented for the same models or in the same language, a particular problem when comparing astrophysical andmore » laboratory searches making it difficult to understand what regions of parameter space remain. Here we present combined constraints on the chameleon model from astrophysical and laboratory searches for the first time and identify the remaining windows of parameter space. We discuss the implications for cosmological chameleon searches and future small-scale probes.« less

Simplified, inverse, ejector design tool

NASA Technical Reports Server (NTRS)

Dechant, Lawrence J.

1993-01-01

A simple lumped parameter based inverse design tool has been developed which provides flow path geometry and entrainment estimates subject to operational, acoustic, and design constraints. These constraints are manifested through specification of primary mass flow rate or ejector thrust, fully-mixed exit velocity, and static pressure matching. Fundamentally, integral forms of the conservation equations coupled with the specified design constraints are combined to yield an easily invertible linear system in terms of the flow path cross-sectional areas. Entrainment is computed by back substitution. Initial comparison with experimental and analogous one-dimensional methods show good agreement. Thus, this simple inverse design code provides an analytically based, preliminary design tool with direct application to High Speed Civil Transport (HSCT) design studies.

Lujan Center Mark-IV Target Neutronics Design Internal Review Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lisowski, Paul W.; Gallmeier, Franz; Guber, Klaus

The 1L Target Moderator Reflector System (TMRS) at the Lujan Center will need to be replaced before the CY 2020 operating cycle. A Physics Division design team investigated options for improving the overall target performance for nuclear science research with minimal reduction in performance for materials science. This review concluded that devoting an optimized arrangement of the Lujan TMRS upper tier to nuclear science and using the lower tier for materials science can achieve those goals. This would open the opportunity for enhanced nuclear science research in an important neutron energy range for NNSA. There will be no other facilitymore » in the US that will compete in the keV energy range provided flight paths and instrumentation are developed to take advantage of the neutron flux and resolution.« less

Design of a liquid membrane target for high repetition rate neutron generation

NASA Astrophysics Data System (ADS)

Poole, Patrick; Andereck, C. David; Storm, Mike; Schumacher, Douglass

2013-10-01

Ultra-bright, pulsed, spatially-small sources of energetic neutrons have applications in radiography and non-destructive remote sensing. Neutrons can be generated by a process wherein ions accelerated from a laser-irradiated primary target subsequently bombard a converter material, causing neutron-producing nuclear reactions, such as 7Li(d,n)8Be. Deuterons from this process are suppressed by contamination that builds up on the rear of the solid primary target. To eliminate this issue we propose a self-replenishing liquid membrane target consisting of heavy water and deuterated surfactant, formed in-vacuum within a moveable wire frame. In addition to removing issues associated with solid target positioning and collateral damage, this apparatus provides flow rate and target thickness control, and allows for the high repetition rates required to generate desired neutron fluxes with a portable laser-based system. The apparatus design will be presented, as well as a novel interferometric method that measures the membrane thickness using tightly-focused light. This work was performed with support from DARPA.

Rational Design of Small Molecules Targeting Oncogenic Noncoding RNAs from Sequence.

PubMed

Disney, Matthew D; Angelbello, Alicia J

2016-12-20

The discovery of RNA catalysis in the 1980s and the dissemination of the human genome sequence at the start of this century inspired investigations of the regulatory roles of noncoding RNAs in biology. In fact, the Encyclopedia of DNA Elements (ENCODE) project has shown that only 1-2% of the human genome encodes protein, yet 75% is transcribed into RNA. Functional studies both preceding and following the ENCODE project have shown that these noncoding RNAs have important roles in regulating gene expression, developmental timing, and other critical functions. RNA's diverse roles are often a consequence of the various folds that it adopts. The single-stranded nature of the biopolymer enables it to adopt intramolecular folds with noncanonical pairings to lower its free energy. These folds can be scaffolds to bind proteins or to form frameworks to interact with other RNAs. Not surprisingly, dysregulation of certain noncoding RNAs has been shown to be causative of disease. Given this as the background, it is easy to see why it would be useful to develop methods that target RNA and manipulate its biology in rational and predictable ways. The antisense approach has afforded strategies to target RNAs via Watson-Crick base pairing and has typically focused on targeting partially unstructured regions of RNA. Small molecule strategies to target RNA would be desirable not only because compounds could be lead optimized via medicinal chemistry but also because structured regions within an RNA of interest could be targeted to directly interfere with RNA folds that contribute to disease. Additionally, small molecules have historically been the most successful drug candidates. Until recently, the ability to design small molecules that target non-ribosomal RNAs has been elusive, creating the perception that they are "undruggable". In this Account, approaches to demystify targeting RNA with small molecules are described. Rather than bulk screening for compounds that bind to singular

Design of relative trajectories for in orbit proximity operations

NASA Astrophysics Data System (ADS)

Opromolla, Roberto; Fasano, Giancarmine; Rufino, Giancarlo; Grassi, Michele

2018-04-01

This paper presents an innovative approach to design relative trajectories suitable for close-proximity operations in orbit, by assigning high-level constraints regarding their stability, shape and orientation. Specifically, this work is relevant to space mission scenarios, e.g. formation flying, on-orbit servicing, and active debris removal, which involve either the presence of two spacecraft carrying out coordinated maneuvers, or a servicing/recovery spacecraft (chaser) performing monitoring, rendezvous and docking with respect to another space object (target). In the above-mentioned scenarios, an important aspect is the capability of reducing collision risks and of providing robust and accurate relative navigation solutions. To this aim, the proposed approach exploits a relative motion model relevant to two-satellite formations, and developed in mean orbit parameters, which takes the perturbation effect due to secular Earth oblateness, as well as the motion of the target along a small-eccentricity orbit, into account. This model is used to design trajectories which ensure safe relative motion, to minimize collision risks and relax control requirements, providing at the same time favorable conditions, in terms of target-chaser relative observation geometry for pose determination and relative navigation with passive or active electro-optical sensors on board the chaser. Specifically, three design strategies are proposed in the context of a space target monitoring scenario, considering as design cases both operational spacecraft and debris, characterized by highly variable shape, size and absolute rotational dynamics. The effectiveness of the proposed design approach in providing favorable observation conditions for target-chaser relative pose estimation is demonstrated within a simulation environment which reproduces the designed target-chaser relative trajectory, the operation of an active LIDAR installed on board the chaser, and pose estimation algorithms.

Solar electric geocentric transfer with attitude constraints: Analysis

NASA Technical Reports Server (NTRS)

Sackett, L. L.; Malchow, H. L.; Delbaum, T. N.

1975-01-01

A time optimal or nearly time optimal trajectory program was developed for solar electric geocentric transfer with or without attitude constraints and with an optional initial high thrust stage. The method of averaging reduces computation time. A nonsingular set of orbital elements is used. The constraints, which are those of one of the SERT-C designs, introduce complexities into the analysis and the solution yields possible discontinuous changes in thrust direction. The power degradation due to VanAllen radiation is modeled analytically. A wide range of solar cell characteristics is assumed. Effects such as oblateness and shadowing are included. The analysis and the results of many example runs are included.

Using High Resolution Design Spaces for Aerodynamic Shape Optimization Under Uncertainty

NASA Technical Reports Server (NTRS)

Li, Wu; Padula, Sharon

2004-01-01

This paper explains why high resolution design spaces encourage traditional airfoil optimization algorithms to generate noisy shape modifications, which lead to inaccurate linear predictions of aerodynamic coefficients and potential failure of descent methods. By using auxiliary drag constraints for a simultaneous drag reduction at all design points and the least shape distortion to achieve the targeted drag reduction, an improved algorithm generates relatively smooth optimal airfoils with no severe off-design performance degradation over a range of flight conditions, in high resolution design spaces parameterized by cubic B-spline functions. Simulation results using FUN2D in Euler flows are included to show the capability of the robust aerodynamic shape optimization method over a range of flight conditions.

Analyses of deep mammalian sequence alignments and constraint predictions for 1% of the human genome

PubMed Central

Margulies, Elliott H.; Cooper, Gregory M.; Asimenos, George; Thomas, Daryl J.; Dewey, Colin N.; Siepel, Adam; Birney, Ewan; Keefe, Damian; Schwartz, Ariel S.; Hou, Minmei; Taylor, James; Nikolaev, Sergey; Montoya-Burgos, Juan I.; Löytynoja, Ari; Whelan, Simon; Pardi, Fabio; Massingham, Tim; Brown, James B.; Bickel, Peter; Holmes, Ian; Mullikin, James C.; Ureta-Vidal, Abel; Paten, Benedict; Stone, Eric A.; Rosenbloom, Kate R.; Kent, W. James; Bouffard, Gerard G.; Guan, Xiaobin; Hansen, Nancy F.; Idol, Jacquelyn R.; Maduro, Valerie V.B.; Maskeri, Baishali; McDowell, Jennifer C.; Park, Morgan; Thomas, Pamela J.; Young, Alice C.; Blakesley, Robert W.; Muzny, Donna M.; Sodergren, Erica; Wheeler, David A.; Worley, Kim C.; Jiang, Huaiyang; Weinstock, George M.; Gibbs, Richard A.; Graves, Tina; Fulton, Robert; Mardis, Elaine R.; Wilson, Richard K.; Clamp, Michele; Cuff, James; Gnerre, Sante; Jaffe, David B.; Chang, Jean L.; Lindblad-Toh, Kerstin; Lander, Eric S.; Hinrichs, Angie; Trumbower, Heather; Clawson, Hiram; Zweig, Ann; Kuhn, Robert M.; Barber, Galt; Harte, Rachel; Karolchik, Donna; Field, Matthew A.; Moore, Richard A.; Matthewson, Carrie A.; Schein, Jacqueline E.; Marra, Marco A.; Antonarakis, Stylianos E.; Batzoglou, Serafim; Goldman, Nick; Hardison, Ross; Haussler, David; Miller, Webb; Pachter, Lior; Green, Eric D.; Sidow, Arend

2007-01-01

A key component of the ongoing ENCODE project involves rigorous comparative sequence analyses for the initially targeted 1% of the human genome. Here, we present orthologous sequence generation, alignment, and evolutionary constraint analyses of 23 mammalian species for all ENCODE targets. Alignments were generated using four different methods; comparisons of these methods reveal large-scale consistency but substantial differences in terms of small genomic rearrangements, sensitivity (sequence coverage), and specificity (alignment accuracy). We describe the quantitative and qualitative trade-offs concomitant with alignment method choice and the levels of technical error that need to be accounted for in applications that require multisequence alignments. Using the generated alignments, we identified constrained regions using three different methods. While the different constraint-detecting methods are in general agreement, there are important discrepancies relating to both the underlying alignments and the specific algorithms. However, by integrating the results across the alignments and constraint-detecting methods, we produced constraint annotations that were found to be robust based on multiple independent measures. Analyses of these annotations illustrate that most classes of experimentally annotated functional elements are enriched for constrained sequences; however, large portions of each class (with the exception of protein-coding sequences) do not overlap constrained regions. The latter elements might not be under primary sequence constraint, might not be constrained across all mammals, or might have expendable molecular functions. Conversely, 40% of the constrained sequences do not overlap any of the functional elements that have been experimentally identified. Together, these findings demonstrate and quantify how many genomic functional elements await basic molecular characterization. PMID:17567995

Two Point Exponential Approximation Method for structural optimization of problems with frequency constraints

NASA Technical Reports Server (NTRS)

Fadel, G. M.

1991-01-01

The point exponential approximation method was introduced by Fadel et al. (Fadel, 1990), and tested on structural optimization problems with stress and displacement constraints. The reports in earlier papers were promising, and the method, which consists of correcting Taylor series approximations using previous design history, is tested in this paper on optimization problems with frequency constraints. The aim of the research is to verify the robustness and speed of convergence of the two point exponential approximation method when highly non-linear constraints are used.

Feasibility of Supersonic Aircraft Concepts for Low-Boom and Flight Trim Constraints

NASA Technical Reports Server (NTRS)

Li, Wu

2015-01-01

This paper documents a process for analyzing whether a particular supersonic aircraft configuration layout and a given cruise condition are feasible to achieve a trimmed low-boom design. This process was motivated by the need to know whether a particular configuration at a given cruise condition could be reshaped to satisfy both low-boom and flight trim constraints. Without such a process, much effort could be wasted on shaping a configuration layout at a cruise condition that could never satisfy both low-boom and flight trim constraints simultaneously. The process helps to exclude infeasible configuration layouts with minimum effort and allows a designer to develop trimmed low-boom concepts more effectively. A notional low-boom supersonic demonstrator concept is used to illustrate the analysis/design process.

Learning Artificial Phonotactic Constraints: Time Course, Durability, and Relationship to Natural Constraints

ERIC Educational Resources Information Center

Taylor, Conrad F.; Houghton, George

2005-01-01

G. S. Dell, K. D. Reed, D. R. Adams, and A. S. Meyer (2000) proposed a "breadth-of-constraint" continuum on phoneme errors, using artificial experiment-wide constraints to investigate a putative middle ground between local and language-wide constraints. The authors report 5 experiments that test the idea of the continuum and the location of the…

Impact Angle and Time Control Guidance Under Field-of-View Constraints and Maneuver Limits

NASA Astrophysics Data System (ADS)

Shim, Sang-Wook; Hong, Seong-Min; Moon, Gun-Hee; Tahk, Min-Jea

2018-04-01

This paper proposes a guidance law which considers the constraints of seeker field-of-view (FOV) as well as the requirements on impact angle and time. The proposed guidance law is designed for a constant speed missile against a stationary target. The guidance law consists of two terms of acceleration commands. The first one is to achieve zero-miss distance and the desired impact angle, while the second is to meet the desired impact time. To consider the limits of FOV and lateral maneuver capability, a varying-gain approach is applied on the second term. Reduction of realizable impact times due to these limits is then analyzed by finding the longest course among the feasible ones. The performance of the proposed guidance law is demonstrated by numerical simulation for various engagement conditions.

Local structure preserving sparse coding for infrared target recognition

PubMed Central

Han, Jing; Yue, Jiang; Zhang, Yi; Bai, Lianfa

2017-01-01

Sparse coding performs well in image classification. However, robust target recognition requires a lot of comprehensive template images and the sparse learning process is complex. We incorporate sparsity into a template matching concept to construct a local sparse structure matching (LSSM) model for general infrared target recognition. A local structure preserving sparse coding (LSPSc) formulation is proposed to simultaneously preserve the local sparse and structural information of objects. By adding a spatial local structure constraint into the classical sparse coding algorithm, LSPSc can improve the stability of sparse representation for targets and inhibit background interference in infrared images. Furthermore, a kernel LSPSc (K-LSPSc) formulation is proposed, which extends LSPSc to the kernel space to weaken the influence of the linear structure constraint in nonlinear natural data. Because of the anti-interference and fault-tolerant capabilities, both LSPSc- and K-LSPSc-based LSSM can implement target identification based on a simple template set, which just needs several images containing enough local sparse structures to learn a sufficient sparse structure dictionary of a target class. Specifically, this LSSM approach has stable performance in the target detection with scene, shape and occlusions variations. High performance is demonstrated on several datasets, indicating robust infrared target recognition in diverse environments and imaging conditions. PMID:28323824

Real Time Target Tracking Using Dedicated Vision Hardware

NASA Astrophysics Data System (ADS)

Kambies, Keith; Walsh, Peter

1988-03-01

This paper describes a real-time vision target tracking system developed by Adaptive Automation, Inc. and delivered to NASA's Launch Equipment Test Facility, Kennedy Space Center, Florida. The target tracking system is part of the Robotic Application Development Laboratory (RADL) which was designed to provide NASA with a general purpose robotic research and development test bed for the integration of robot and sensor systems. One of the first RADL system applications is the closing of a position control loop around a six-axis articulated arm industrial robot using a camera and dedicated vision processor as the input sensor so that the robot can locate and track a moving target. The vision system is inside of the loop closure of the robot tracking system, therefore, tight throughput and latency constraints are imposed on the vision system that can only be met with specialized hardware and a concurrent approach to the processing algorithms. State of the art VME based vision boards capable of processing the image at frame rates were used with a real-time, multi-tasking operating system to achieve the performance required. This paper describes the high speed vision based tracking task, the system throughput requirements, the use of dedicated vision hardware architecture, and the implementation design details. Important to the overall philosophy of the complete system was the hierarchical and modular approach applied to all aspects of the system, hardware and software alike, so there is special emphasis placed on this topic in the paper.

Control of articulated snake robot under dynamic active constraints.

PubMed

Kwok, Ka-Wai; Vitiello, Valentina; Yang, Guang-Zhong

2010-01-01

Flexible, ergonomically enhanced surgical robots have important applications to transluminal endoscopic surgery, for which path-following and dynamic shape conformance are essential. In this paper, kinematic control of a snake robot for motion stabilisation under dynamic active constraints is addressed. The main objective is to enable the robot to track the visual target accurately and steadily on deforming tissue whilst conforming to pre-defined anatomical constraints. The motion tracking can also be augmented with manual control. By taking into account the physical limits in terms of maximum frequency response of the system (manifested as a delay between the input of the manipulator and the movement of the end-effector), we show the importance of visual-motor synchronisation for performing accurate smooth pursuit movements. Detailed user experiments are performed to demonstrate the practical value of the proposed control mechanism.

Examination of CRISPR/Cas9 design tools and the effect of target site accessibility on Cas9 activity.

PubMed

Lee, Ciaran M; Davis, Timothy H; Bao, Gang

2018-04-01

What is the topic of this review? In this review, we analyse the performance of recently described tools for CRISPR/Cas9 guide RNA design, in particular, design tools that predict CRISPR/Cas9 activity. What advances does it highlight? Recently, many tools designed to predict CRISPR/Cas9 activity have been reported. However, the majority of these tools lack experimental validation. Our analyses indicate that these tools have poor predictive power. Our preliminary results suggest that target site accessibility should be considered in order to develop better guide RNA design tools with improved predictive power. The recent adaptation of the clustered regulatory interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system for targeted genome engineering has led to its widespread application in many fields worldwide. In order to gain a better understanding of the design rules of CRISPR/Cas9 systems, several groups have carried out large library-based screens leading to some insight into sequence preferences among highly active target sites. To facilitate CRISPR/Cas9 design, these studies have spawned a plethora of guide RNA (gRNA) design tools with algorithms based solely on direct or indirect sequence features. Here, we demonstrate that the predictive power of these tools is poor, suggesting that sequence features alone cannot accurately inform the cutting efficiency of a particular CRISPR/Cas9 gRNA design. Furthermore, we demonstrate that DNA target site accessibility influences the activity of CRISPR/Cas9. With further optimization, we hypothesize that it will be possible to increase the predictive power of gRNA design tools by including both sequence and target site accessibility metrics. © 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.

New method to design stellarator coils without the winding surface

DOE PAGES

Zhu, Caoxiang; Hudson, Stuart R.; Song, Yuntao; ...

2017-11-06

Finding an easy-to-build coils set has been a critical issue for stellarator design for decades. Conventional approaches assume a toroidal 'winding' surface, but a poorly chosen winding surface can unnecessarily constrain the coil optimization algorithm, This article presents a new method to design coils for stellarators. Each discrete coil is represented as an arbitrary, closed, one-dimensional curve embedded in three-dimensional space. A target function to be minimized that includes both physical requirements and engineering constraints is constructed. The derivatives of the target function with respect to the parameters describing the coil geometries and currents are calculated analytically. A numerical code,more » named flexible optimized coils using space curves (FOCUS), has been developed. Furthermore, applications to a simple stellarator configuration, W7-X and LHD vacuum fields are presented.« less

New method to design stellarator coils without the winding surface

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu, Caoxiang; Hudson, Stuart R.; Song, Yuntao

Finding an easy-to-build coils set has been a critical issue for stellarator design for decades. Conventional approaches assume a toroidal 'winding' surface, but a poorly chosen winding surface can unnecessarily constrain the coil optimization algorithm, This article presents a new method to design coils for stellarators. Each discrete coil is represented as an arbitrary, closed, one-dimensional curve embedded in three-dimensional space. A target function to be minimized that includes both physical requirements and engineering constraints is constructed. The derivatives of the target function with respect to the parameters describing the coil geometries and currents are calculated analytically. A numerical code,more » named flexible optimized coils using space curves (FOCUS), has been developed. Furthermore, applications to a simple stellarator configuration, W7-X and LHD vacuum fields are presented.« less

Integrity Constraint Monitoring in Software Development: Proposed Architectures

NASA Technical Reports Server (NTRS)

Fernandez, Francisco G.

1997-01-01

In the development of complex software systems, designers are required to obtain from many sources and manage vast amounts of knowledge of the system being built and communicate this information to personnel with a variety of backgrounds. Knowledge concerning the properties of the system, including the structure of, relationships between and limitations of the data objects in the system, becomes increasingly more vital as the complexity of the system and the number of knowledge sources increases. Ensuring that violations of these properties do not occur becomes steadily more challenging. One approach toward managing the enforcement or system properties, called context monitoring, uses a centralized repository of integrity constraints and a constraint satisfiability mechanism for dynamic verification of property enforcement during program execution. The focus of this paper is to describe possible software architectures that define a mechanism for dynamically checking the satisfiability of a set of constraints on a program. The next section describes the context monitoring approach in general. Section 3 gives an overview of the work currently being done toward the addition of an integrity constraint satisfiability mechanism to a high-level program language, SequenceL, and demonstrates how this model is being examined to develop a general software architecture. Section 4 describes possible architectures for a general constraint satisfiability mechanism, as well as an alternative approach that, uses embedded database queries in lieu of an external monitor. The paper concludes with a brief summary outlining the, current state of the research and future work.

Computational and Pharmacological Target of Neurovascular Unit for Drug Design and Delivery

PubMed Central

2015-01-01

The blood-brain barrier (BBB) is a dynamic and highly selective permeable interface between central nervous system (CNS) and periphery that regulates the brain homeostasis. Increasing evidences of neurological disorders and restricted drug delivery process in brain make BBB as special target for further study. At present, neurovascular unit (NVU) is a great interest and highlighted topic of pharmaceutical companies for CNS drug design and delivery approaches. Some recent advancement of pharmacology and computational biology makes it convenient to develop drugs within limited time and affordable cost. In this review, we briefly introduce current understanding of the NVU, including molecular and cellular composition, physiology, and regulatory function. We also discuss the recent technology and interaction of pharmacogenomics and bioinformatics for drug design and step towards personalized medicine. Additionally, we develop gene network due to understand NVU associated transporter proteins interactions that might be effective for understanding aetiology of neurological disorders and new target base protective therapies development and delivery. PMID:26579539

Games and teams with shared constraints.

PubMed

Kulkarni, Ankur A

2017-08-13

Energy systems of the future are envisaged to encompass multiple interacting autonomous entities. The theory of games provides the foundations for the design and analysis of such systems. This paper reviews models and results that would be of use for such analysis. Classically, games have involved players whose strategies are coupled only through the dependence of utility functions on strategies of other players. However, in many practical settings in the energy domain, system-level limitations bind the choices players can make. In 1965, Rosen ( Econometrica 33 , 520-534 (doi:10.2307/1911749)) pioneered the study of a class of games where there is a common constraint, called a shared constraint , that couples the strategies available to the players. We discuss how this seemingly benign extension has important ramifications, ranging from the very definition of an equilibrium concept, to other key issues such as existence, uniqueness and efficiency of equilibria. We show how the presence of a shared constraint naturally leads to notions of a price and forms the motivations for more recent models. Although most of the paper has the character of a survey, occasionally we also prove new results.This article is part of the themed issue 'Energy management: flexibility, risk and optimization'. © 2017 The Author(s).

Global reverse supply chain design for solid waste recycling under uncertainties and carbon emission constraint.

PubMed

Xu, Zhitao; Elomri, Adel; Pokharel, Shaligram; Zhang, Qin; Ming, X G; Liu, Wenjie

2017-06-01

The emergence of concerns over environmental protection, resource conservation as well as the development of logistics operations and manufacturing technology has led several countries to implement formal collection and recycling systems of solid waste. Such recycling system has the benefits of reducing environmental pollution, boosting the economy by creating new jobs, and generating income from trading the recyclable materials. This leads to the formation of a global reverse supply chain (GRSC) of solid waste. In this paper, we investigate the design of such a GRSC with a special emphasis on three aspects; (1) uncertainty of waste collection levels, (2) associated carbon emissions, and (3) challenges posed by the supply chain's global aspect, particularly the maritime transportation costs and currency exchange rates. To the best of our knowledge, this paper is the first attempt to integrate the three above-mentioned important aspects in the design of a GRSC. We have used mixed integer-linear programming method along with robust optimization to develop the model which is validated using a sample case study of e-waste management. Our results show that using a robust model by taking the complex interactions characterizing global reverse supply chain networks into account, we can create a better GRSC. The effect of uncertainties and carbon constraints on decisions to reduce costs and emissions are also shown. Copyright © 2017 Elsevier Ltd. All rights reserved.

New Boundary Constraints for Elliptic Systems used in Grid Generation Problems

NASA Technical Reports Server (NTRS)

Kaul, Upender K.; Clancy, Daniel (Technical Monitor)

2002-01-01

This paper discusses new boundary constraints for elliptic partial differential equations as used in grid generation problems in generalized curvilinear coordinate systems. These constraints, based on the principle of local conservation of thermal energy in the vicinity of the boundaries, are derived using the Green's Theorem. They uniquely determine the so called decay parameters in the source terms of these elliptic systems. These constraints' are designed for boundary clustered grids where large gradients in physical quantities need to be resolved adequately. It is observed that the present formulation also works satisfactorily for mild clustering. Therefore, a closure for the decay parameter specification for elliptic grid generation problems has been provided resulting in a fully automated elliptic grid generation technique. Thus, there is no need for a parametric study of these decay parameters since the new constraints fix them uniquely. It is also shown that for Neumann type boundary conditions, these boundary constraints uniquely determine the solution to the internal elliptic problem thus eliminating the non-uniqueness of the solution of an internal Neumann boundary value grid generation problem.

Reconciling Scientific Aspirations and Engineering Constraints for a Lunar Mission via Hyperdimensional Interpolation

NASA Technical Reports Server (NTRS)

Weisbin, Charles R.; Clark, Pamela; Elfes, Alberto; Smith, Jeffrey H.; Mrozinski, Joseph; Adumitroaie, Virgil; Hua, Hook; Shelton, Kacie; Lincoln, William; Silberg, Robert

2010-01-01

Virtually every NASA space-exploration mission represents a compromise between the interests of two expert, dedicated, but very different communities: scientists, who want to go quickly to the places that interest them most and spend as much time there as possible conducting sophisticated experiments, and the engineers and designers charged with maximizing the probability that a given mission will be successful and cost-effective. Recent work at NASA's Jet Propulsion Laboratory (JPL) seeks to enhance communication between these two groups, and to help them reconcile their interests, by developing advanced modeling capabilities with which they can analyze the achievement of science goals and objectives against engineering design and operational constraints. The analyses conducted prior to this study have been point-design driven. Each analysis has been of one hypothetical case which addresses the question: Given a set of constraints, how much science can be done? But the constraints imposed by the architecture team-e.g., rover speed, time allowed for extravehicular activity (EVA), number of sites at which science experiments are to be conducted- are all in early development and carry a great deal of uncertainty. Variations can be incorporated into the analysis, and indeed that has been done in sensitivity studies designed to see which constraint variations have the greatest impact on results. But if a very large number of variations can be analyzed all at once, producing a table that includes virtually the entire trade space under consideration, then we have a tool that enables scientists and mission architects to ask the inverse question: For a given desired level of science (or any other objective), what is the range of constraints that would be needed? With this tool, mission architects could determine, for example, what combinations of rover speed, EVA duration, and other constraints produce the desired results. Further, this tool would help them identify which

Vector design for liver specific expression of multiple interfering RNAs that target hepatitis B virus transcripts

PubMed Central

Snyder, Lindsey L.; Esser, Jonathan M.; Pachuk, Catherine J.; Steel, Laura F.

2008-01-01

RNA interference (RNAi) is a process that can target intracellular RNAs for degradation in a highly sequence specific manner, making it a powerful tool that is being pursued in both research and therapeutic applications. Hepatitis B virus (HBV) is a serious public health problem in need of better treatment options, and aspects of its life cycle make it an excellent target for RNAi-based therapeutics. We have designed a vector that expresses interfering RNAs that target HBV transcripts, including both viral RNA replicative intermediates and mRNAs encoding viral proteins. Our vector design incorporates many features of endogenous microRNA (miRNA) gene organization that are proving useful for the development of reagents for RNAi. In particular, our vector contains an RNA pol II driven gene cassette that leads to tissue specific expression and efficient processing of multiple interfering RNAs from a single transcript, without the co-expression of any protein product. This vector shows potent silencing of HBV targets in cell culture models of HBV infection. The vector design will be applicable to silencing of additional cellular or disease-related genes. PMID:18499277

Using diagnostic experiences in experience-based innovative design

NASA Astrophysics Data System (ADS)

Prabhakar, Sattiraju; Goel, Ashok K.

1992-03-01

Designing a novel class of devices requires innovation. Often, the design knowledge of these devices does not identify and address the constraints that are required for their performance in the real world operating environment. So any new design adapted from these devices tend to be similarly sketchy. In order to address this problem, we propose a case-based reasoning method called performance driven innovation (PDI). We model the design as a dynamic process, arrive at a design by adaptation from the known designs, generate failures for this design for some new constraints, and then use this failure knowledge to generate the required design knowledge for the new constraints. In this paper, we discuss two aspects of PDI: the representation of PDI cases and the translation of the failure knowledge into design knowledge for a constraint. Each case in PDI has two components: design and failure knowledge. Both of them are represented using a substance-behavior-function model. Failure knowledge has internal device failure behaviors and external environmental behaviors. The environmental behavior, for a constraint, interacting with the design behaviors, results in the failure internal behavior. The failure adaptation strategy generates functions, from the failure knowledge, which can be addressed using the routine design methods. These ideas are illustrated using a coffee-maker example.

Design of an FMCW radar baseband signal processing system for automotive application.

PubMed

Lin, Jau-Jr; Li, Yuan-Ping; Hsu, Wei-Chiang; Lee, Ta-Sung

2016-01-01

For a typical FMCW automotive radar system, a new design of baseband signal processing architecture and algorithms is proposed to overcome the ghost targets and overlapping problems in the multi-target detection scenario. To satisfy the short measurement time constraint without increasing the RF front-end loading, a three-segment waveform with different slopes is utilized. By introducing a new pairing mechanism and a spatial filter design algorithm, the proposed detection architecture not only provides high accuracy and reliability, but also requires low pairing time and computational loading. This proposed baseband signal processing architecture and algorithms balance the performance and complexity, and are suitable to be implemented in a real automotive radar system. Field measurement results demonstrate that the proposed automotive radar signal processing system can perform well in a realistic application scenario.

Maximize, minimize or target - optimization for a fitted response from a designed experiment

DOE PAGES

Anderson-Cook, Christine Michaela; Cao, Yongtao; Lu, Lu

2016-04-01

One of the common goals of running and analyzing a designed experiment is to find a location in the design space that optimizes the response of interest. Depending on the goal of the experiment, we may seek to maximize or minimize the response, or set the process to hit a particular target value. After the designed experiment, a response model is fitted and the optimal settings of the input factors are obtained based on the estimated response model. Furthermore, the suggested optimal settings of the input factors are then used in the production environment.

Phonological Constraint Induction in a Connectionist Network: Learning OCP-Place Constraints from Data

ERIC Educational Resources Information Center

Alderete, John; Tupper, Paul; Frisch, Stefan A.

2013-01-01

A significant problem in computational language learning is that of inferring the content of well-formedness constraints from input data. In this article, we approach the constraint induction problem as the gradual adjustment of subsymbolic constraints in a connectionist network. In particular, we develop a multi-layer feed-forward network that…

Designer interface peptide grafts target estrogen receptor alpha dimerization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chakraborty, S.; Asare, B.K.; Biswas, P.K., E-mail: pbiswas@tougaloo.edu

The nuclear transcription factor estrogen receptor alpha (ERα), triggered by its cognate ligand estrogen, regulates a variety of cellular signaling events. ERα is expressed in 70% of breast cancers and is a widely validated target for anti-breast cancer drug discovery. Administration of anti-estrogen to block estrogen receptor activation is still a viable anti-breast cancer treatment option but anti-estrogen resistance has been a significant bottle-neck. Dimerization of estrogen receptor is required for ER activation. Blocking ERα dimerization is therefore a complementary and alternative strategy to combat anti-estrogen resistance. Dimer interface peptide “I-box” derived from ER residues 503–518 specifically blocks ER dimerization.more » Recently using a comprehensive molecular simulation we studied the interaction dynamics of ERα LBDs in a homo-dimer. Based on this study, we identified three interface recognition peptide motifs LDKITDT (ERα residues 479–485), LQQQHQRLAQ (residues 497–506), and LSHIRHMSNK (residues 511–520) and reported the suitability of using LQQQHQRLAQ (ER 497–506) as a template to design inhibitors of ERα dimerization. Stability and self-aggregation of peptide based therapeutics poses a significant bottle-neck to proceed further. In this study utilizing peptide grafted to preserve their pharmacophoric recognition motif and assessed their stability and potential to block ERα mediated activity in silico and in vitro. The Grafted peptides blocked ERα mediated cell proliferation and viability of breast cancer cells but did not alter their apoptotic fate. We believe the structural clues identified in this study can be used to identify novel peptidometics and small molecules that specifically target ER dimer interface generating a new breed of anti-cancer agents. - Highlights: • Designer peptide grafts retain core molecular recognition motif during MD simulations. • Designer peptide grafts with Poly-ALA helix form stable

A Designed Peptide Targets Two Types of Modifications of p53 with Anti-cancer Activity.

PubMed

Liang, Lunxi; Wang, Huanbin; Shi, Hubing; Li, Zhaoli; Yao, Han; Bu, Zhigao; Song, Ningning; Li, Chushu; Xiang, Dabin; Zhang, Yao; Wang, Jilin; Hu, Ye; Xu, Qi; Ma, Yanlei; Cheng, Zhongyi; Wang, Yingchao; Zhao, Shuliang; Qian, Jin; Chen, Yingxuan; Fang, Jing-Yuan; Xu, Jie

2018-06-21

Many cancer-related proteins are controlled by composite post-translational modifications (PTMs), but prevalent strategies only target one type of modification. Here we describe a designed peptide that controls two types of modifications of the p53 tumor suppressor, based on the discovery of a protein complex that suppresses p53 (suppresome). We found that Morn3, a cancer-testis antigen, recruits different PTM enzymes, such as sirtuin deacetylase and ubiquitin ligase, to confer composite modifications on p53. The molecular functions of Morn3 were validated through in vivo assays and chemico-biological intervention. A rationally designed Morn3-targeting peptide (Morncide) successfully activated p53 and suppressed tumor growth. These findings shed light on the regulation of protein PTMs and present a strategy for targeting two modifications with one molecule. Copyright © 2018 Elsevier Ltd. All rights reserved.

Optimization of Car Body under Constraints of Noise, Vibration, and Harshness (NVH), and Crash

NASA Technical Reports Server (NTRS)

Kodiyalam, Srinivas; Yang, Ren-Jye; Sobieszczanski-Sobieski, Jaroslaw (Editor)

2000-01-01

To be competitive on the today's market, cars have to be as light as possible while meeting the Noise, Vibration, and Harshness (NVH) requirements and conforming to Government-man dated crash survival regulations. The latter are difficult to meet because they involve very compute-intensive, nonlinear analysis, e.g., the code RADIOSS capable of simulation of the dynamics, and the geometrical and material nonlinearities of a thin-walled car structure in crash, would require over 12 days of elapsed time for a single design of a 390K elastic degrees of freedom model, if executed on a single processor of the state-of-the-art SGI Origin2000 computer. Of course, in optimization that crash analysis would have to be invoked many times. Needless to say, that has rendered such optimization intractable until now. The car finite element model is shown. The advent of computers that comprise large numbers of concurrently operating processors has created a new environment wherein the above optimization, and other engineering problems heretofore regarded as intractable may be solved. The procedure, shown, is a piecewise approximation based method and involves using a sensitivity based Taylor series approximation model for NVH and a polynomial response surface model for Crash. In that method the NVH constraints are evaluated using a finite element code (MSC/NASTRAN) that yields the constraint values and their derivatives with respect to design variables. The crash constraints are evaluated using the explicit code RADIOSS on the Origin 2000 operating on 256 processors simultaneously to generate data for a polynomial response surface in the design variable domain. The NVH constraints and their derivatives combined with the response surface for the crash constraints form an approximation to the system analysis (surrogate analysis) that enables a cycle of multidisciplinary optimization within move limits. In the inner loop, the NVH sensitivities are recomputed to update the NVH

Target detection in GPR data using joint low-rank and sparsity constraints

NASA Astrophysics Data System (ADS)

Bouzerdoum, Abdesselam; Tivive, Fok Hing Chi; Abeynayake, Canicious

2016-05-01

In ground penetrating radars, background clutter, which comprises the signals backscattered from the rough, uneven ground surface and the background noise, impairs the visualization of buried objects and subsurface inspections. In this paper, a clutter mitigation method is proposed for target detection. The removal of background clutter is formulated as a constrained optimization problem to obtain a low-rank matrix and a sparse matrix. The low-rank matrix captures the ground surface reflections and the background noise, whereas the sparse matrix contains the target reflections. An optimization method based on split-Bregman algorithm is developed to estimate these two matrices from the input GPR data. Evaluated on real radar data, the proposed method achieves promising results in removing the background clutter and enhancing the target signature.

High-resolution imaging and target designation through clouds or smoke

DOEpatents

Perry, Michael D.

2003-01-01

A method and system of combining gated intensifiers and advances in solid-state, short-pulse laser technology, compact systems capable of producing high resolution (i.e., approximately less than 20 centimeters) optical images through a scattering medium such as dense clouds, fog, smoke, etc. may be achieved from air or ground based platforms. Laser target designation through a scattering medium is also enabled by utilizing a short pulse illumination laser and a relatively minor change to the detectors on laser guided munitions.

Membrane-spanning α-helical barrels as tractable protein-design targets.

PubMed

Niitsu, Ai; Heal, Jack W; Fauland, Kerstin; Thomson, Andrew R; Woolfson, Derek N

2017-08-05

The rational ( de novo ) design of membrane-spanning proteins lags behind that for water-soluble globular proteins. This is due to gaps in our knowledge of membrane-protein structure, and experimental difficulties in studying such proteins compared to water-soluble counterparts. One limiting factor is the small number of experimentally determined three-dimensional structures for transmembrane proteins. By contrast, many tens of thousands of globular protein structures provide a rich source of 'scaffolds' for protein design, and the means to garner sequence-to-structure relationships to guide the design process. The α-helical coiled coil is a protein-structure element found in both globular and membrane proteins, where it cements a variety of helix-helix interactions and helical bundles. Our deep understanding of coiled coils has enabled a large number of successful de novo designs. For one class, the α-helical barrels-that is, symmetric bundles of five or more helices with central accessible channels-there are both water-soluble and membrane-spanning examples. Recent computational designs of water-soluble α-helical barrels with five to seven helices have advanced the design field considerably. Here we identify and classify analogous and more complicated membrane-spanning α-helical barrels from the Protein Data Bank. These provide tantalizing but tractable targets for protein engineering and de novo protein design.This article is part of the themed issue 'Membrane pores: from structure and assembly, to medicine and technology'. © 2017 The Author(s).

Environmental design implications for two deep space SmallSats

NASA Astrophysics Data System (ADS)

Kahn, Peter; Imken, Travis; Elliott, John; Sherwood, Brent; Frick, Andreas; Sheldon, Douglas; Lunine, Jonathan

2017-10-01

The extreme environmental challenges of deep space exploration force unique solutions to small satellite design in order to enable their use as scientifically viable spacecraft. The challenges of implementing small satellites within limited resources can be daunting when faced with radiation effects on delicate electronics that require shielding or unique adaptations for protection, or mass, power and volume limitations due to constraints placed by the carrier spacecraft, or even Planetary Protection compliant design techniques that drive assembly and testing. This paper will explore two concept studies where the environmental constraints and/or planetary protection mitigations drove the design of the Flight System. The paper will describe the key technical drivers on the Sylph mission concept to explore a plume at Europa as a secondary free-flyer as a part of the planned Europa Mission. Sylph is a radiation-hardened smallsat concept that would utilize terrain relative navigation to fly at low altitudes through a plume, if found, and relay the mass spectra data back through the flyby spacecraft during its 24-h mission. The second topic to be discussed will be the mission design constraints of the Near Earth Asteroid (NEA) Scout concept. NEAScout is a 6U cubesat that would utilize an 86 sq. m solar sail as propulsion to execute a flyby with a near-Earth asteroid and help retire Strategic Knowledge Gaps for future human exploration. NEAScout would cruise for 24 months to reach and characterize one Near-Earth asteroid that is representative of Human Exploration targets and telemeter that data directly back to Earth at the end of its roughly 2.5 year mission.

Nuclease Target Site Selection for Maximizing On-target Activity and Minimizing Off-target Effects in Genome Editing

PubMed Central

Lee, Ciaran M; Cradick, Thomas J; Fine, Eli J; Bao, Gang

2016-01-01

The rapid advancement in targeted genome editing using engineered nucleases such as ZFNs, TALENs, and CRISPR/Cas9 systems has resulted in a suite of powerful methods that allows researchers to target any genomic locus of interest. A complementary set of design tools has been developed to aid researchers with nuclease design, target site selection, and experimental validation. Here, we review the various tools available for target selection in designing engineered nucleases, and for quantifying nuclease activity and specificity, including web-based search tools and experimental methods. We also elucidate challenges in target selection, especially in predicting off-target effects, and discuss future directions in precision genome editing and its applications. PMID:26750397

Size Matters: Developing Design Rules to Engineer Nanoparticles for Solid Tumour Targeting

NASA Astrophysics Data System (ADS)

Sykes, Edward Alexander

Nanotechnology enables the design of highly customizable platforms for producing minimally invasive and programmable strategies for cancer diagnosis and treatment. Advances in this field have demonstrated that nanoparticles can enhance specificity of anti-cancer agents, respond to tumour-specific cues, and direct the visualization of biological targets in vivo. . Nanoparticles can be synthesized within the 1 to 100 nm range to achieve different electromagnetic properties and specifically interact with biological tissues by tuning their size, shape, and surface chemistry. However, it remains unclear which physicochemical parameters are critical for delivering nanomaterials to the tumour site. With less than 5% of administered nanoparticles reaching the tumour, engineering of nanoparticles for effective delivery to solid tumours remains a critical challenge to cancer nanomedicine. A more comprehensive understanding of the interplay between the nanomaterial physicochemical properties and biological systems is necessary to enhance the efficacy of nanoparticle tumour targeting. This thesis explores how nanoparticle size and functionalization with cancer cell specific agents impact nanoparticle delivery to tumours. Furthermore, this doctoral work (i) discusses how tumour structure evolves with growth, (ii) elucidates how such changes modulate nanoparticle accumulation, and (iii) identifies how the skin serves as a significant off-target site for nanoparticle uptake. This thesis also demonstrates the utility of empirically-derived parametric models, Monte Carlo simulations, and decision matrices for mechanistically understanding and predicting the impact of nanomaterial features and tumour biology on nanoparticle fate in vivo. These topics establish key design considerations to tailor nanoparticles for enhanced tumour targeting. Collectively, the concepts presented herein form a fundamental framework for the development of personalized nanomedicine and nano

Constraints on the pre-impact orbits of Solar system giant impactors

NASA Astrophysics Data System (ADS)

Jackson, Alan P.; Gabriel, Travis S. J.; Asphaug, Erik I.

2018-03-01

We provide a fast method for computing constraints on impactor pre-impact orbits, applying this to the late giant impacts in the Solar system. These constraints can be used to make quick, broad comparisons of different collision scenarios, identifying some immediately as low-probability events, and narrowing the parameter space in which to target follow-up studies with expensive N-body simulations. We benchmark our parameter space predictions, finding good agreement with existing N-body studies for the Moon. We suggest that high-velocity impact scenarios in the inner Solar system, including all currently proposed single impact scenarios for the formation of Mercury, should be disfavoured. This leaves a multiple hit-and-run scenario as the most probable currently proposed for the formation of Mercury.

Mechanical design of experimental apparatus for FIREX cryo-target cooling

NASA Astrophysics Data System (ADS)

Iwamoto, A.; Norimatsu, T.; Nakai, M.; Sakagami, H.; Fujioka, S.; Shiraga, H.; Azechi, H.

2016-05-01

Mechanical design of an experimental apparatus for FIREX cryo-target cooling is described. Gaseous helium (GHe) sealing system at a cryogenic environment is an important issue for laser fusion experiments. The dedicated loading system was designed for a metal gasket. We take U-TIGHTSEAL® (Usui Kokusai Sangyo Kaisha. Ltd.) with an indium plated copper jacket as an example. According to its specification, a linear load of 110 N/m along its circumference is the optimum compression; however a lower load would still maintain helium (He) leak below the required level. Its sealing performance was investigated systematically. Our system demanded 27 N/mm of the load to keep He leak tightness in a cryogenic environment. Once leak tightness was obtained, it could be reduced to 9.5 N/mm.

Constraints of Implementing Free Secondary Education in Mandera West Sub-County, Mandera County, Kenya

ERIC Educational Resources Information Center

Adan, Mohammed Abdi; Orodho, John Aluko

2015-01-01

This study sought to find out the constraints of implementing free secondary education (FSE) in secondary schools in Mandera West Sub-County, Mandera County, Kenya. The study is based on the theory of constraints as the researcher examines the factors constraining the achievement of FSE objectives. The study used the survey design. The main…

From laptop to benchtop to bedside: Structure-based Drug Design on Protein Targets

PubMed Central

Chen, Lu; Morrow, John K.; Tran, Hoang T.; Phatak, Sharangdhar S.; Du-Cuny, Lei; Zhang, Shuxing

2013-01-01

As an important aspect of computer-aided drug design, structure-based drug design brought a new horizon to pharmaceutical development. This in silico method permeates all aspects of drug discovery today, including lead identification, lead optimization, ADMET prediction and drug repurposing. Structure-based drug design has resulted in fruitful successes drug discovery targeting protein-ligand and protein-protein interactions. Meanwhile, challenges, noted by low accuracy and combinatoric issues, may also cause failures. In this review, state-of-the-art techniques for protein modeling (e.g. structure prediction, modeling protein flexibility, etc.), hit identification/optimization (e.g. molecular docking, focused library design, fragment-based design, molecular dynamic, etc.), and polypharmacology design will be discussed. We will explore how structure-based techniques can facilitate the drug discovery process and interplay with other experimental approaches. PMID:22316152

Development of a multistage compliant mechanism with new boundary constraint

NASA Astrophysics Data System (ADS)

Ling, Mingxiang; Cao, Junyi; Jiang, Zhou; Li, Qisheng

2018-01-01

This paper presents a piezo-actuated compliant mechanism with a new boundary constraint to provide concurrent large workspace and high dynamic frequency for precision positioning or other flexible manipulation applications. A two-stage rhombus-type displacement amplifier with the "sliding-sliding" boundary constraint is presented to maximize the dynamic frequency while retaining a large output displacement. The vibration mode is also improved by the designed boundary constraint. A theoretical kinematic model of the compliant mechanism is established to optimize the geometric parameters, and a prototype is fabricated with a compact dimension of 60 mm × 60 mm × 12 mm. The experimental testing shows that the maximum stroke is approximately 0.6 mm and the output stiffness is 1.1 N/μm with the fundamental frequency of larger than 2.2 kHz. Lastly, the excellent performance of the presented compliant mechanism is compared with several mechanisms in the previous literature. As a conclusion, the presented boundary constraint strategy provides a new way to balance the trade-off between the frequency response and the stroke range widely existed in compliant mechanisms.

Colon-targeted oral drug delivery systems: design trends and approaches.

PubMed

Amidon, Seth; Brown, Jack E; Dave, Vivek S

2015-08-01

Colon-specific drug delivery systems (CDDS) are desirable for the treatment of a range of local diseases such as ulcerative colitis, Crohn's disease, irritable bowel syndrome, chronic pancreatitis, and colonic cancer. In addition, the colon can be a potential site for the systemic absorption of several drugs to treat non-colonic conditions. Drugs such as proteins and peptides that are known to degrade in the extreme gastric pH, if delivered to the colon intact, can be systemically absorbed by colonic mucosa. In order to achieve effective therapeutic outcomes, it is imperative that the designed delivery system specifically targets the drugs into the colon. Several formulation approaches have been explored in the development colon-targeted drug delivery systems. These approaches involve the use of formulation components that interact with one or more aspects of gastrointestinal (GI) physiology, such as the difference in the pH along the GI tract, the presence of colonic microflora, and enzymes, to achieve colon targeting. This article highlights the factors influencing colon-specific drug delivery and colonic bioavailability, and the limitations associated with CDDS. Further, the review provides a systematic discussion of various conventional, as well as relatively newer formulation approaches/technologies currently being utilized for the development of CDDS.

Constant-Envelope Waveform Design for Optimal Target-Detection and Autocorrelation Performances

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sen, Satyabrata

2013-01-01

We propose an algorithm to directly synthesize in time-domain a constant-envelope transmit waveform that achieves the optimal performance in detecting an extended target in the presence of signal-dependent interference. This approach is in contrast to the traditional indirect methods that synthesize the transmit signal following the computation of the optimal energy spectral density. Additionally, we aim to maintain a good autocorrelation property of the designed signal. Therefore, our waveform design technique solves a bi-objective optimization problem in order to simultaneously improve the detection and autocorrelation performances, which are in general conflicting in nature. We demonstrate this compromising characteristics of themore » detection and autocorrelation performances with numerical examples. Furthermore, in the absence of the autocorrelation criterion, our designed signal is shown to achieve a near-optimum detection performance.« less

The impact of target site accessibility on the design of effective siRNAs.

PubMed

Tafer, Hakim; Ameres, Stefan L; Obernosterer, Gregor; Gebeshuber, Christoph A; Schroeder, Renée; Martinez, Javier; Hofacker, Ivo L

2008-05-01

Small-interfering RNAs (siRNAs) assemble into RISC, the RNA-induced silencing complex, which cleaves complementary mRNAs. Despite their fluctuating efficacy, siRNAs are widely used to assess gene function. Although this limitation could be ascribed, in part, to variations in the assembly and activation of RISC, downstream events in the RNA interference (RNAi) pathway, such as target site accessibility, have so far not been investigated extensively. In this study we present a comprehensive analysis of target RNA structure effects on RNAi by computing the accessibility of the target site for interaction with the siRNA. Based on our observations, we developed a novel siRNA design tool, RNAxs, by combining known siRNA functionality criteria with target site accessibility. We calibrated our method on two data sets comprising 573 siRNAs for 38 genes, and tested it on an independent set of 360 siRNAs targeting four additional genes. Overall, RNAxs proves to be a robust siRNA selection tool that substantially improves the prediction of highly efficient siRNAs.

Constraint factor in optimization of truss structures via flower pollination algorithm

NASA Astrophysics Data System (ADS)

Bekdaş, Gebrail; Nigdeli, Sinan Melih; Sayin, Baris

2017-07-01

The aim of the paper is to investigate the optimum design of truss structures by considering different stress and displacement constraints. For that reason, the flower pollination algorithm based methodology was applied for sizing optimization of space truss structures. Flower pollination algorithm is a metaheuristic algorithm inspired by the pollination process of flowering plants. By the imitation of cross-pollination and self-pollination processes, the randomly generation of sizes of truss members are done in two ways and these two types of optimization are controlled with a switch probability. In the study, a 72 bar space truss structure was optimized by using five different cases of the constraint limits. According to the results, a linear relationship between the optimum structure weight and constraint limits was observed.

[sgRNA design for the CRISPR/Cas9 system and evaluation of its off-target effects].

PubMed

Xie, Sheng-song; Zhang, Yi; Zhang, Li-sheng; Li, Guang-lei; Zhao, Chang-zhi; Ni, Pan; Zhao, Shu-hong

2015-11-01

The third generation of CRISPR/Cas9-mediated genome editing technology has been successfully applied to genome modification of various species including animals, plants and microorganisms. How to improve the efficiency of CRISPR/Cas9 genome editing and reduce its off-target effects has been extensively explored in this field. Using sgRNA (Small guide RNA) with high efficiency and specificity is one of the critical factors for successful genome editing. Several software have been developed for sgRNA design and/or off-target evaluation, which have advantages and disadvantages respectively. In this review, we summarize characters of 16 kinds online and standalone software for sgRNA design and/or off-target evaluation and conduct a comparative analysis of these different kinds of software through developing 38 evaluation indexes. We also summarize 11 experimental approaches for testing genome editing efficiency and off-target effects as well as how to screen highly efficient and specific sgRNA.

Statistical inference on censored data for targeted clinical trials under enrichment design.

PubMed

Chen, Chen-Fang; Lin, Jr-Rung; Liu, Jen-Pei

2013-01-01

For the traditional clinical trials, inclusion and exclusion criteria are usually based on some clinical endpoints; the genetic or genomic variability of the trial participants are not totally utilized in the criteria. After completion of the human genome project, the disease targets at the molecular level can be identified and can be utilized for the treatment of diseases. However, the accuracy of diagnostic devices for identification of such molecular targets is usually not perfect. Some of the patients enrolled in targeted clinical trials with a positive result for the molecular target might not have the specific molecular targets. As a result, the treatment effect may be underestimated in the patient population truly with the molecular target. To resolve this issue, under the exponential distribution, we develop inferential procedures for the treatment effects of the targeted drug based on the censored endpoints in the patients truly with the molecular targets. Under an enrichment design, we propose using the expectation-maximization algorithm in conjunction with the bootstrap technique to incorporate the inaccuracy of the diagnostic device for detection of the molecular targets on the inference of the treatment effects. A simulation study was conducted to empirically investigate the performance of the proposed methods. Simulation results demonstrate that under the exponential distribution, the proposed estimator is nearly unbiased with adequate precision, and the confidence interval can provide adequate coverage probability. In addition, the proposed testing procedure can adequately control the size with sufficient power. On the other hand, when the proportional hazard assumption is violated, additional simulation studies show that the type I error rate is not controlled at the nominal level and is an increasing function of the positive predictive value. A numerical example illustrates the proposed procedures. Copyright © 2013 John Wiley & Sons, Ltd.

On the optimization of discrete structures with aeroelastic constraints

NASA Technical Reports Server (NTRS)

Mcintosh, S. C., Jr.; Ashley, H.

1978-01-01

The paper deals with the problem of dynamic structural optimization where constraints relating to flutter of a wing (or other dynamic aeroelastic performance) are imposed along with conditions of a more conventional nature such as those relating to stress under load, deflection, minimum dimensions of structural elements, etc. The discussion is limited to a flutter problem for a linear system with a finite number of degrees of freedom and a single constraint involving aeroelastic stability, and the structure motion is assumed to be a simple harmonic time function. Three search schemes are applied to the minimum-weight redesign of a particular wing: the first scheme relies on the method of feasible directions, while the other two are derived from necessary conditions for a local optimum so that they can be referred to as optimality-criteria schemes. The results suggest that a heuristic redesign algorithm involving an optimality criterion may be best suited for treating multiple constraints with large numbers of design variables.

Constraint Maintenance with Preferences and Underlying Flexible Solution

NASA Technical Reports Server (NTRS)

Bresina, John; Jonsson, Ari; Morris, Paul; Rajan, Kanna

2003-01-01

This paper describes an aspect of the constraint reasoning mechanism. that is part of a ground planning system slated to be used for the Mars Exploration Rovers mission, where two rovers are scheduled to land on Mars in January of 2003. The planning system combines manual planning software from JPL with an automatic planning/scheduling system from NASA Ames Research Center, and is designed to be used in a mixed-initiative mode. Among other things, this means that after a plan has been produced, the human operator can perform extensive modifications under the supervision of the automated. system. For each modification to an activity, the automated system must adjust other activities as needed to ensure that constraints continue to be satisfied. Thus, the system must accommodate change in an interactive setting. Performance is of critical importance for interactive use. This is achieved by maintaining an underlying flexible solution to the temporal constraints, while the system presents a fixed schedule to the user. Adjustments are then a matter of constraint propagation rather than completely re-solving the problem. However, this begs the important question of which fixed schedule (among the ones sanctioned by the underlying flexible solution) should be presented to the user.Our approach uses least-change and other preferences as a prism through which the user views the flexible solution.

Rational design of micro-RNA-like bifunctional siRNAs targeting HIV and the HIV coreceptor CCR5.

PubMed

Ehsani, Ali; Saetrom, Pål; Zhang, Jane; Alluin, Jessica; Li, Haitang; Snøve, Ola; Aagaard, Lars; Rossi, John J

2010-04-01

Small-interfering RNAs (siRNAs) and micro-RNAs (miRNAs) are distinguished by their modes of action. SiRNAs serve as guides for sequence-specific cleavage of complementary mRNAs and the targets can be in coding or noncoding regions of the target transcripts. MiRNAs inhibit translation via partially complementary base-pairing to 3' untranslated regions (UTRs) and are generally ineffective when targeting coding regions of a transcript. In this study, we deliberately designed siRNAs that simultaneously direct cleavage and translational suppression of HIV RNAs, or cleavage of the mRNA encoding the HIV coreceptor CCR5 and suppression of translation of HIV. These bifunctional siRNAs trigger inhibition of HIV infection and replication in cell culture. The design principles have wide applications throughout the genome, as about 90% of genes harbor sites that make the design of bifunctional siRNAs possible.

Design of a multisensor data fusion system for target detection

NASA Astrophysics Data System (ADS)

Thomopoulos, Stelios C.; Okello, Nickens N.; Kadar, Ivan; Lovas, Louis A.

1993-09-01

The objective of this paper is to discuss the issues that are involved in the design of a multisensor fusion system and provide a systematic analysis and synthesis methodology for the design of the fusion system. The system under consideration consists of multifrequency (similar) radar sensors. However, the fusion design must be flexible to accommodate additional dissimilar sensors such as IR, EO, ESM, and Ladar. The motivation for the system design is the proof of the fusion concept for enhancing the detectability of small targets in clutter. In the context of down-selecting the proper configuration for multisensor (similar and dissimilar, and centralized vs. distributed) data fusion, the issues of data modeling, fusion approaches, and fusion architectures need to be addressed for the particular application being considered. Although the study of different approaches may proceed in parallel, the interplay among them is crucial in selecting a fusion configuration for a given application. The natural sequence for addressing the three different issues is to begin from the data modeling, in order to determine the information content of the data. This information will dictate the appropriate fusion approach. This, in turn, will lead to a global fusion architecture. Both distributed and centralized fusion architectures are used to illustrate the design issues along with Monte-Carlo simulation performance comparison of a single sensor versus a multisensor centrally fused system.

Constraint-Based Routing Models for the Transport of Radioactive Materials

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peterson, Steven K

2015-01-01

The Department of Energy (DOE) has a historic programmatic interest in the safe and secure routing, tracking, and transportation risk analysis of radiological materials in the United States. In order to address these program goals, DOE has funded the development of several tools and related systems designed to provide insight to planners and other professionals handling radioactive materials shipments. These systems include the WebTRAGIS (Transportation Routing Analysis Geographic Information System) platform. WebTRAGIS is a browser-based routing application developed at Oak Ridge National Laboratory (ORNL) focused primarily on the safe transport of spent nuclear fuel from US nuclear reactors via railway,more » highway, or waterway. It is also used for the transport planning of low-level radiological waste to depositories such as the Waste Isolation Pilot Plant (WIPP) facility. One particular feature of WebTRAGIS is its coupling with high-resolution population data from ORNL s LandScan project. This allows users to obtain highly accurate population count and density information for use in route planning and risk analysis. To perform the routing and risk analysis WebTRAGIS incorporates a basic routing model methodology, with the additional application of various constraints designed to mimic US Department of Transportation (DOT), DOE, and Nuclear Regulatory Commission (NRC) regulations. Aside from the routing models available in WebTRAGIS, the system relies on detailed or specialized modal networks for the route solutions. These include a highly detailed network model of the US railroad system, the inland and coastal waterways, and a specialized highway network that focuses on the US interstate system and the designated hazardous materials and Highway Route Controlled Quantity (HRCQ) -designated roadways. The route constraints in WebTRAGIS rely upon a series of attributes assigned to the various components of the different modal networks. Routes are determined via

[3-D finite element modeling of internal fixation of mandibular mental fracture and the design of boundary constraints].

PubMed

Luo, Xiaohui; Wang, Hang; Fan, Yubo

2007-04-01

This study was aimed to develop a 3-D finite element (3-D FE) model of the mental fractured mandible and design the boundary constrains. The CT images from a health volunteer were used as the original information and put into ANSYS program to build a 3-D FE model. The model of the miniplate and screw which were used for the internal fixation was established by Pro/E. The boundary constrains of different muscle loadings were used to simulate the 3 functional conditions of the mandible. A 3-D FE model of mental fractured mandible under the miniplate-screw internal fixation system was constructed. And by the boundary constraints, the 3 biting conditions were simulated and the model could serve as a foundation on which to analyze the biomechanical behavior of the fractured mandible.

Thin and thick targets for radioactive ion beam production at SPIRAL1 facility

NASA Astrophysics Data System (ADS)

Jardin, P.; Bajeat, O.; Delahaye, P.; Dubois, M.; Kuchi, V.; Maunoury, L.

2018-05-01

The upgrade of the Système de Production d'Ions Radioactifs Accélérés en Ligne (SPIRAL1) facility will deliver its new Radioactive Ion Beams (RIB) by summer 2017. The goal of the upgrade is an improvement of the performances of the installation in terms of isotopes species and ion charge states [1]. Ion beams are produced using the Isotope Separator On Line Method, consisting in an association of a primary beam of stable ions, a hot target and an ion source. The primary beam impinges on the material of the target. Radioactive isotopes are produced by nuclear reactions and propagate up to the source, where they are ionized and accelerated to create a RIB. One advantage of SPIRAL1 driver is the variety of its available primary beams, from carbon to uranium with energies up to 95 MeV/A. Within the SPIRAL1 upgrade, they will be combined with targets made of a large choice of materials, extending in this way the number of possible nuclear reactions (fusion-evaporation, transfer, fragmentation) for producing a wider range of isotopes, up to regions of the nuclide chart still scarcely explored. Depending on the reaction process, on the collision energy and on the primary beam power, thin and thick targets are used. As their functions can be different, their design must cope with specific constraints which will be described. After a presentation of the goals of present and future SPIRAL1 Target Ion Source System, the main target features, studies and designs under progress are presented.

Design study of a raster scanning system for moving target irradiation in heavy-ion radiotherapy.

PubMed

Furukawa, Takuji; Inaniwa, Taku; Sato, Shinji; Tomitani, Takehiro; Minohara, Shinichi; Noda, Koji; Kanai, Tatsuaki

2007-03-01

A project to construct a new treatment facility as an extension of the existing heavy-ion medical accelerator in chiba (HIMAC) facility has been initiated for further development of carbon-ion therapy. The greatest challenge of this project is to realize treatment of a moving target by scanning irradiation. For this purpose, we decided to combine the rescanning technique and the gated irradiation method. To determine how to avoid hot and/or cold spots by the relatively large number of rescannings within an acceptable irradiation time, we have studied the scanning strategy, scanning magnets and their control, and beam intensity dynamic control. We have designed a raster scanning system and carried out a simulation of irradiating moving targets. The result shows the possibility of practical realization of moving target irradiation with pencil beam scanning. We describe the present status of our design study of the raster scanning system for the HIMAC new treatment facility.

Multi-load Groups Coordinated Load Control Strategy Considering Power Network Constraints

NASA Astrophysics Data System (ADS)

Liu, Meng; Zhao, Binchao; Wang, Jun; Zhang, Guohui; Wang, Xin

2017-05-01

Loads with energy storage property can actively participate in power balance for power systems, this paper takes air conditioner as a controllable load example, proposing a multi-load groups coordinated load control strategy considering power network constraints. Firstly, two load control modes considering recovery of load diversity are designed, blocking power oscillation of aggregated air conditioners. As the same time, air conditioner temperature setpoint recovery control strategy is presented to avoid power recovery peak. Considering inherent characteristics of two load control modes, an coordinated load control mode is designed by combining the both. Basing on this, a multi-load groups coordinated load control strategy is proposed. During the implementing of load control, power network constraints should be satisfied. An indice which can reflect the security of power system operating is defined. By minimizing its value through optimization, the change of air conditioning loads’ aggregated power on each load bus can be calculated. Simulations are conducted on an air conditioners group and New England 10-generator 39-bus system, verifying the effectiveness of the proposed multi-load groups coordinated load control strategy considering power network constraints.

Common aero vehicle autonomous reentry trajectory optimization satisfying waypoint and no-fly zone constraints

NASA Astrophysics Data System (ADS)

Jorris, Timothy R.

2007-12-01

To support the Air Force's Global Reach concept, a Common Aero Vehicle is being designed to support the Global Strike mission. "Waypoints" are specified for reconnaissance or multiple payload deployments and "no-fly zones" are specified for geopolitical restrictions or threat avoidance. Due to time critical targets and multiple scenario analysis, an autonomous solution is preferred over a time-intensive, manually iterative one. Thus, a real-time or near real-time autonomous trajectory optimization technique is presented to minimize the flight time, satisfy terminal and intermediate constraints, and remain within the specified vehicle heating and control limitations. This research uses the Hypersonic Cruise Vehicle (HCV) as a simplified two-dimensional platform to compare multiple solution techniques. The solution techniques include a unique geometric approach developed herein, a derived analytical dynamic optimization technique, and a rapidly emerging collocation numerical approach. This up-and-coming numerical technique is a direct solution method involving discretization then dualization, with pseudospectral methods and nonlinear programming used to converge to the optimal solution. This numerical approach is applied to the Common Aero Vehicle (CAV) as the test platform for the full three-dimensional reentry trajectory optimization problem. The culmination of this research is the verification of the optimality of this proposed numerical technique, as shown for both the two-dimensional and three-dimensional models. Additionally, user implementation strategies are presented to improve accuracy and enhance solution convergence. Thus, the contributions of this research are the geometric approach, the user implementation strategies, and the determination and verification of a numerical solution technique for the optimal reentry trajectory problem that minimizes time to target while satisfying vehicle dynamics and control limitation, and heating, waypoint, and no

RNAiFold: a web server for RNA inverse folding and molecular design.

PubMed

Garcia-Martin, Juan Antonio; Clote, Peter; Dotu, Ivan

2013-07-01

Synthetic biology and nanotechnology are poised to make revolutionary contributions to the 21st century. In this article, we describe a new web server to support in silico RNA molecular design. Given an input target RNA secondary structure, together with optional constraints, such as requiring GC-content to lie within a certain range, requiring the number of strong (GC), weak (AU) and wobble (GU) base pairs to lie in a certain range, the RNAiFold web server determines one or more RNA sequences, whose minimum free-energy secondary structure is the target structure. RNAiFold provides access to two servers: RNA-CPdesign, which applies constraint programming, and RNA-LNSdesign, which applies the large neighborhood search heuristic; hence, it is suitable for larger input structures. Both servers can also solve the RNA inverse hybridization problem, i.e. given a representation of the desired hybridization structure, RNAiFold returns two sequences, whose minimum free-energy hybridization is the input target structure. The web server is publicly accessible at http://bioinformatics.bc.edu/clotelab/RNAiFold, which provides access to two specialized servers: RNA-CPdesign and RNA-LNSdesign. Source code for the underlying algorithms, implemented in COMET and supported on linux, can be downloaded at the server website.

Thermodynamic Constraints Improve Metabolic Networks.

PubMed

Krumholz, Elias W; Libourel, Igor G L

2017-08-08

In pursuit of establishing a realistic metabolic phenotypic space, the reversibility of reactions is thermodynamically constrained in modern metabolic networks. The reversibility constraints follow from heuristic thermodynamic poise approximations that take anticipated cellular metabolite concentration ranges into account. Because constraints reduce the feasible space, draft metabolic network reconstructions may need more extensive reconciliation, and a larger number of genes may become essential. Notwithstanding ubiquitous application, the effect of reversibility constraints on the predictive capabilities of metabolic networks has not been investigated in detail. Instead, work has focused on the implementation and validation of the thermodynamic poise calculation itself. With the advance of fast linear programming-based network reconciliation, the effects of reversibility constraints on network reconciliation and gene essentiality predictions have become feasible and are the subject of this study. Networks with thermodynamically informed reversibility constraints outperformed gene essentiality predictions compared to networks that were constrained with randomly shuffled constraints. Unconstrained networks predicted gene essentiality as accurately as thermodynamically constrained networks, but predicted substantially fewer essential genes. Networks that were reconciled with sequence similarity data and strongly enforced reversibility constraints outperformed all other networks. We conclude that metabolic network analysis confirmed the validity of the thermodynamic constraints, and that thermodynamic poise information is actionable during network reconciliation. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Package design and nutritional profile of foods targeted at children in supermarkets in Montevideo, Uruguay.

PubMed

Giménez, Ana; Saldamando, Luis de; Curutchet, María Rosa; Ares, Gastón

2017-06-12

Marketing of unhealthy products has been identified as one of the main characteristics of the food environment that negatively affects children's eating patterns. Restrictions on advertising of unhealthy foods to children have already been imposed in different countries. However, marketing strategies are not limited to broadcast and digital advertising, but also include package design. In this context, the current study aimed to describe the food products targeted at children and sold in supermarkets in Montevideo, Uruguay, in terms of package design and nutrient profile. Two supermarkets in Montevideo were selected for data collection. In each supermarket, all products targeted at children were identified. Products were analyzed in terms of package design and nutritional profile, considering the Pan American Health Organization Nutrient Profile Model. A total of 180 unique products were identified, which included a wide range of product categories. The great majority of the products corresponded to ultra-processed products with excessive amounts of sodium, free sugars, total fat, saturated fat, and/or trans fat, which are not recommended for frequent consumption. Several marketing strategies were identified in the design of packages to attract children's attention and drive their preferences. The most common strategies were the inclusion of cartoon characters, bright colors, childish lettering, and a wide range of claims related to health and nutrition, as well as the products' sensory and hedonic characteristics. The study's findings provide additional evidence on the need to regulate packaging of products targeted at children.

Finite-time stabilisation of a class of switched nonlinear systems with state constraints

NASA Astrophysics Data System (ADS)

Huang, Shipei; Xiang, Zhengrong

2018-06-01

This paper investigates the finite-time stabilisation for a class of switched nonlinear systems with state constraints. Some power orders of the system are allowed to be ratios of positive even integers over odd integers. A Barrier Lyapunov function is introduced to guarantee that the state constraint is not violated at any time. Using the convex combination method and a recursive design approach, a state-dependent switching law and state feedback controllers of individual subsystems are constructed such that the closed-loop system is finite-time stable without violation of the state constraint. Two examples are provided to show the effectiveness of the proposed method.

Study of design constraints on helicopter noise

NASA Technical Reports Server (NTRS)

Sternfeld, H., Jr.; Wiedersum, C. W.

1979-01-01

A means of estimating the noise generated by a helicopter main rotor using information which is generally available during the preliminary design phase of aircraft development is presented. The method utilizes design charts and tables which do not require an understanding of acoustical theory or computational procedures in order to predict the perceived noise level, a weighted sound pressure level, or C weighted sound pressure level of a single hovering rotor. A method for estimating the effective perceived noise level in forward flight is also included. In order to give the designer an assessment of the relative rotor performance, which may be traded off against noise, an additional chart for estimating the percent of available rotor thrust which must be expended in lifting the rotor and drive system, is included as well as approach for comparing the subjective acceptability of various rotors once the absolute sound pressure levels are predicted.

Fuel assembly design for APR1400 with low CBC

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hah, Chang Joo, E-mail: changhah@kings.ac.kr

2015-04-29

APR 1400 is a PWR (Pressurized Water Reactor) with rated power of 3983 MWth and 241 assemblies. Recently, demand for extremely longer cycle up to 24 months is increasing with challenge of higher critical boron concentration (CBC). In this paper, assembly design method of selecting Gd-rods is introduced to reduce CBC. The purpose of the method is to lower the critical boron concentration of the preliminary core loading pattern (PLP), and consequently to achieve more negative or less positive moderator temperature coefficient (MTC). In this method, both the ratio of the number of low-Gd rod to the number of high-Gdmore » rod (r) and assembly average Gd wt% (w) are the decision variables. The target function is the amount of soluble boron concentration reduction, which can be converted to Δk{sub TARGET}. A set of new designed fuel assembly satisfies an objective function, min [f=∑{sub i}(Δk{sub FA}−Δk{sub i})], and enables a final loading pattern to reach a target CBC. The constraints required to determine a set of Δk are physically realizable pair, (r,w), and the sum of Δk of new designed assemblies as close to Δk{sub TARGET} as possible. New Gd-bearing assemblies selected based on valid pairs of (r,w) are replaced with existing assemblies in a PLP. This design methodology is applied to Shin-Kori Unit 3 Cycle 1 used as a reference model. CASMO-3/MASTER code is used for depletion calculation. CASMO-3/MASTER calculations with new designed assemblies produce lower CBC than the expected CBC, proving that the proposed method works successful.« less

Constraint-based strain design using continuous modifications (CosMos) of flux bounds finds new strategies for metabolic engineering.

PubMed

Cotten, Cameron; Reed, Jennifer L

2013-05-01

In recent years, a growing number of metabolic engineering strain design techniques have employed constraint-based modeling to determine metabolic and regulatory network changes which are needed to improve chemical production. These methods use systems-level analysis of metabolism to help guide experimental efforts by identifying deletions, additions, downregulations, and upregulations of metabolic genes that will increase biological production of a desired metabolic product. In this work, we propose a new strain design method with continuous modifications (CosMos) that provides strategies for deletions, downregulations, and upregulations of fluxes that will lead to the production of the desired products. The method is conceptually simple and easy to implement, and can provide additional strategies over current approaches. We found that the method was able to find strain design strategies that required fewer modifications and had larger predicted yields than strategies from previous methods in example and genome-scale networks. Using CosMos, we identified modification strategies for producing a variety of metabolic products, compared strategies derived from Escherichia coli and Saccharomyces cerevisiae metabolic models, and examined how imperfect implementation may affect experimental outcomes. This study gives a powerful and flexible technique for strain engineering and examines some of the unexpected outcomes that may arise when strategies are implemented experimentally. Copyright © 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.

Relationship between participation in leisure activities and constraints on Taiwanese breastfeeding mothers during leisure activities

PubMed Central

2013-01-01

Background Participation in leisure activities strongly associates with health and well-being. Little research has explored the relationship between participation in leisure activities and constraints on breastfeeding mothers during leisure activities. The purposes of this study are: 1) to investigate constraints on breastfeeding mothers during leisure activities and participation in leisure activities; 2) to investigate the differences between preferences for leisure activities and actual participation by breastfeeding mothers; 3) to segment breastfeeding mothers with similar patterns, using a cluster analysis based on the delineated participation in leisure activities and leisure preferences; 4) to explore any differences between clusters of breastfeeding mothers with respect to socio-demographic characteristics, breastfeeding behaviours and leisure constraints. Methods This study has a cross-sectional design using an online survey conducted among mothers having breastfeeding experiences of more than four months. The questionnaire includes demographic variables, breastfeeding behaviours, preferences for leisure activities participation, and constraints on leisure activities. Collection of data occurred between March and July 2011, producing 415 valid responses for analysis. Results For breastfeeding mothers, this study identifies constraints on breastfeeding related to leisure activities in addition to the three traditional factors for constraints in the model. This study demonstrates that reports of constraints related to children, family, and nursing environments are the most frequent. Breastfeeding mothers in Taiwan participate regularly in family activities or activities related to their children. Cluster analysis classified breastfeeding mothers into Action and Contemplation groups, and found that mothers within the latter group participate less in leisure activities and experienced more constraints related to breastfeeding. Conclusions Implications provide

Optimization of flexible wing structures subject to strength and induced drag constraints

NASA Technical Reports Server (NTRS)

Haftka, R. T.

1977-01-01

An optimization procedure for designing wing structures subject to stress, strain, and drag constraints is presented. The optimization method utilizes an extended penalty function formulation for converting the constrained problem into a series of unconstrained ones. Newton's method is used to solve the unconstrained problems. An iterative analysis procedure is used to obtain the displacements of the wing structure including the effects of load redistribution due to the flexibility of the structure. The induced drag is calculated from the lift distribution. Approximate expressions for the constraints used during major portions of the optimization process enhance the efficiency of the procedure. A typical fighter wing is used to demonstrate the procedure. Aluminum and composite material designs are obtained. The tradeoff between weight savings and drag reduction is investigated.

INFO-RNA--a server for fast inverse RNA folding satisfying sequence constraints.

PubMed

Busch, Anke; Backofen, Rolf

2007-07-01

INFO-RNA is a new web server for designing RNA sequences that fold into a user given secondary structure. Furthermore, constraints on the sequence can be specified, e.g. one can restrict sequence positions to a fixed nucleotide or to a set of nucleotides. Moreover, the user can allow violations of the constraints at some positions, which can be advantageous in complicated cases. The INFO-RNA web server allows biologists to design RNA sequences in an automatic manner. It is clearly and intuitively arranged and easy to use. The procedure is fast, as most applications are completed within seconds and it proceeds better and faster than other existing tools. The INFO-RNA web server is freely available at http://www.bioinf.uni-freiburg.de/Software/INFO-RNA/

Deformable image registration with local rigidity constraints for cone-beam CT-guided spine surgery

NASA Astrophysics Data System (ADS)

Reaungamornrat, S.; Wang, A. S.; Uneri, A.; Otake, Y.; Khanna, A. J.; Siewerdsen, J. H.

2014-07-01

Image-guided spine surgery (IGSS) is associated with reduced co-morbidity and improved surgical outcome. However, precise localization of target anatomy and adjacent nerves and vessels relative to planning information (e.g., device trajectories) can be challenged by anatomical deformation. Rigid registration alone fails to account for deformation associated with changes in spine curvature, and conventional deformable registration fails to account for rigidity of the vertebrae, causing unrealistic distortions in the registered image that can confound high-precision surgery. We developed and evaluated a deformable registration method capable of preserving rigidity of bones while resolving the deformation of surrounding soft tissue. The method aligns preoperative CT to intraoperative cone-beam CT (CBCT) using free-form deformation (FFD) with constraints on rigid body motion imposed according to a simple intensity threshold of bone intensities. The constraints enforced three properties of a rigid transformation—namely, constraints on affinity (AC), orthogonality (OC), and properness (PC). The method also incorporated an injectivity constraint (IC) to preserve topology. Physical experiments involving phantoms, an ovine spine, and a human cadaver as well as digital simulations were performed to evaluate the sensitivity to registration parameters, preservation of rigid body morphology, and overall registration accuracy of constrained FFD in comparison to conventional unconstrained FFD (uFFD) and Demons registration. FFD with orthogonality and injectivity constraints (denoted FFD+OC+IC) demonstrated improved performance compared to uFFD and Demons. Affinity and properness constraints offered little or no additional improvement. The FFD+OC+IC method preserved rigid body morphology at near-ideal values of zero dilatation ({ D} = 0.05, compared to 0.39 and 0.56 for uFFD and Demons, respectively) and shear ({ S} = 0.08, compared to 0.36 and 0.44 for uFFD and Demons

Design and optimal control of on-orbit servicing trajectory for target vehicle in non-coplanar elliptical orbit

NASA Astrophysics Data System (ADS)

Zhou, Wenyong; Yuan, Jianping; Luo, Jianjun

2005-11-01

Autonomous on-orbit servicing provides flexibility to space systems and has great value both in civil and in military. When a satellite performs on-orbit servicing tasks, flying around is the basic type of motion. This paper is concerned with the design and control problems of a chaser satellite flying around a target spacecraft in non-coplanar elliptical orbit for a long time. At first, a mathematical model used to design a long-term flying around trajectory is presented, which is applicable to the situation that the target spacecraft flies in an elliptical orbit. The conditions of the target at the centre of the flying around path are deduced. Considering the safety and task requirements, a long-term flying around trajectory is designed. Taking into account perturbations and navigation errors which can cause the trajectory unstable and mission impossible, a two-impulse control method is put forward. Genetic algorithm is used to minimize the cost function which considers fuel consumption and bias simultaneously. Some simulation works are carried out and the results indicate the flying around mathematical model and the trajectory control method can be used in the design and control of a long-term flying around trajectory.

Some design constraints required for the assembly of software components: The incorporation of atomic abstract types into generically structured abstract types

NASA Technical Reports Server (NTRS)

Johnson, Charles S.

1986-01-01

It is nearly axiomatic, that to take the greatest advantage of the useful features available in a development system, and to avoid the negative interactions of those features, requires the exercise of a design methodology which constrains their use. A major design support feature of the Ada language is abstraction: for data, functions processes, resources, and system elements in general. Atomic abstract types can be created in packages defining those private types and all of the overloaded operators, functions, and hidden data required for their use in an application. Generically structured abstract types can be created in generic packages defining those structured private types, as buildups from the user-defined data types which are input as parameters. A study is made of the design constraints required for software incorporating either atomic or generically structured abstract types, if the integration of software components based on them is to be subsequently performed. The impact of these techniques on the reusability of software and the creation of project-specific software support environments is also discussed.

Design and engineering of a target for x-ray Thomson scattering measurements on matter at extreme densities and gigabar pressures

DOE PAGES

Boehm, K. -J.; Hash, N.; Barker, D.; ...

2016-06-24

Reconciling the experimental and system requirements during the development of a new target system is one of the most challenging tasks in the design and engineering of targets used in the National Ignition Facility. Targets for the GigaBar 3 campaign were meant to allow the detection of extremely weak Thomson scattering from matter at extreme densities in the face of very bright backlighter and laser entry hole plasma emissions. The problem was to shield the detector sufficiently while maintaining beamline and view clearances, and observing target mass restrictions. A new construction process, based on a rapid prototype frame structure, wasmore » used to develop this target. As a result, details of the design process for these targets are described, and lessons from this development for production and target assembly teams are discussed.« less

Lunar Orbit Insertion Targeting and Associated Outbound Mission Design for Lunar Sortie Missions

NASA Technical Reports Server (NTRS)

Condon, Gerald L.

2007-01-01

This report details the Lunar Orbit Insertion (LOI) arrival targeting and associated mission design philosophy for Lunar sortie missions with up to a 7-day surface stay and with global Lunar landing site access. It also documents the assumptions, methodology, and requirements validated by TDS-04-013, Integrated Transit Nominal and Abort Characterization and Sensitivity Study. This report examines the generation of the Lunar arrival parking orbit inclination and Longitude of the Ascending Node (LAN) targets supporting surface missions with global Lunar landing site access. These targets support the Constellation Program requirement for anytime abort (early return) by providing for a minimized worst-case wedge angle [and an associated minimum plane change delta-velocity (V) cost] between the Crew Exploration Vehicle (CEV) and the Lunar Surface Access Module (LSAM) for an LSAM launch anytime during the Lunar surface stay.

Design of a bioactive small molecule that targets r(AUUCU) repeats in spinocerebellar ataxia 10.

PubMed

Yang, Wang-Yong; Gao, Rui; Southern, Mark; Sarkar, Partha S; Disney, Matthew D

2016-06-01

RNA is an important target for chemical probes of function and lead therapeutics; however, it is difficult to target with small molecules. One approach to tackle this problem is to identify compounds that target RNA structures and utilize them to multivalently target RNA. Here we show that small molecules can be identified to selectively bind RNA base pairs by probing a library of RNA-focused small molecules. A small molecule that selectively binds AU base pairs informed design of a dimeric compound (2AU-2) that targets the pathogenic RNA, expanded r(AUUCU) repeats, that causes spinocerebellar ataxia type 10 (SCA10) in patient-derived cells. Indeed, 2AU-2 (50 nM) ameliorates various aspects of SCA10 pathology including improvement of mitochondrial dysfunction, reduced activation of caspase 3, and reduction of nuclear foci. These studies provide a first-in-class chemical probe to study SCA10 RNA toxicity and potentially define broadly applicable compounds targeting RNA AU base pairs in cells.

Possibility-based robust design optimization for the structural-acoustic system with fuzzy parameters

NASA Astrophysics Data System (ADS)

Yin, Hui; Yu, Dejie; Yin, Shengwen; Xia, Baizhan

2018-03-01

The conventional engineering optimization problems considering uncertainties are based on the probabilistic model. However, the probabilistic model may be unavailable because of the lack of sufficient objective information to construct the precise probability distribution of uncertainties. This paper proposes a possibility-based robust design optimization (PBRDO) framework for the uncertain structural-acoustic system based on the fuzzy set model, which can be constructed by expert opinions. The objective of robust design is to optimize the expectation and variability of system performance with respect to uncertainties simultaneously. In the proposed PBRDO, the entropy of the fuzzy system response is used as the variability index; the weighted sum of the entropy and expectation of the fuzzy response is used as the objective function, and the constraints are established in the possibility context. The computations for the constraints and objective function of PBRDO are a triple-loop and a double-loop nested problem, respectively, whose computational costs are considerable. To improve the computational efficiency, the target performance approach is introduced to transform the calculation of the constraints into a double-loop nested problem. To further improve the computational efficiency, a Chebyshev fuzzy method (CFM) based on the Chebyshev polynomials is proposed to estimate the objective function, and the Chebyshev interval method (CIM) is introduced to estimate the constraints, thereby the optimization problem is transformed into a single-loop one. Numerical results on a shell structural-acoustic system verify the effectiveness and feasibility of the proposed methods.

Multiplex Degenerate Primer Design for Targeted Whole Genome Amplification of Many Viral Genomes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gardner, Shea N.; Jaing, Crystal J.; Elsheikh, Maher M.

Background . Targeted enrichment improves coverage of highly mutable viruses at low concentration in complex samples. Degenerate primers that anneal to conserved regions can facilitate amplification of divergent, low concentration variants, even when the strain present is unknown. Results . A tool for designing multiplex sets of degenerate sequencing primers to tile overlapping amplicons across multiple whole genomes is described. The new script, run_tiled_primers, is part of the PriMux software. Primers were designed for each segment of South American hemorrhagic fever viruses, tick-borne encephalitis, Henipaviruses, Arenaviruses, Filoviruses, Crimean-Congo hemorrhagic fever virus, Rift Valley fever virus, and Japanese encephalitis virus. Eachmore » group is highly diverse with as little as 5% genome consensus. Primer sets were computationally checked for nontarget cross reactions against the NCBI nucleotide sequence database. Primers for murine hepatitis virus were demonstrated in the lab to specifically amplify selected genes from a laboratory cultured strain that had undergone extensive passage in vitro and in vivo. Conclusions . This software should help researchers design multiplex sets of primers for targeted whole genome enrichment prior to sequencing to obtain better coverage of low titer, divergent viruses. Applications include viral discovery from a complex background and improved sensitivity and coverage of rapidly evolving strains or variants in a gene family.« less

Multiplex Degenerate Primer Design for Targeted Whole Genome Amplification of Many Viral Genomes